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  1. Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements.

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    Carl O Olson

    Full Text Available MeCP2 is a critical epigenetic regulator in brain and its abnormal expression or compromised function leads to a spectrum of neurological disorders including Rett Syndrome and autism. Altered expression of the two MeCP2 isoforms, MeCP2E1 and MeCP2E2 has been implicated in neurological complications. However, expression, regulation and functions of the two isoforms are largely uncharacterized. Previously, we showed the role of MeCP2E1 in neuronal maturation and reported MeCP2E1 as the major protein isoform in the adult mouse brain, embryonic neurons and astrocytes. Recently, we showed that DNA methylation at the regulatory elements (REs within the Mecp2 promoter and intron 1 impact the expression of Mecp2 isoforms in differentiating neural stem cells. This current study is aimed for a comparative analysis of temporal, regional and cell type-specific expression of MeCP2 isoforms in the developing and adult mouse brain. MeCP2E2 displayed a later expression onset than MeCP2E1 during mouse brain development. In the adult female and male brain hippocampus, both MeCP2 isoforms were detected in neurons, astrocytes and oligodendrocytes. Furthermore, MeCP2E1 expression was relatively uniform in different brain regions (olfactory bulb, striatum, cortex, hippocampus, thalamus, brainstem and cerebellum, whereas MeCP2E2 showed differential enrichment in these brain regions. Both MeCP2 isoforms showed relatively similar distribution in these brain regions, except for cerebellum. Lastly, a preferential correlation was observed between DNA methylation at specific CpG dinucleotides within the REs and Mecp2 isoform-specific expression in these brain regions. Taken together, we show that MeCP2 isoforms display differential expression patterns during brain development and in adult mouse brain regions. DNA methylation patterns at the Mecp2 REs may impact this differential expression of Mecp2/MeCP2 isoforms in brain regions. Our results significantly contribute

  2. MECP2 Duplication Syndrome

    DEFF Research Database (Denmark)

    Signorini, Cinzia; De Felice, Claudio; Leoncini, Silvia

    2016-01-01

    Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients...... and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy...... similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P work shows unique data in patients affected by MDS. For the first...

  3. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation.

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    Nagarajan, Raman P; Hogart, Amber R; Gwye, Ynnez; Martin, Michelle R; LaSalle, Janine M

    2006-01-01

    Mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2), cause most cases of Rett syndrome (RTT), an X-linked neurodevelopmental disorder. Both RTT and autism are "pervasive developmental disorders" and share a loss of social, cognitive and language skills and a gain in repetitive stereotyped behavior, following apparently normal perinatal development. Although MECP2 coding mutations are a rare cause of autism, MeCP2 expression defects were previously found in autism brain. To further study the role of MeCP2 in autism spectrum disorders (ASDs), we determined the frequency of MeCP2 expression defects in brain samples from autism and other ASDs. We also tested the hypotheses that MECP2 promoter mutations or aberrant promoter methylation correlate with reduced expression in cases of idiopathic autism. MeCP2 immunofluorescence in autism and other neurodevelopmental disorders was quantified by laser scanning cytometry and compared with control postmortem cerebral cortex samples on a large tissue microarray. A significant reduction in MeCP2 expression compared to age-matched controls was found in 11/14 autism (79%), 9/9 RTT (100%), 4/4 Angelman syndrome (100%), 3/4 Prader-Willi syndrome (75%), 3/5 Down syndrome (60%), and 2/2 attention deficit hyperactivity disorder (100%) frontal cortex samples. One autism female was heterozygous for a rare MECP2 promoter variant that correlated with reduced MeCP2 expression. A more frequent occurrence was significantly increased MECP2 promoter methylation in autism male frontal cortex compared to controls. Furthermore, percent promoter methylation of MECP2 significantly correlated with reduced MeCP2 protein expression. These results suggest that both genetic and epigenetic defects lead to reduced MeCP2 expression and may be important in the complex etiology of autism.

  4. Circadian cycle-dependent MeCP2 and brain chromatin changes.

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    Alexia Martínez de Paz

    Full Text Available Methyl CpG binding protein 2 (MeCP2 is a chromosomal protein of the brain, very abundant especially in neurons, where it plays an important role in the regulation of gene expression. Hence it has the potential to be affected by the mammalian circadian cycle. We performed expression analyses of mice brain frontal cortices obtained at different time points and we found that the levels of MeCP2 are altered circadianly, affecting overall organization of brain chromatin and resulting in a circadian-dependent regulation of well-stablished MeCP2 target genes. Furthermore, this data suggests that alterations of MeCP2 can be responsible for the sleeping disorders arising from pathological stages, such as in autism and Rett syndrome.

  5. Novel MeCP2 isoform-specific antibody reveals the endogenous MeCP2E1 expression in murine brain, primary neurons and astrocytes.

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    Robby M Zachariah

    Full Text Available Rett Syndrome (RTT is a severe neurological disorder in young females, and is caused by mutations in the X-linked MECP2 gene. MECP2/Mecp2 gene encodes for two protein isoforms; MeCP2E1 and MeCP2E2 that are identical except for the N-terminus region of the protein. In brain, MECP2E1 transcripts are 10X higher, and MeCP2E1 is suggested to be the relevant isoform for RTT. However, due to the unavailability of MeCP2 isoform-specific antibodies, the endogenous expression pattern of MeCP2E1 is unknown. To gain insight into the expression of MeCP2E1 in brain, we have developed an anti-MeCP2E1 antibody and validated its specificity in cells exogenously expressing individual MeCP2 isoforms. This antibody does not show any cross-reactivity with MeCP2E2 and detects endogenous MeCP2E1 in mice brain, with no signal in Mecp2(tm1.1Bird y/- null mice. Additionally, we show the endogenous MeCP2E1 expression throughout different brain regions in adult mice, and demonstrate its highest expression in the brain cortex. Our results also indicate that MeCP2E1 is highly expressed in primary neurons, as compared to primary astrocytes. This is the first report of the endogenous MeCP2E1 expression at the protein levels, providing novel avenues for understanding different aspects of MeCP2 function.

  6. Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery

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    Sarah E. Sinnett

    2017-06-01

    Full Text Available Intravenous administration of adeno-associated virus serotype 9 (AAV9/hMECP2 has been shown to extend the lifespan of Mecp2−/y mice, but this delivery route induces liver toxicity in wild-type (WT mice. To reduce peripheral transgene expression, we explored the safety and efficacy of AAV9/hMECP2 injected into the cisterna magna (ICM. AAV9/hMECP2 (1 × 1012 viral genomes [vg]; ICM extended Mecp2−/y survival but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 × 1012 vg of AAV9/hMECP2 induced clasping and abnormal gait. A lower dose mitigated these adverse phenotypes but failed to extend survival of Mecp2−/y mice. Thus, ICM delivery of this vector is impractical as a treatment for Rett syndrome (RTT. To improve the safety of MeCP2 gene therapy, the gene expression cassette was modified to include more endogenous regulatory elements believed to modulate MeCP2 expression in vivo. In Mecp2−/y mice, ICM injection of the modified vector extended lifespan and was well tolerated by the liver but did not rescue RTT behavioral phenotypes. In WT mice, these same doses of the modified vector had no adverse effects on survival or neurological phenotypes. In summary, we identified limitations of the original vector and demonstrated that an improved vector design extends Mecp2−/y survival, without apparent toxicity.

  7. MeCP2 regulates ethanol sensitivity and intake.

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    Repunte-Canonigo, Vez; Chen, Jihuan; Lefebvre, Celine; Kawamura, Tomoya; Kreifeldt, Max; Basson, Oan; Roberts, Amanda J; Sanna, Pietro Paolo

    2014-09-01

    We have investigated the expression of chromatin-regulating genes in the prefrontal cortex and in the shell subdivision of the nucleus accumbens during protracted withdrawal in mice with increased ethanol drinking after chronic intermittent ethanol (CIE) vapor exposure and in mice with a history of non-dependent drinking. We observed that the methyl-CpG binding protein 2 (MeCP2) was one of the few chromatin-regulating genes to be differentially regulated by a history of dependence. As MeCP2 has the potential of acting as a broad gene regulator, we investigated sensitivity to ethanol and ethanol drinking in MeCP2(308/) (Y) mice, which harbor a truncated MeCP2 allele but have a milder phenotype than MeCP2 null mice. We observed that MeCP2(308/) (Y) mice were more sensitive to ethanol's stimulatory and sedative effects than wild-type (WT) mice, drank less ethanol in a limited access 2 bottle choice paradigm and did not show increased drinking after induction of dependence with exposure to CIE vapors. Alcohol metabolism did not differ in MeCP2(308/) (Y) and WT mice. Additionally, MeCP2(308/) (Y) mice did not differ from WT mice in ethanol preference in a 24-hour paradigm nor in their intake of graded solutions of saccharin or quinine, suggesting that the MeCP2(308/) (Y) mutation did not alter taste function. Lastly, using the Gene Set Enrichment Analysis algorithm, we found a significant overlap in the genes regulated by alcohol and by MeCP2. Together, these results suggest that MeCP2 contributes to the regulation of ethanol sensitivity and drinking. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

  8. Mild expression differences of MECP2 influencing aggressive social behavior.

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    Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

    2014-05-01

    The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.

  9. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands.

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    Carlos Bueno

    Full Text Available Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others suggest that MeCP2 post-transcriptional processing generates multiple molecular forms linked to cell signaling, but so far they have not been properly analyzed in relation to Rett syndrome experimental models. The purpose of this study is to advance understanding of multiple MeCP2 immunoreactive bands in control neural cells and p.T158M MeCP2e1 mutant cells. We have generated stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Application of N- and C- terminal MeCP2 antibodies, and also, RFP antibody minimized concerns about nonspecific cross-reactivity, since they react with the same antigen at different epitopes. We report the existence of multiple MeCP2 immunoreactive bands in control cells, stable wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Also, MeCP2 immunoreactive bands differences were found between wild-type and p.T158M MeCP2e1-RFP mutant expressing cells. Slower migration phosphorylated band around 70kDa disappeared in p.T158M MeCP2e1-RFP mutant expressing cells. These data suggest that threonine 158 could represent an important phosphorylation site potentially involved in protein function. Our results clearly indicate that MeCP2 antibodies have no cross-reactivity with similar epitopes on others proteins, supporting the

  10. MeCP2-Related Diseases and Animal Models

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    Chinelo D. Ezeonwuka

    2014-01-01

    Full Text Available The role of epigenetics in human disease has become an area of increased research interest. Collaborative efforts from scientists and clinicians have led to a better understanding of the molecular mechanisms by which epigenetic regulation is involved in the pathogenesis of many human diseases. Several neurological and non-neurological disorders are associated with mutations in genes that encode for epigenetic factors. One of the most studied proteins that impacts human disease and is associated with deregulation of epigenetic processes is Methyl CpG binding protein 2 (MeCP2. MeCP2 is an epigenetic regulator that modulates gene expression by translating epigenetic DNA methylation marks into appropriate cellular responses. In order to highlight the importance of epigenetics to development and disease, we will discuss how MeCP2 emerges as a key epigenetic player in human neurodevelopmental, neurological, and non-neurological disorders. We will review our current knowledge on MeCP2-related diseases, including Rett Syndrome, Angelman Syndrome, Fetal Alcohol Spectrum Disorder, Hirschsprung disease, and Cancer. Additionally, we will briefly discuss about the existing MeCP2 animal models that have been generated for a better understanding of how MeCP2 impacts certain human diseases.

  11. Regulatory functions and pathological relevance of the MECP2 3′UTR in the central nervous system

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    Heather McGowan

    2015-01-01

    Full Text Available Methyl-CpG-binding protein 2 (MeCP2, encoded by the gene MECP2, is a transcriptional regulator and chromatin-remodeling protein, which is ubiquitously expressed and plays an essential role in the development and maintenance of the central nervous system (CNS. Highly enriched in post-migratory neurons, MeCP2 is needed for neuronal maturation, including dendritic arborization and the development of synapses. Loss-of-function mutations in MECP2 cause Rett syndrome (RTT, a debilitating neurodevelopmental disorder characterized by a phase of normal development, followed by the progressive loss of milestones and cognitive disability. While a great deal has been discovered about the structure, function, and regulation of MeCP2 in the time since its discovery as the genetic cause of RTT, including its involvement in a number of RTT-related syndromes that have come to be known as MeCP2-spectrum disorders, much about this multifunctional protein remains enigmatic. One unequivocal fact that has become apparent is the importance of maintaining MeCP2 protein levels within a narrow range, the limits of which may depend upon the cell type and developmental time point. As such, MeCP2 is amenable to complex, multifactorial regulation. Here, we summarize the role of the MECP2 3' untranslated region (UTR in the regulation of MeCP2 protein levels and how mutations in this region contribute to autism and other non-RTT neuropsychiatric disorders.

  12. Evolving role of MeCP2 in Rett syndrome and autism.

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    LaSalle, Janine M; Yasui, Dag H

    2009-10-01

    Rett syndrome is an X-linked autism-spectrum disorder caused by mutations in MECP2, encoding methyl CpG-binding protein 2. Since the discovery of MECP2 mutations as the genetic cause of Rett syndrome, the understanding of MeCP2 function has evolved. Although MeCP2 was predicted to be a global transcriptional repressor of methylated promoters, large-scale combined epigenomic approaches of MeCP2 binding, methylation and gene expression have demonstrated that MeCP2 binds preferentially to intergenic and intronic regions, and sparsely methylated promoters of active genes. This review compares the evolution of thought within two ‘classic’ epigenetic mechanisms of parental imprinting and X chromosome inactivation to that of the MeCP2 field, and considers the future relevance of integrated epigenomic databases to understanding autism and Rett syndrome.

  13. MeCP2 Rett mutations affect large scale chromatin organization

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    Gupta, Noopur Agarwal; Becker, Annette; Jost, K Laurence

    2011-01-01

    Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene...... expression, we have now explored the possibility that Rett mutations may affect the ability of MeCP2 to bind and organize chromatin. We found that all but one of the 21 missense MeCP2 mutants analyzed accumulated at heterochromatin and about half of them were significantly affected. Furthermore, two......-thirds of all mutants showed a significantly decreased ability to cluster heterochromatin. Three mutants containing different proline substitutions (P101H, P101R and P152R) were severely affected only in heterochromatin clustering and located far away from the DNA interface in the MeCP2 methyl-binding domain...

  14. MECP2 promoter methylation and X chromosome inactivation in autism.

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    Nagarajan, Raman P; Patzel, Katherine A; Martin, Michelle; Yasui, Dag H; Swanberg, Susan E; Hertz-Picciotto, Irva; Hansen, Robin L; Van de Water, Judy; Pessah, Isaac N; Jiang, Ruby; Robinson, Wendy P; LaSalle, Janine M

    2008-06-01

    Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were peformed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCTC-binding factor (CTCF) bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes.

  15. Role of Mecp2 in Experience-Dependent Epigenetic Programming

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    Christoph A. Zimmermann

    2015-03-01

    Full Text Available Mutations in the X-linked gene MECP2, the founding member of a family of proteins recognizing and binding to methylated DNA, are the genetic cause of a devastating neurodevelopmental disorder in humans, called Rett syndrome. Available evidence suggests that MECP2 protein has a critical role in activity-dependent neuronal plasticity and transcription during brain development. Moreover, recent studies in mice show that various posttranslational modifications, notably phosphorylation, regulate Mecp2’s functions in learning and memory, drug addiction, depression-like behavior, and the response to antidepressant treatment. The hypothalamic-pituitary-adrenal (HPA axis drives the stress response and its deregulation increases the risk for a variety of mental disorders. Early-life stress (ELS typically results in sustained HPA-axis deregulation and is a major risk factor for stress related diseases, in particular major depression. Interestingly, Mecp2 protein has been shown to contribute to ELS-dependent epigenetic programming of Crh, Avp, and Pomc, all of these genes enhance HPA-axis activity. Hereby ELS regulates Mecp2 phosphorylation, DNA binding, and transcriptional activities in a tissue-specific and temporospatial manner. Overall, these findings suggest MECP2 proteins are so far underestimated and have a more dynamic role in the mediation of the gene-environment dialog and epigenetic programming of the neuroendocrine stress system in health and disease.

  16. Mild overexpression of Mecp2 in mice causes a higher susceptibility toward seizures.

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    Bodda, Chiranjeevi; Tantra, Martesa; Mollajew, Rustam; Arunachalam, Jayamuruga P; Laccone, Franco A; Can, Karolina; Rosenberger, Albert; Mironov, Sergej L; Ehrenreich, Hannelore; Mannan, Ashraf U

    2013-07-01

    An intriguing finding about the gene encoding methyl-CpG binding protein 2 (MeCP2) is that the loss-of-function mutations cause Rett syndrome and duplication (gain-of-function) of MECP2 leads to another neurological disorder termed MECP2 duplication syndrome. To ensure proper neurodevelopment, a precise regulation of MeCP2 expression is critical, and any gain or loss of MeCP2 over a narrow threshold level may lead to postnatal neurological impairment. To evaluate MeCP2 dosage effects, we generated Mecp2(WT_EGFP) transgenic (TG) mouse in which MeCP2 (endogenous plus TG) is mildly overexpressed (approximately 1.5×). The TG MeCP2(WT_EGFP) fusion protein is functionally active, as cross breeding of these mice with Mecp2 knockout mice led to alleviation of major phenotypes in the null mutant mice, including premature lethality. To characterize the Mecp2(WT_EGFP) mouse model, we performed an extensive battery of behavioral tests, which revealed that these mice manifest increased aggressiveness and higher pentylenetetrazole (PTZ)-induced seizure propensity. Evaluation of neuronal parameters revealed a reduction in the number of tertiary branching sites and increased spine density in Mecp2(WT_EGFP) transgenic (TG) neurons. Treatment of TG neurons with epileptogenic compound-PTZ led to a marked increase in amplitude and frequency of calcium spikes. Based on our ex vivo and in vivo data, we conclude that epileptic seizures are manifested as the first symptom when MeCP2 is mildly overexpressed in mice. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Molecular analysis of MECP2 gene in Egyptian patients with Rett ...

    African Journals Online (AJOL)

    Molecular analysis of MECP2 gene in Egyptian patients with Rett syndrome. ... Egyptian Journal of Medical Human Genetics ... This study represents one of the limited MECP2 molecular analyses done on Egyptian patients with RTT, in which direct sequencing of MECP2 coding region in 10 female Egyptian patients ...

  18. Increasing brain serotonin corrects CO2 chemosensitivity in methyl-CpG-binding protein 2 (Mecp2)-deficient mice

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    Toward, Marie A.; Abdala, Ana P.; Knopp, Sharon J.; Paton, Julian F. R.; Bissonnette, John M.

    2013-01-01

    Mice deficient in the transcription factor methyl-CpG-binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO2 chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for Mecp2 show reduced levels of brain serotonin (5-HT). Serotonin is known to play a role in central chemosensitivity, and we hypothesized that increasing the availability of 5-HT in this mouse model would improve their respiratory response to CO2. Here we determined the apnoeic threshold in heterozygous Mecp2-deficient female mice and examined the effects of blocking 5-HT reuptake on the CO2 response in Mecp2-null male mice. Studies were performed in B6.129P2(C)-Mecp2τm1.1Bird null males and heterozygous females. In an in situ preparation, seven of eight Mecp2-deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO2 was lowered to 3%, whereas the wild-types maintained phrenic nerve amplitude at 53 ± 3% of maximal. In vivo plethysmography studies were used to determine CO2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO2. The percentage increase in minute ventilation in response to increased inspired CO2 was less in Mecp2−/y than in Mecp2+/y mice. Pretreatment with citalopram, a selective 5-HT reuptake inhibitor (2.5 mg kg−1 I.P.), 40 min prior to CO2 exposure, in Mecp2−/y mice resulted in an improvement in CO2 chemosensitivity to wild-type levels. These results suggest that decreased 5-HT in Mecp2-deficient mice reduces CO2 chemosensitivity, and restoring 5-HT levels can reverse this effect. PMID:23180809

  19. CDKL5 is a brain MeCP2 target gene regulated by DNA methylation.

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    Carouge, Delphine; Host, Lionel; Aunis, Dominique; Zwiller, Jean; Anglard, Patrick

    2010-06-01

    Rett syndrome and its "early-onset seizure" variant are severe neurodevelopmental disorders associated with mutations within the MECP2 and the CDKL5 genes. Antidepressants and drugs of abuse induce the expression of the epigenetic factor MeCP2, thereby influencing chromatin remodeling. We show that increased MeCP2 levels resulted in the repression of Cdkl5 in rat brain structures in response to cocaine, as well as in cells exposed to serotonin, or overexpressing MeCP2. In contrast, Cdkl5 was induced by siRNA-mediated knockdown of Mecp2 and by DNA-methyltransferase inhibitors, demonstrating its regulation by MeCP2 and by DNA methylation. Cdkl5 gene methylation and its methylation-dependent binding to MeCP2 were increased in the striatum of cocaine-treated rats. Our data demonstrate that Cdkl5 is a MeCP2-repressed target gene providing a link between genes the mutation of which generates overlapping symptoms. They highlight DNA methylation changes as a potential mechanism participating in the long-term plasticity triggered by pharmacological agents.

  20. Sex difference in mecp2 expression during a critical period of rat brain development.

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    Kurian, Joseph R; Forbes-Lorman, Robin M; Auger, Anthony P

    2007-09-01

    Pervasive developmental disorder is a classification covering five related conditions including the neurodevelopmental disorder Rett syndrome (RTT) and autism. Of these five conditions, only RTT has a known genetic cause with mutations in Methyl-CpG-binding protein 2 (MeCP2), a global repressor of gene expression, responsible for the majority of RTT cases. However, recent evidence indicates that reduced MeCP2 expression or activity is also found in autism and other disorders with overlapping phenotypes. Considering the sex difference in autism diagnosis, with males diagnosed four times more often than females, we questioned if a sex difference existed in the expression of MeCP2, in particular within the amygdala, a region that develops atypically in autism. We found that male rats express significantly less mecp2 mRNA and protein than females within the amygdala, as well as the ventromedial hypothalamus (VMH), but not within the preoptic area (POA) on post-natal day 1 (PN1). At PN10 these differences were gone; however, on this day males had more mecp2 mRNA than females within the POA. The transient sex difference of mecp2 expression during the steroid-sensitive period of brain development suggests that mecp2 may participate in normal sexual differentiation of the rat brain. Considering the strong link between MeCP2 and neurodevelopmental disorders, the lower levels of mecp2 expression in males may also underlie a biological risk for mecp2-related neural disorders.

  1. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

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    Hara, Munetsugu; Takahashi, Tomoyuki; Mitsumasu, Chiaki; Igata, Sachiyo; Takano, Makoto; Minami, Tomoko; Yasukawa, Hideo; Okayama, Satoko; Nakamura, Keiichiro; Okabe, Yasunori; Tanaka, Eiichiro; Takemura, Genzou; Kosai, Ken-ichiro; Yamashita, Yushiro; Matsuishi, Toyojiro

    2015-01-01

    Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure. PMID:26073556

  2. Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations.

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    Alison A Williams

    Full Text Available Methyl-CpG binding protein 2 (MeCP2 is a widely abundant, multifunctional protein most highly expressed in post-mitotic neurons. Mutations causing Rett syndrome and related neurodevelopmental disorders have been identified along the entire MECP2 locus, but symptoms vary depending on mutation type and location. C-terminal mutations are prevalent, but little is known about the function of the MeCP2 C-terminus. We employ the genetic efficiency of Drosophila to provide evidence that expression of p.Arg294* (more commonly identified as R294X, a human MECP2 E2 mutant allele causing truncation of the C-terminal domains, promotes apoptosis of identified neurons in vivo. We confirm this novel finding in HEK293T cells and then use Drosophila to map the region critical for neuronal apoptosis to a small sequence at the end of the C-terminal domain. In vitro studies in mammalian systems previously indicated a role of the MeCP2 E2 isoform in apoptosis, which is facilitated by phosphorylation at serine 80 (S80 and decreased by interactions with the forkhead protein FoxG1. We confirm the roles of S80 phosphorylation and forkhead domain transcription factors in affecting MeCP2-induced apoptosis in Drosophila in vivo, thus indicating mechanistic conservation between flies and mammalian cells. Our findings are consistent with a model in which C- and N-terminal interactions are required for healthy function of MeCP2.

  3. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

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    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

    2014-01-01

    Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

  4. A rare male patient with classic Rett syndrome caused by MeCP2_e1 mutation.

    Science.gov (United States)

    Tokaji, Narumi; Ito, Hiromichi; Kohmoto, Tomohiro; Naruto, Takuya; Takahashi, Rizu; Goji, Aya; Mori, Tatsuo; Toda, Yoshihiro; Saito, Masako; Tange, Shoichiro; Masuda, Kiyoshi; Kagami, Shoji; Imoto, Issei

    2018-03-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder typically affecting females. It is mainly caused by loss-of-function mutations that affect the coding sequence of exon 3 or 4 of methyl-CpG-binding protein 2 (MECP2). Severe neonatal encephalopathy resulting in death before the age of 2 years is the most common phenotype observed in males affected by a pathogenic MECP2 variant. Mutations in MECP2 exon 1 affecting the MeCP2_e1 isoform are relatively rare causes of RTT in females, and only one case of a male patient with MECP2-related severe neonatal encephalopathy caused by a mutation in MECP2 exon 1 has been reported. This is the first reported case of a male with classic RTT caused by a 5-bp duplication in the open-reading frame of MECP2 exon 1 (NM_001110792.1:c.23_27dup) that introduced a premature stop codon [p.(Ser10Argfs*36)] in the MeCP2_e1 isoform, which has been reported in one female patient with classic RTT. Therefore, both males and females displaying at least some type of MeCP2_e1 mutation may exhibit the classic RTT phenotype. © 2018 Wiley Periodicals, Inc.

  5. Early progressive encephalopathy in boys and MECP2 mutations.

    Science.gov (United States)

    Kankirawatana, P; Leonard, H; Ellaway, C; Scurlock, J; Mansour, A; Makris, C M; Dure, L S; Friez, M; Lane, J; Kiraly-Borri, C; Fabian, V; Davis, M; Jackson, J; Christodoulou, J; Kaufmann, W E; Ravine, D; Percy, A K

    2006-07-11

    MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

  6. MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2

    Directory of Open Access Journals (Sweden)

    Yunjia Zhang

    2016-06-01

    Full Text Available ABSTRACT MicroRNAs (miRNAs are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function mutations in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Furthermore, expression of the wild-type MeCP2, but not a loss-of-function mutant, rescues the miR-130a-induced phenotype. Our study uncovers the MECP2 gene as a previous unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by regulating MeCP2. Together with data from other groups, our work suggests that a feedback regulatory mechanism involving both miR-130a and MeCP2 may serve to ensure their appropriate expression and function in neural development.

  7. Prenatal diagnosis of foetuses with congenital abnormalities and duplication of the MECP2 region.

    Science.gov (United States)

    Fu, Fang; Liu, Huan-ling; Li, Ru; Han, Jin; Yang, Xin; Min, Pan; Zhen, Li; Zhang, Yong-ling; Xie, Gui-e; Lei, Ting-ying; Li, Yan; Li, Jian; Li, Dong-zhi; Liao, Can

    2014-08-10

    MECP2 duplication results in a well-recognised syndrome in 100% of affected male children; this syndrome is characterised by severe neurodevelopmental disabilities and recurrent infections. However, no sonographic findings have been reported for affected foetuses, and prenatal molecular diagnosis has not been possible for this disease due to lack of prenatal clinical presentation. In this study, we identified a small duplication comprising the MECP2 and L1CAM genes in the Xq28 region in a patient from a family with severe X-linked mental retardation and in a prenatal foetus with brain structural abnormalities. Using high-resolution chromosome microarray analysis (CMA) to screen 108 foetuses with congenital structural abnormalities, we identified additional three foetuses with the MECP2 duplication. Our study indicates that ventriculomegaly, hydrocephalus, agenesis of the corpus callosum, choroid plexus cysts, foetal growth restriction and hydronephrosis might be common ultrasound findings in prenatal foetuses with the MECP2 duplication and provides the first set of prenatal cases with MECP2 duplication, the ultrasonographic phenotype described in these patients will help to recognise the foetuses with possible MECP2 duplication and prompt the appropriate molecular testing. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

    Directory of Open Access Journals (Sweden)

    Valentina Conti

    Full Text Available Rett syndrome (RTT is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions.

  9. MECP2 variation in Rett syndrome-An overview of current coverage of genetic and phenotype data within existing databases.

    Science.gov (United States)

    Townend, Gillian S; Ehrhart, Friederike; van Kranen, Henk J; Wilkinson, Mark; Jacobsen, Annika; Roos, Marco; Willighagen, Egon L; van Enckevort, David; Evelo, Chris T; Curfs, Leopold M G

    2018-04-27

    Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases, it results from a loss-of-function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counseling for parents. In this study, 13 genotype-phenotype databases were surveyed for their general functionality and availability of RTT-specific MECP2 variation data. For each database, we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis, or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.

  10. Sequential chromatin immunoprecipitation to detect SUMOylated MeCP2 in neurons

    Directory of Open Access Journals (Sweden)

    Tao Wu

    2016-03-01

    Full Text Available The small ubiquitin-like modifier (SUMO is a short peptide that can be covalently linked to proteins altering their function. SUMOylation is an essential post-translational modification (PTM. Because of its dynamic nature, low abundance levels, and technical limitations, the occupation of endogenous SUMOylated transcription factors at genomic loci is challenging to detect. The chromatin regulator Methyl CpG binding protein 2 (MeCP2 is subjected to PTMs including SUMO. Mutations in MeCP2 lead to Rett syndrome, a severe neurodevelopmental disorder. Here, we present an efficient method to perform sequential chromatin immunoprecipitation (Seq-ChIP for detecting SUMOylated MeCP2 in neurons. This Seq-ChIP technique is a useful tool to determine the occupancy of SUMOylated transcription and chromatin factors at specific genomic regions.

  11. Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

    Science.gov (United States)

    Sampathkumar, Charanya; Wu, Yuan-Ju; Vadhvani, Mayur; Trimbuch, Thorsten; Eickholt, Britta; Rosenmund, Christian

    2016-01-01

    Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. DOI: http://dx.doi.org/10.7554/eLife.19374.001 PMID:27782879

  12. Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate.

    Science.gov (United States)

    Pandey, Somnath; Pruitt, Kevin

    2017-06-01

    Ever since the first report that mutations in methyl-CpG-binding protein 2 (MeCP2) causes Rett syndrome (RTT), a severe neurological disorder in females world-wide, there has been a keen interest to gain a comprehensive understanding of this protein. While the classical model associated with MeCP2 function suggests its role in gene suppression via recruitment of co-repressor complexes and histone deacetylases to methylated CpG-sites, recent discoveries have brought to light its role in transcription activation, modulation of RNA splicing, and chromatin compaction. Various post-translational modifications (PTMs) of MeCP2 further increase its functional versatility. Involvement of MeCP2 in pathologies other than RTT, such as tumorigenesis however, remains poorly explored and understood. This review provides a survey of the literature implicating MeCP2 in breast, colon and prostate cancer.

  13. MeCP2 silencing of LncRNA H19 controls hepatic stellate cell proliferation by targeting IGF1R

    International Nuclear Information System (INIS)

    Yang, Jing-Jing; Liu, Li-Ping; Tao, Hui; Hu, Wei; Shi, Peng; Deng, Zi-Yu; Li, Jun

    2016-01-01

    Highlights: • H19 plays a key role in HSCs proliferation and fibrosis. • MeCP2/H19 axis involvement in HSCs activation and fibrosis. • MeCP2 negative controls H19 expression in activated HSCs. • Identification of IGF1R as new target of H19 in HSC. - Abstract: Methyl-CpG-binding protein 2 (MeCP2) plays a key role in liver fibrosis. However, the potential mechanism of MeCP2 in liver fibrosis remains unclear. Early reports suggest that LncRNA H19 is important epigenetic regulator with critical roles in cell proliferation, but its role in hepatic fibrosis remains elusive. Sprague-Dawley rats liver fibrosis was generated by 12-weeks treatment with CCl 4 intraperitoneal injection. HSC-T6 cells were used in vitro study. The expression levels of MeCP2, H19, IGF1R, α-SMA, and Col1A1 were estimated by Western blotting, qRT-PCR and Immunohistochemistry. HSC-T6 cells were transfected with MeCP2-siRNA, pEGF-C1-MeCP2, pEX-3-H19, and H19-siRNA. Finally, cell proliferation ability was assessed by the MTT assay. Here, we found that H19 was significantly down-regulated in HSCs and fibrosis tissues, and an opposite pattern is observed for MeCP2 and IGF1R. Silencing of MeCP2 blocked HSCs proliferation. Knockdown of MeCP2 elevated H19 expression in activated HSCs, and over-expression of MeCP2 inhibited H19 expression in activated HSCs. Moreover, we investigated the effect of H19 on IGF1R expression. Overexpression of H19 in HSCs repressed the expression of IGF1R, and an opposite pattern is observed for H19 silenced. In addition, we reported that overexpression of H19 inhibited the TGF-β1-induced proliferation of HSCs. Furthermore, MeCP2 negative regulation of H19 by targeting the protein IGF1R. Taken together, these results demonstrated that MeCP2 silencing of H19 can alter the IGF1R overexpression, thus contributing to HSCs proliferation. These data could suggest the development of combination therapies that target the MeCP2.

  14. MECP2 duplication phenotype in symptomatic females: report of three further cases

    OpenAIRE

    Novara, Francesca; Simonati, Alessandro; Sicca, Federico; Battini, Roberta; Fiori, Simona; Contaldo, Annarita; Criscuolo, Lucia; Zuffardi, Orsetta; Ciccone, Roberto

    2014-01-01

    Background Xq28 duplications, including MECP2 (methyl CpG-binding protein 2; OMIM 300005), have been identified in approximately 140 male patients presenting with hypotonia, severe developmental delay/intellectual disability, limited or absent speech and ambulation, and recurrent respiratory infections. Female patients with Xq28 duplication have been rarely reported and are usually asymptomatic. Altogether, only fifteen symptomatic females with Xq28 duplications including MECP2 have been repo...

  15. Generation and characterization of rat and mouse monoclonal antibodies specific for MeCP2 and their use in X-inactivation studies.

    Directory of Open Access Journals (Sweden)

    K Laurence Jost

    Full Text Available Methyl CpG binding protein 2 (MeCP2 binds DNA, and has a preference for methylated CpGs and, hence, in cells, it accumulates in heterochromatin. Even though it is expressed ubiquitously MeCP2 is particularly important during neuronal maturation. This is underscored by the fact that in Rett syndrome, a neurological disease, 80% of patients carry a mutation in the MECP2 gene. Since the MECP2 gene lies on the X chromosome and is subjected to X chromosome inactivation, affected patients are usually chimeric for wild type and mutant MeCP2. Here, we present the generation and characterization of the first rat monoclonal MeCP2 specific antibodies as well as mouse monoclonal antibodies and a rabbit polyclonal antibody. We demonstrate that our antibodies are suitable for immunoblotting, (chromatin immunoprecipitation and immunofluorescence of endogenous and ectopically expressed MeCP2. Epitope mapping revealed that most of the MeCP2 monoclonal antibodies recognize the C-terminal domain and one the N-terminal domain of MeCP2. Using slot blot analysis, we determined a high sensitivity of all antibodies, detecting amounts as low as 1 ng of MeCP2 protein. Moreover, the antibodies recognize MeCP2 from different species, including human, mouse, rat and pig. Lastly, we have validated their use by analyzing and quantifying X chromosome inactivation skewing using brain tissue of MeCP2 heterozygous null female mice. The new MeCP2 specific monoclonal antibodies described here perform well in a large variety of immunological applications making them a very valuable set of tools for studies of MeCP2 pathophysiology in situ and in vitro.

  16. Melittin induces PTCH1 expression by down-regulating MeCP2 in human hepatocellular carcinoma SMMC-7721 cells

    International Nuclear Information System (INIS)

    Wu, Xiaoqin; Zhao, Bin; Cheng, Yahui; Yang, Yang; Huang, Cheng; Meng, Xiaoming; Wu, Baoming; Zhang, Lei; Lv, Xiongwen; Li, Jun

    2015-01-01

    Hepatocellular carcinoma (HCC) has a high mortality rate worldwide and still remains to be a noticeable public health problem. Therefore, new remedies are urgently needed. Melittin, a major component of bee venom, is known to suppress cell growth in various cancers including HCC. However, the mechanism of the anticancer effect of melittin on HCC has not been fully elucidated. It has been reported that Methyl-CpG binding protein 2 (MeCP2) plays a key role in tumor proliferation, apoptosis, migration and invasion. In the present study, we found the high expression of MeCP2 in human HCC tissues and in the SMMC-7721 cell line. MeCP2 silencing inhibited cell proliferation, while over-expression of MeCP2 promoted cell growth in SMMC-7721 cells. It indicates that MeCP2 may be an attractive target for human HCC. We further found that melittin could inhibit cell proliferation by reducing MeCP2 expression in vitro. Interestingly, the inhibitory effect of melittin on cell proliferation was due to a delay in G 0 /G 1 cell cycle progression, without influencing cell apoptosis. Next, we investigated the potential molecular mechanisms and found that MeCP2 could modulate Shh signaling in SMMC-7721 cells. Further study indicates that melittin may induce the demethylation of PTCH1 promoter, resulting in the increased expression of PTCH1. Furthermore, the expression of Shh and GLI1 was significantly lowered upon treatment of melittin. These results suggest that melittin can block Shh signaling in vitro. In short, these results indicate that melittin inhibits cell proliferation by down-regulating MeCP2 through Shh signaling in SMMC-7721 cells. - Highlights: • MeCP2 plays a key role in the proliferation of human HCC cells. • Melittin reduces MeCP2 expression in vitro. • Melittin induces G 0 /G 1 cell cycle arrest in SMMC-7721 cells. • MeCP2 modulates the Shh signaling pathway in SMMC-7721 cells. • Melittin blocks the Shh signaling pathway in SMMC-7721 cells.

  17. Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Sampathkumar Rangasamy

    2016-09-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN cultures from mutant (Mecp2A140V/y and wild type (Mecp2+/y male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele. In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1 treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2  mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”.

  18. Melittin induces PTCH1 expression by down-regulating MeCP2 in human hepatocellular carcinoma SMMC-7721 cells

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Xiaoqin; Zhao, Bin; Cheng, Yahui; Yang, Yang; Huang, Cheng; Meng, Xiaoming; Wu, Baoming; Zhang, Lei; Lv, Xiongwen; Li, Jun, E-mail: xqwu01@foxmail.com

    2015-10-01

    Hepatocellular carcinoma (HCC) has a high mortality rate worldwide and still remains to be a noticeable public health problem. Therefore, new remedies are urgently needed. Melittin, a major component of bee venom, is known to suppress cell growth in various cancers including HCC. However, the mechanism of the anticancer effect of melittin on HCC has not been fully elucidated. It has been reported that Methyl-CpG binding protein 2 (MeCP2) plays a key role in tumor proliferation, apoptosis, migration and invasion. In the present study, we found the high expression of MeCP2 in human HCC tissues and in the SMMC-7721 cell line. MeCP2 silencing inhibited cell proliferation, while over-expression of MeCP2 promoted cell growth in SMMC-7721 cells. It indicates that MeCP2 may be an attractive target for human HCC. We further found that melittin could inhibit cell proliferation by reducing MeCP2 expression in vitro. Interestingly, the inhibitory effect of melittin on cell proliferation was due to a delay in G{sub 0}/G{sub 1} cell cycle progression, without influencing cell apoptosis. Next, we investigated the potential molecular mechanisms and found that MeCP2 could modulate Shh signaling in SMMC-7721 cells. Further study indicates that melittin may induce the demethylation of PTCH1 promoter, resulting in the increased expression of PTCH1. Furthermore, the expression of Shh and GLI1 was significantly lowered upon treatment of melittin. These results suggest that melittin can block Shh signaling in vitro. In short, these results indicate that melittin inhibits cell proliferation by down-regulating MeCP2 through Shh signaling in SMMC-7721 cells. - Highlights: • MeCP2 plays a key role in the proliferation of human HCC cells. • Melittin reduces MeCP2 expression in vitro. • Melittin induces G{sub 0}/G{sub 1} cell cycle arrest in SMMC-7721 cells. • MeCP2 modulates the Shh signaling pathway in SMMC-7721 cells. • Melittin blocks the Shh signaling pathway in SMMC-7721 cells.

  19. Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus.

    Science.gov (United States)

    Zhang, Ying; Cao, Shu-Xia; Sun, Peng; He, Hai-Yang; Yang, Ci-Hang; Chen, Xiao-Juan; Shen, Chen-Jie; Wang, Xiao-Dong; Chen, Zhong; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

    2016-06-01

    Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.

  20. A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene

    Energy Technology Data Exchange (ETDEWEB)

    Fendri-Kriaa, Nourhene, E-mail: nourhene.fendri@gmail.com [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Hsairi, Ines [Service de Neurologie Infantile, C.H.U. Hedi Chaker de Sfax (Tunisia); Kifagi, Chamseddine [Laboratoire internationale associe LIA135, Centre de Biotechnologie de Sfax (Tunisia); Ellouze, Emna [Service de Neurologie Infantile, C.H.U. Hedi Chaker de Sfax (Tunisia); Mkaouar-Rebai, Emna [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Triki, Chahnez [Service de Neurologie Infantile, C.H.U. Hedi Chaker de Sfax (Tunisia); Fakhfakh, Faiza [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)

    2011-06-03

    Highlights: {yields} Sequencing of the MECP2 gene, modeling and comparison of the two variants were performed in a Tunisian classical Rett patient. {yields} A double-mutation: a new and de novo mutation c.535C > T and the common one c.763C > T of the MECP2 gene was identified. {yields} The P179S transition may change local electrostatic properties which may affect the function and stability of the protein MeCP2. -- Abstract: Rett syndrome is an X-linked dominant disorder caused frequently by mutations in the methyl-CpG-binding protein 2 gene (MECP2). Rett patients present an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. The aim of this study was to perform a mutational analysis of the MECP2 gene in a classical Rett patient by sequencing the corresponding gene and modeling the found variants. The results showed the presence of a double-mutation: a new and de novo mutation c.535C > T (p.P179S) and the common c.763C > T (p.R255X) transition of the MECP2 gene. The p.P179S mutation was located in a conserved amino acid in CRIR domain (corepressor interacting region). Modeling results showed that the P179S transition could change local electrostatic properties by adding a negative charge due to serine hydroxyl group of this region of MeCP2 which may affect the function and stability of the protein. The p.R255X mutation is located in TRD-NLS domain (transcription repression domain-nuclear localization signal) of MeCP2 protein.

  1. A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene

    International Nuclear Information System (INIS)

    Fendri-Kriaa, Nourhene; Hsairi, Ines; Kifagi, Chamseddine; Ellouze, Emna; Mkaouar-Rebai, Emna; Triki, Chahnez; Fakhfakh, Faiza

    2011-01-01

    Highlights: → Sequencing of the MECP2 gene, modeling and comparison of the two variants were performed in a Tunisian classical Rett patient. → A double-mutation: a new and de novo mutation c.535C > T and the common one c.763C > T of the MECP2 gene was identified. → The P179S transition may change local electrostatic properties which may affect the function and stability of the protein MeCP2. -- Abstract: Rett syndrome is an X-linked dominant disorder caused frequently by mutations in the methyl-CpG-binding protein 2 gene (MECP2). Rett patients present an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. The aim of this study was to perform a mutational analysis of the MECP2 gene in a classical Rett patient by sequencing the corresponding gene and modeling the found variants. The results showed the presence of a double-mutation: a new and de novo mutation c.535C > T (p.P179S) and the common c.763C > T (p.R255X) transition of the MECP2 gene. The p.P179S mutation was located in a conserved amino acid in CRIR domain (corepressor interacting region). Modeling results showed that the P179S transition could change local electrostatic properties by adding a negative charge due to serine hydroxyl group of this region of MeCP2 which may affect the function and stability of the protein. The p.R255X mutation is located in TRD-NLS domain (transcription repression domain-nuclear localization signal) of MeCP2 protein.

  2. Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome.

    Science.gov (United States)

    Samaco, Rodney C; Mandel-Brehm, Caleigh; McGraw, Christopher M; Shaw, Chad A; McGill, Bryan E; Zoghbi, Huda Y

    2012-01-08

    Genomic duplications spanning Xq28 are associated with a spectrum of phenotypes, including anxiety and autism. The minimal region shared among affected individuals includes MECP2 and IRAK1, although it is unclear which gene when overexpressed causes anxiety and social behavior deficits. We report that doubling MECP2 levels causes heightened anxiety and autism-like features in mice and alters the expression of genes that influence anxiety and social behavior, such as Crh and Oprm1. To test the hypothesis that alterations in these two genes contribute to heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) that have reduced Crh and Oprm1 expression. In MECP2-TG1 animals, reducing the levels of Crh or its receptor, Crhr1, suppressed anxiety-like behavior; in contrast, reducing Oprm1 expression improved abnormal social behavior. These data indicate that increased MeCP2 levels affect molecular pathways underlying anxiety and social behavior and provide new insight into potential therapies for MECP2-related disorders.

  3. De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynaecomastia.

    NARCIS (Netherlands)

    Kleefstra, T.; Yntema, H.G.; Oudakker, A.R.; Romein, T.; Sistermans, E.A.; Nillessen, W.; Bokhoven, J.H.L.M. van; Vries, L.B.A. de; Hamel, B.C.J.

    2002-01-01

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene, with apparent lethality in male embryos. However, recent studies indicate that mutations in the MECP2 gene can cause congenital encephalopathy, an Angelman-like phenotype and even nonspecific mental

  4. Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2(308/y) Mouse Model.

    Science.gov (United States)

    Rousseaud, Audrey; Delépine, Chloé; Nectoux, Juliette; Billuart, Pierre; Bienvenu, Thierry

    2015-08-01

    Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in methyl-CpG-binding protein 2 (MECP2), which encodes a transcriptional modulator of many genes including BDNF. BDNF comprises nine distinct promoter regions, each triggering the expression of a specific transcript. The role of this diversity of transcripts remains unknown. MeCP2 being highly expressed in neurons, RTT was initially considered as a neuronal disease. However, recent studies have shown that MeCP2 was also expressed in astrocytes. Though several studies explored Bdnf IV expression in Mecp2-deficient mice, the differential expression of Bdnf isoforms in Mecp2-deficient neurons and astrocytes was never studied. By using TaqMan technology and a mouse model expressing a truncated Mecp2 (Mecp2(308/y)), we firstly showed in neurons that Bdnf transcripts containing exon I, IIb, IIc, IV, and VI are prominently expressed, whereas in astrocytes, Bdnf transcript containing exon VI is preferentially expressed, suggesting a specific regulation of Bdnf expression at the cellular level. Secondly, we confirmed the repressive role of Mecp2 only on the expression of Bdnf VI in neurons. Our data suggested that the truncated Mecp2 protein maintains its function on Bdnf expression regulation in neurons and in astrocytes. Interestingly, we observed that Bdnf transcripts (I and IXA), regulated by neural activity induced by bicuculline in Mecp2(308/y) neurons, were not affected by histone deacetylase inhibition. In contrast, Bdnf transcripts (IIb, IIc, and VI), regulated by histone deacetylation, were not affected by bicuculline treatment in wild-type and Mecp2(308/y) neurons. All these results reflect the complexity of regulation of Bdnf gene.

  5. Experimental Autoimmune Encephalomyelitis (EAE-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1: Implications in Multiple Sclerosis (MS-Induced Neurological Disability and Associated Myelin Damage

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    Tina Khorshid Ahmad

    2017-06-01

    Full Text Available Multiple sclerosis (MS is a chronic neurological disease characterized by the destruction of central nervous system (CNS myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2 called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE-induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the myelin repair process by repressing BDNF expression. Using an EAE model of MS, we identify the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF. The expression changes of these key biological targets were then correlated with the temporal changes in neurological disability scores (NDS over the entire disease course. Our results indicate that MeCP2E1 mRNA levels are elevated in EAE animals relative to naïve control (NC and active control (AC animals during all time points of disease progression. Our results suggest that the EAE-induced elevations in MeCP2E1 expression contribute to the repressed BDNF production in the spinal cord (SC. The sub-optimal levels of BDNF result in sustained NDS and associated myelin damage throughout the entire disease course. Conversely, we observed no significant differences in the expression patterns displayed for the MeCP2E2 isoform amongst our experimental groups. However, our results demonstrate that baseline protein expression ratios between the MeCP2E1 versus MeCP2E2 isoforms in the SC are higher than those identified within the dorsal root ganglia (DRG. Thus, the DRG represents a more conducive environment than that of the SC for BDNF production and transport to the CNS to assist in myelin repair. Henceforth, the sub-optimal BDNF levels we report in the SC

  6. Experimental Autoimmune Encephalomyelitis (EAE)-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1): Implications in Multiple Sclerosis (MS)-Induced Neurological Disability and Associated Myelin Damage.

    Science.gov (United States)

    Khorshid Ahmad, Tina; Zhou, Ting; AlTaweel, Khaled; Cortes, Claudia; Lillico, Ryan; Lakowski, Ted Martin; Gozda, Kiana; Namaka, Michael Peter

    2017-06-12

    Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE)-induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the myelin repair process by repressing BDNF expression. Using an EAE model of MS, we identify the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF. The expression changes of these key biological targets were then correlated with the temporal changes in neurological disability scores (NDS) over the entire disease course. Our results indicate that MeCP2E1 mRNA levels are elevated in EAE animals relative to naïve control (NC) and active control (AC) animals during all time points of disease progression. Our results suggest that the EAE-induced elevations in MeCP2E1 expression contribute to the repressed BDNF production in the spinal cord (SC). The sub-optimal levels of BDNF result in sustained NDS and associated myelin damage throughout the entire disease course. Conversely, we observed no significant differences in the expression patterns displayed for the MeCP2E2 isoform amongst our experimental groups. However, our results demonstrate that baseline protein expression ratios between the MeCP2E1 versus MeCP2E2 isoforms in the SC are higher than those identified within the dorsal root ganglia (DRG). Thus, the DRG represents a more conducive environment than that of the SC for BDNF production and transport to the CNS to assist in myelin repair. Henceforth, the sub-optimal BDNF levels we report in the SC may arise

  7. MeCP2 Promotes Gastric Cancer Progression Through Regulating FOXF1/Wnt5a/β-Catenin and MYOD1/Caspase-3 Signaling Pathways

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    Lingyu Zhao

    2017-02-01

    Full Text Available Methyl-CpG binding protein 2 (MeCP2 has recently been characterized as an oncogene frequently amplified in several types of cancer. However, its precise role in gastric cancer (GC and the molecular mechanism of MeCP2 regulation are still largely unknown. Here we report that MeCP2 is highly expressed in primary GC tissues and the expression level is correlated with the clinicopathologic features of GC. In our experiments, knockdown of MeCP2 inhibited tumor growth. Molecular mechanism of MeCP2 regulation was investigated using an integrated approach with combination of microarray analysis and chromatin immunoprecipitation sequencing (ChIP-Seq. The results suggest that MeCP2 binds to the methylated CpG islands of FOXF1 and MYOD1 promoters and inhibits their expression at the transcription level. Furthermore, we show that MeCP2 promotes GC cell proliferation via FOXF1-mediated Wnt5a/β-Catenin signaling pathway and suppresses apoptosis through MYOD1-mediated Caspase-3 signaling pathway. Due to its high expression level in GC and its critical function in driving GC progression, MeCP2 represents a promising therapeutic target for GC treatment.

  8. miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes

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    Keita Tsujimura

    2015-09-01

    Full Text Available Rett syndrome (RTT is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR, which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling.

  9. Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons

    NARCIS (Netherlands)

    S. Yazdani (Saami); R. Deogracias (Rubén); J.A. Guy (Jacqueline); R.A. Poot (Raymond); A. Bird (Adrian); Y.A. Barde

    2012-01-01

    textabstractMutations in the gene encoding the methyl-CpG-binding protein MECP2 are the major cause of Rett syndrome, an autism spectrum disorder mainly affecting young females. MeCP2 is an abundant chromatin-associated protein, but how and when its absence begins to alter brain function is still

  10. Histone Variants and Composition in the Developing Brain: Should MeCP2 Care?

    Science.gov (United States)

    Zago, Valentina; Pinar-CabezaDeVaca, Cristina; Vincent, John B; Ausio, Juan

    2017-01-01

    Specific compositional chromatin features distinguish brain/neuronal chromatin from that of other tissues and are critical to this organ and cell type development and neuroplasticity. These features include a significant turnover of the major constitutive chromosomal proteins, including the (canonical) replication-dependent histones, the replication-independent replacement histone variants, as well as the chromatin associated transcriptional regulator MeCP2 (methyl CpG binding protein 2). Alterations of histones and MeCP2 have already been implicated in many brain disorders. Despite the relevance of histone variants to chromatin structure and function, only recently has some exciting literature started to re-emerge that directly relates them to neuron plasticity and cognition. However, the amount of information available on the functional role of these histones is still very limited. The purpose of this review is to focus attention to this important group of chromatin proteins, which, in the brain, possess overlapping structural and functional roles with the highly abundant presence of MeCP2. There is an imperative need to understand how all these proteins communicate with each other, and future research will hopefully provide us with answers.

  11. Characterization of the Relationship of CDKL5 with MeCP2 and Dnmt1 in PrimaryRat Cortical Neurons

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    Zhi Yi

    Full Text Available ABSTRACT Cyclin-dependent kinase-like 5 (CDKL5 is a protein kinase that is homologous to mitogen-activated protein kinases (MAPKs and cyclin-dependent kinases (CDKs. Mutations in the CDKL5 gene cause X-linked infantile spasms and phenotypes that overlap with that of Rett syndrome, which is a neurodevelopmental disorder caused primarily by mutations in the methyl CpG binding protein 2 gene (MECP2. Previous studies in transfected cell lines showed that CDKL5 interacts with MeCP2 and DNA (cytosine-5-methyltransferase 1 (Dnmt1. However, little is known about the relationships of CDKL5 with interacting proteins in primary neuronal cultures. In this study, we investigated the expression patterns of CDKL5, MeCP2 and Dnmt1, and their interaction in cultured rat cortical neurons. Using real-time PCR analysis, we found that CDKL5, MeCP2 and Dnmt1 have similar expression patterns at the mRNA level. In contrast, the expression patterns of those proteins at the protein level are different and could be inversely correlated, as shown by western blotting. Using co-immunoprecipitation, we further demonstrated that CDKL5 interacts with MeCP2 and Dnmt1 in primary rat cortical neurons. These data suggest that a functional link exists among CDKL5, MeCP2 and Dnmt1 during neuronal development and may provide further insight into the pathogenesis of Rett syndrome.

  12. MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation

    Science.gov (United States)

    Agarwal, Noopur; Hardt, Tanja; Brero, Alessandro; Nowak, Danny; Rothbauer, Ulrich; Becker, Annette; Leonhardt, Heinrich; Cardoso, M. Cristina

    2007-01-01

    There is increasing evidence of crosstalk between epigenetic modifications such as histone and DNA methylation, recognized by HP1 and methyl CpG-binding proteins, respectively. We have previously shown that the level of methyl CpG-binding proteins increased dramatically during myogenesis leading to large-scale heterochromatin reorganization. In this work, we show that the level of HP1 isoforms did not change significantly throughout myogenic differentiation but their localization did. In particular, HP1γ relocalization to heterochromatin correlated with MeCP2 presence. Using co-immunoprecipitation assays, we found that these heterochromatic factors interact in vivo via the chromo shadow domain of HP1 and the first 55 amino acids of MeCP2. We propose that this dynamic interaction of HP1 and MeCP2 increases their concentration at heterochromatin linking two major gene silencing pathways to stabilize transcriptional repression during differentiation. PMID:17698499

  13. Updating the profile of C-terminal MECP2 deletions in Rett syndrome

    Science.gov (United States)

    Bebbington, A; Percy, A; Christodoulou, J; Ravine, D; Ho, G; Jacoby, P; Anderson, A; Pineda, M; Ben Zeev, B; Bahi-Buisson, N; Smeets, E; Leonard, H

    2014-01-01

    Objectives This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. Methods Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. Results Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, pmiddle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome. PMID:19914908

  14. Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.

    Science.gov (United States)

    Nectoux, J; Fichou, Y; Rosas-Vargas, H; Cagnard, N; Bahi-Buisson, N; Nusbaum, P; Letourneur, F; Chelly, J; Bienvenu, T

    2010-07-01

    More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.

  15. Network models predict that reduced excitatory fluctuations can give rise to hippocampal network hyper-excitability in MeCP2-null mice.

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    Ernest C Y Ho

    Full Text Available Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2. Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.

  16. Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation.

    Science.gov (United States)

    Bijlsma, E K; Collins, A; Papa, F T; Tejada, M I; Wheeler, P; Peeters, E A J; Gijsbers, A C J; van de Kamp, J M; Kriek, M; Losekoot, M; Broekma, A J; Crolla, J A; Pollazzon, M; Mucciolo, M; Katzaki, E; Disciglio, V; Ferreri, M I; Marozza, A; Mencarelli, M A; Castagnini, C; Dosa, L; Ariani, F; Mari, F; Canitano, R; Hayek, G; Botella, M P; Gener, B; Mínguez, M; Renieri, A; Ruivenkamp, C A L

    2012-06-01

    Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  17. MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle

    Science.gov (United States)

    Zheng, Zhaoqing; Ambigapathy, Ganesh; Keifer, Joyce

    2017-01-01

    MECP2 mutations underlying Rett syndrome cause widespread misregulation of gene expression. Functions for MeCP2 other than transcriptional are not well understood. In an ex vivo brain preparation from the pond turtle Trachemys scripta elegans, an intraexonic splicing event in the brain-derived neurotrophic factor (BDNF) gene generates a truncated mRNA transcript in naïve brain that is suppressed upon classical conditioning. MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naïve but dissociate during conditioning; the dissociation correlating with decreased DNA methylation. Surprisingly, conditioning results in new occupancy of BDNF chromatin by DNA insulator protein CCCTC-binding factor (CTCF), which is associated with suppression of splicing in conditioning. Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing. DOI: http://dx.doi.org/10.7554/eLife.25384.001 PMID:28594324

  18. MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

    DEFF Research Database (Denmark)

    Neupane, Manish; Clark, Allison P.; Landini, Serena

    2016-01-01

    An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers,...

  19. The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site.

    Science.gov (United States)

    Claveria-Gimeno, Rafael; Lanuza, Pilar M; Morales-Chueca, Ignacio; Jorge-Torres, Olga C; Vega, Sonia; Abian, Olga; Esteller, Manel; Velazquez-Campoy, Adrian

    2017-01-31

    Methyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairment. Unstructured regions in MeCP2 provide the plasticity for establishing interactions with multiple binding partners. We present a biophysical characterization of the methyl binding domain (MBD) from MeCP2 reporting the contribution of flanking domains to its structural stability and dsDNA interaction. The flanking disordered intervening domain (ID) increased the structural stability of MBD, modified its dsDNA binding profile from an entropically-driven moderate-affinity binding to an overwhelmingly enthalpically-driven high-affinity binding. Additionally, ID provided an additional site for simultaneously and autonomously binding an independent dsDNA molecule, which is a key feature linked to the chromatin remodelling and looping activity of MeCP2, as well as its ability to interact with nucleosomes replacing histone H1. The dsDNA interaction is characterized by an unusually large heat capacity linked to a cluster of water molecules trapped within the binding interface. The dynamics of disordered regions together with extrinsic factors are key determinants of MeCP2 global structural properties and functional capabilities.

  20. MeCP2 Expression and Promoter Methylation of Cyclin D1 Gene Are Associated with Cyclin D1 Expression in Developing Rat Epididymal Duct

    International Nuclear Information System (INIS)

    Darwanto, Agus; Kitazawa, Riko; Mori, Kiyoshi; Kondo, Takeshi; Kitazawa, Sohei

    2008-01-01

    Hypermethylation-dependent silencing of the gene is achieved by recruiting methyl-CpG binding proteins (MeCPs). Among the MeCPs, MeCP2 is the most abundantly and ubiquitously expressed in various types of cells. We first screened the distribution and expression pattern of MeCP2 in adult and developing rat tissues and found strong MeCP2 expression, albeit rather ubiquitously among normal tissues, in ganglion cells and intestinal epithelium in the small intestine, in Purkinje cells and neurons in the brain, in spermatogonia and in epithelial cells in the epididymal duct of the testis. We then assessed the expression and the methylation pattern of the promoter region of cyclin D1 by immunohistochemistry and sodium bisulfite mapping, and found that cyclin D1 expression in the epididymal duct decreased rapidly during rat development: strong in newborn rats and very weak or almost negative in 7-day-old rats. Mirroring the decrease of cyclin D1 expression, methylated cytosine at both CpG and non-CpG loci in the cyclin D1 promoter was frequently observed in the epididymal duct of 7-day-old rats but not in that of newborn rats. Interestingly, MeCP2 expression also increased concomitant with the increase of methylation. Cyclin D1 expression in the epididymal duct may be efficiently regulated by the epigenetic mechanism of the cooperative increase of MeCP2 expression and promoter methylation

  1. A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections.

    Science.gov (United States)

    Xu, Xiu; Xu, Qiong; Zhang, Ying; Zhang, Xiaodi; Cheng, Tianlin; Wu, Bingbing; Ding, Yanhua; Lu, Ping; Zheng, Jingjing; Zhang, Min; Qiu, Zilong; Yu, Xiang

    2012-08-21

    Autistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism. Here, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2-containing duplication (151,369,305 - 153,589,577) from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy. To our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients.

  2. Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs.

    Science.gov (United States)

    Leoncini, Silvia; De Felice, Claudio; Signorini, Cinzia; Zollo, Gloria; Cortelazzo, Alessio; Durand, Thierry; Galano, Jean-Marie; Guerranti, Roberto; Rossi, Marcello; Ciccoli, Lucia; Hayek, Joussef

    2015-01-01

    An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5-Rett syndrome (CDKL5-RTT) (n = 8), before and after ω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

  3. Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs

    Directory of Open Access Journals (Sweden)

    Silvia Leoncini

    2015-01-01

    Full Text Available An involvement of the immune system has been suggested in Rett syndrome (RTT, a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2 or, more rarely, cyclin-dependent kinase-like 5 (CDKL5. To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg response, as well as chemokines, were investigated in MECP2- (MECP2-RTT (n=16 and CDKL5-Rett syndrome (CDKL5-RTT (n=8, before and after ω-3 polyunsaturated fatty acids (PUFAs supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4 were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

  4. Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.

    Science.gov (United States)

    Plummer, J T; Evgrafov, O V; Bergman, M Y; Friez, M; Haiman, C A; Levitt, P; Aldinger, K A

    2013-10-22

    Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

  5. A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections

    Directory of Open Access Journals (Sweden)

    Xu Xiu

    2012-08-01

    Full Text Available Abstract Background Autistic spectrum disorders (ASDs are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism. Case presentation Here, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2-containing duplication (151,369,305 – 153,589,577 from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy. Conclusions To our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients.

  6. Biophysical characterization of the basic cluster in the transcription repression domain of human MeCP2 with AT-rich DNA.

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    Mushtaq, Ameeq Ul; Lee, Yejin; Hwang, Eunha; Bang, Jeong Kyu; Hong, Eunmi; Byun, Youngjoo; Song, Ji-Joon; Jeon, Young Ho

    2018-01-01

    MeCP2 is a chromatin associated protein which is highly expressed in brain and relevant with Rett syndrome (RTT). There are AT-hook motifs in MeCP2 which can bind with AT-rich DNA, suggesting a role in chromatin binding. Here, we report the identification and characterization of another AT-rich DNA binding motif (residues 295 to 313) from the C-terminal transcription repression domain of MeCP2 by nuclear magnetic resonance (NMR) and isothermal calorimetry (ITC). This motif shows a micromolar affinity to AT-rich DNA, and it binds to the minor groove of DNA like AT-hook motifs. Together with the previous studies, our results provide an insight into a critical role of this motif in chromatin structure and function. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.

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    Livide, Gabriella; Patriarchi, Tommaso; Amenduni, Mariangela; Amabile, Sonia; Yasui, Dag; Calcagno, Eleonora; Lo Rizzo, Caterina; De Falco, Giulia; Ulivieri, Cristina; Ariani, Francesca; Mari, Francesca; Mencarelli, Maria Antonietta; Hell, Johannes Wilhelm; Renieri, Alessandra; Meloni, Ilaria

    2015-02-01

    Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or CDKL5 genes. In spite of their involvement in the same disease, a functional interaction between the two genes has not been proven. MeCP2 is a transcriptional regulator; CDKL5 encodes for a kinase protein that might be involved in the regulation of gene expression. Therefore, we hypothesized that mutations affecting the two genes may lead to similar phenotypes by dysregulating the expression of common genes. To test this hypothesis we used induced pluripotent stem (iPS) cells derived from fibroblasts of one Rett patient with a MECP2 mutation (p.Arg306Cys) and two patients with mutations in CDKL5 (p.Gln347Ter and p.Thr288Ile). Expression profiling was performed in CDKL5-mutated cells and genes of interest were confirmed by real-time RT-PCR in both CDKL5- and MECP2-mutated cells. The only major change in gene expression common to MECP2- and CDKL5-mutated cells was for GRID1, encoding for glutamate D1 receptor (GluD1), a member of the δ-family of ionotropic glutamate receptors. GluD1 does not form AMPA or NMDA glutamate receptors. It acts like an adhesion molecule by linking the postsynaptic and presynaptic compartments, preferentially inducing the inhibitory presynaptic differentiation of cortical neurons. Our results demonstrate that GRID1 expression is downregulated in both MECP2- and CDKL5-mutated iPS cells and upregulated in neuronal precursors and mature neurons. These data provide novel insights into disease pathophysiology and identify possible new targets for therapeutic treatment of Rett syndrome.

  8. Structural, Dynamical, and Energetical Consequences of Rett Syndrome Mutation R133C in MeCP2

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    Tugba G. Kucukkal

    2015-01-01

    Full Text Available Rett Syndrome (RTT is a progressive neurodevelopmental disease affecting females. RTT is caused by mutations in the MECP2 gene and various amino acid substitutions have been identified clinically in different domains of the multifunctional MeCP2 protein encoded by this gene. The R133C variant in the methylated-CpG-binding domain (MBD of MeCP2 is the second most common disease-causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. The mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. The structural, dynamical, and energetical consequences of R133C mutation were investigated in detail at the atomic resolution. Several important implications of this have been shown regarding protein stability and hydration dynamics as well as its interaction with DNA. The results are in agreement with previous experimental studies and further provide atomic level understanding of the molecular origin of RTT associated with R133C variant.

  9. Progressive Encephalopathy in Boys with Symptoms of Rett Syndrome and MECP2 Mutations

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    J Gordon Millichap

    2006-08-01

    Full Text Available Four young boys with neonatal onset of encephalopathy, a progressive course, and MECP2 mutations are reported from the University of Alabama, Birmingham, AL Symptoms suggestive of Rett syndrome included failure to thrive, respiratory insufficiency, microcephaly, hypotonia, movement disorder, with myoclonic, dyskinetic, and choreiform patterns, and repetitive face scratching or nose rubbing stereotypies.

  10. Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice

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    Li, Qun; Degano, Alicia L.; Penati, Judith; Zhuo, Justin; Roe, Charles R.; Ronnett, Gabriele V.

    2014-01-01

    Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT. PMID:25299635

  11. MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males).

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    Maortua, Hiart; Martínez-Bouzas, Cristina; García-Ribes, Ainhoa; Martínez, María-Jesus; Guillen, Encarna; Domingo, María-Rosario; Calvo, María-Teresa; Guitart, Miriam; Gabau, Elisabeth; Botella, María-Pilar; Gener, Blanca; Rubio, Izaskun; López-Aríztegui, María-Asunción; Tejada, María-Isabel

    2013-09-01

    The MECP2 gene located on Xq28 is one of the most important genes contributing to the spectrum of neurodevelopmental disorders. Therefore, we present our experience in the molecular study of this gene. MECP2 was thoroughly tested for the presence of mutations (sequencing of four exons and rearrangements) in 120 female patients: 28 with classic Rett syndrome, five with atypical Rett syndrome, and 87 with heterogeneous phenotypes with some Rett-like features. Another 120 female patients with intellectual disability of unknown origin were also studied, but in these cases we only tested exons 3 and 4. Finally, 861 healthy controls (519 females and 342 males) were also studied for exon 3 and 4. Eighteen different pathological mutations were found, five of them previously undescribed, and four large deletions detected by multiplex ligation-dependent probe amplification. All were de novo mutations not present in the parents. In conclusion, i) MECP2 is one of the most important genes in the diagnosis of genetic intellectual disability in females; ii) MECP2 must be studied not only in patients with classical/atypical Rett syndrome but also in patients with other phenotypes related to Rett syndrome; and iii) for the new variants, it is important to perform complementary studies, including the analysis of large populations of healthy individuals and the use of in silico programs. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  12. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele.

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    Reiterová, Jana; Štekrová, Jitka; Merta, Miroslav; Kotlas, Jaroslav; Elišáková, Veronika; Lněnička, Petr; Korabečná, Marie; Kohoutová, Milada; Tesař, Vladimír

    2013-03-15

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. ADPKD is a systemic disorder with cysts and connective tissue abnormalities involving many organs. ADPKD caused by mutations in PKD1 gene is significantly more severe than the cases caused by PKD2 gene mutations. The large intra-familial variability of ADPKD highlights a role for genetic background. Here we report a case of ADPKD family initially appearing unlinked to the PKD1 or PKD2 loci and the influence of mosaicism and hypomorphic allele on the variability of the clinical course of the disease. A grandmother with the PKD1 gene mutation in mosaicism (p.Val1105ArgfsX4) and with mild clinical course of ADPKD (end stage renal failure at the age of 77) seemed to have ADPKD because of PKD2 gene mutation. On the other hand, her grandson had a severe clinical course (end stage renal disease at the age of 45) in spite of the early treatment of mild hypertension. There was found by mutational analysis of PKD genes that the severe clinical course was caused by PKD1 gene frameshifting mutation inherited from his father and mildly affected grandmother in combination with inherited hypomorphic PKD1 allele with described missense mutation (p.Thr2250Met) from his clinically healthy mother. The sister with two cysts and with PKD1 hypomorphic allele became the kidney donor to her severely affected brother. We present the first case of ADPKD with the influence of mosaicism and hypomorphic allele of the PKD1 gene on clinical course of ADPKD in one family. Moreover, this report illustrates the role of molecular genetic testing in assessing young related kidney donors for patients with ADPKD.

  13. Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia.

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    Baohu Ji

    Full Text Available It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67 in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.

  14. Mecp2 deficiency leads to altered Htr2c pre-mRNA editing and HTR2C isoform distribution in mouse hippocampus and cerebellum

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    Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, a methyl-CpG binding protein and transcriptional repressor. CpG methylation plays an important role in genomic imprinting since imprinted genes are regulated by regions of differentially methylated CpGs (or ICs). A ...

  15. Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.

    Science.gov (United States)

    Hadzsiev, Kinga; Polgar, Noemi; Bene, Judit; Komlosi, Katalin; Karteszi, Judit; Hollody, Katalin; Kosztolanyi, Gyorgy; Renieri, Alessandra; Melegh, Bela

    2011-03-01

    Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C >T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G >T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G >T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

  16. Repression of TSC1/TSC2 mediated by MeCP2 regulates human embryo lung fibroblast cell differentiation and proliferation.

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    Wang, Yuanyuan; Chen, Chen; Deng, Ziyu; Bian, Erbao; Huang, Cheng; Lei, Ting; Lv, Xiongwen; Liu, Liping; Li, Jun

    2017-03-01

    Pulmonary fibrosis (PF) is a severe inflammatory disease with limited effective treatments. It is known that the transdifferentiation of human embryo lung fibroblast (HELF) cells from pulmonary fibroblasts into myofibroblasts, contributes to the progression of pulmonary fibrogenesis. The tuberous sclerosis proteins TSC1 and TSC2 are two key signaling factors which can suppress cell growth and proliferation. However, the roles of TSC1 and TSC2 in lung fibroblast are unclear. Here, we developed a PF model with bleomycin (BLM) in mice and conducted several simulation experiments in HELF cells. Our study shows that the expression of TSC1 and TSC2 in fibrotic mice lung was reduced and stimulation of HELF cells with TGF-β1 resulted in a down-regulation of TSC1 and TSC2. In addition, overexpression of TSC1 or TSC2 decreased cell proliferation and differentiation. Furthermore, we found that reduced expression of TSC1 and TSC2 caused by TGF-β1 is associated with the promoter methylation status of TSC1 and TSC2. MeCP2, controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. We found that expression of TSC1 and TSC2 can be repressed by MeCP2, which regulates HELF cell differentiation and proliferation as myofibroblasts and lead to PF ultimately. Copyright © 2016. Published by Elsevier B.V.

  17. Therapeutic Interference With Vascular Calcification—Lessons From Klotho-Hypomorphic Mice and Beyond

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    Florian Lang

    2018-05-01

    Full Text Available Medial vascular calcification, a major pathophysiological process associated with cardiovascular disease and mortality, involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs. In chronic kidney disease (CKD, osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification is mainly driven by hyperphosphatemia, resulting from impaired elimination of phosphate by the diseased kidneys. Hyperphosphatemia with subsequent vascular calcification is a hallmark of klotho-hypomorphic mice, which are characterized by rapid development of multiple age-related disorders and early death. In those animals, hyperphosphatemia results from unrestrained formation of 1,25(OH2D3 with subsequent retention of calcium and phosphate. Analysis of klotho-hypomorphic mice and mice with vitamin D3 overload uncovered several pathophysiological mechanisms participating in the orchestration of vascular calcification and several therapeutic opportunities to delay or even halt vascular calcification. The present brief review addresses the beneficial effects of bicarbonate, carbonic anhydrase inhibition, magnesium supplementation, mineralocorticoid receptor (MR blockage, and ammonium salts. The case is made that bicarbonate is mainly effective by decreasing intestinal phosphate absorption, and that carbonic anhydrase inhibition leads to metabolic acidosis, which counteracts calcium-phosphate precipitation and VSMC transdifferentiation. Magnesium supplementation, MR blockage and ammonium salts are mainly effective by interference with osteo-/chondrogenic signaling in VSMCs. It should be pointed out that the, by far, most efficient substances are ammonium salts, which may virtually prevent vascular calcification. Future research will probably uncover further therapeutic options and, most importantly, reveal whether these observations in mice can be translated into treatment of patients suffering from vascular calcification, such

  18. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features.

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    Miguet, Marguerite; Faivre, Laurence; Amiel, Jeanne; Nizon, Mathilde; Touraine, Renaud; Prieur, Fabienne; Pasquier, Laurent; Lefebvre, Mathilde; Thevenon, Julien; Dubourg, Christèle; Julia, Sophie; Sarret, Catherine; Remerand, Ganaëlle; Francannet, Christine; Laffargue, Fanny; Boespflug-Tanguy, Odile; David, Albert; Isidor, Bertrand; Vigneron, Jacqueline; Leheup, Bruno; Lambert, Laetitia; Philippe, Christophe; Béri-Dexheimer, Mylène; Cuisset, Jean-Marie; Andrieux, Joris; Plessis, Ghislaine; Toutain, Annick; Guibaud, Laurent; Cormier-Daire, Valérie; Rio, Marlene; Bonnefont, Jean-Paul; Echenne, Bernard; Journel, Hubert; Burglen, Lydie; Chantot-Bastaraud, Sandrine; Bienvenu, Thierry; Baumann, Clarisse; Perrin, Laurence; Drunat, Séverine; Jouk, Pierre-Simon; Dieterich, Klaus; Devillard, Françoise; Lacombe, Didier; Philip, Nicole; Sigaudy, Sabine; Moncla, Anne; Missirian, Chantal; Badens, Catherine; Perreton, Nathalie; Thauvin-Robinet, Christel; AChro-Puce, Réseau; Pedespan, Jean-Michel; Rooryck, Caroline; Goizet, Cyril; Vincent-Delorme, Catherine; Duban-Bedu, Bénédicte; Bahi-Buisson, Nadia; Afenjar, Alexandra; Maincent, Kim; Héron, Delphine; Alessandri, Jean-Luc; Martin-Coignard, Dominique; Lesca, Gaëtan; Rossi, Massimiliano; Raynaud, Martine; Callier, Patrick; Mosca-Boidron, Anne-Laure; Marle, Nathalie; Coutton, Charles; Satre, Véronique; Caignec, Cédric Le; Malan, Valérie; Romana, Serge; Keren, Boris; Tabet, Anne-Claude; Kremer, Valérie; Scheidecker, Sophie; Vigouroux, Adeline; Lackmy-Port-Lis, Marilyn; Sanlaville, Damien; Till, Marianne; Carneiro, Maryline; Gilbert-Dussardier, Brigitte; Willems, Marjolaine; Van Esch, Hilde; Portes, Vincent Des; El Chehadeh, Salima

    2018-04-04

    The Xq28 duplication involving the MECP2 gene ( MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity.

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    Lambert, Sophie; Maystadt, Isabelle; Boulanger, Sébastien; Vrielynck, Pascal; Destrée, Anne; Lederer, Damien; Moortgat, Stéphanie

    2016-10-01

    Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. The Effects of Maternal Separation on Adult Methamphetamine Self-Administration, Extinction, Reinstatement, and MeCP2 Immunoreactivity in the Nucleus Accumbens

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    Candace R. Lewis

    2013-06-01

    Full Text Available The maternal separation (MS paradigm is an animal model of early life stress. Animals subjected to MS during the first two weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA of various drugs of abuse including cocaine, ethanol, opioids, and amphetamine. Methamphetamine (METH causes great harm to both the individual user and to society; yet, no studies have examined the effects of MS on METH SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2 in the nucleus accumbens (NAc core were also investigated. Long-Evans pups and dams were separated on postnatal days (PND 2-14 for either 180 (MS180 or 15 min (MS15. Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion in 15 2-hr daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.

  1. Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities.

    Science.gov (United States)

    Leach, P T; Crawley, J N

    2017-12-20

    Mutant mouse models of neurodevelopmental disorders with intellectual disabilities provide useful translational research tools, especially in cases where robust cognitive deficits are reproducibly detected. However, motor, sensory and/or health issues consequent to the mutation may introduce artifacts that preclude testing in some standard cognitive assays. Touchscreen learning and memory tasks in small operant chambers have the potential to circumvent these confounds. Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2 Bird mouse model of Rett syndrome. Significant deficits in acquisition of a 2-choice visual discrimination task were detected in both Ube3a and Ts65Dn mice. Procedural control measures showed no genotype differences during pretraining phases or during acquisition. Mecp2 males did not survive long enough for touchscreen training, consistent with previous reports. Most Mecp2 females failed on pretraining criteria. Significant impairments on Morris water maze spatial learning were detected in both Ube3a and Ts65Dn, replicating previous findings. Abnormalities on rotarod in Ube3a, and on open field in Ts65Dn, replicating previous findings, may have contributed to the observed acquisition deficits and swim speed abnormalities during water maze performance. In contrast, these motor phenotypes do not appear to have affected touchscreen procedural abilities during pretraining or visual discrimination training. Our findings of slower touchscreen learning in 2 mouse models of neurodevelopmental disorders with intellectual disabilities indicate that operant tasks offer promising outcome measures for the preclinical discovery of effective pharmacological therapeutics. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  2. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

    NARCIS (Netherlands)

    Witteveen, Josefine S.; Willemsen, Marjolein H.; Dombroski, Thais C. D.; van Bakel, Nick H. M.; Nillesen, Willy M.; van Hulten, Josephus A.; Jansen, Eric J. R.; Verkaik, Dave; Veenstra-Knol, Hermine E.; van Ravenswaaij-Arts, Conny M. A.; Wassink-Ruiter, Jolien S. Klein; Vincent, Marie; David, Albert; Le Caignec, Cedric; Schieving, Jolanda; Gilissen, Christian; Foulds, Nicola; Rump, Patrick; Strom, Tim; Cremer, Kirsten; Zink, Alexander M.; Engels, Hartmut; de Munnik, Sonja A.; Visser, Jasper E.; Brunner, Han G.; Martens, Gerard J. M.; Pfundt, Rolph; Kleefstra, Tjitske; Kolk, Sharon M.

    Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder ( ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor

  3. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

    NARCIS (Netherlands)

    Witteveen, J.S.; Willemsen, M.H.; Dombroski, T.C.; Bakel, N.H. van; Nillesen, W.M.; Hulten, J.A. van; Jansen, E.J.; Verkaik, D.; Veenstra-Knol, H.E.; Ravenswaaij-Arts, C.M.A. van; Wassink-Ruiter, J.S.; Vincent, M.; David, A.; Le Caignec, C.; Schieving, J.; Gilissen, C.; Foulds, N.; Rump, P.; Strom, T.; Cremer, K.; Zink, A.M.; Engels, H.; Munnik, S.A. de; Visser, J.E.; Brunner, H.G.; Martens, G.J.; Pfundt, R.P.; Kleefstra, T.; Kolk, S.M.

    2016-01-01

    Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor

  4. Spectrum of MECP2 gene mutations in a cohort of Indian patients with Rett syndrome: report of two novel mutations.

    Science.gov (United States)

    Das, Dhanjit Kumar; Raha, Sarbani; Sanghavi, Daksha; Maitra, Anurupa; Udani, Vrajesh

    2013-02-15

    Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, primarily affecting females and characterized by developmental regression, epilepsy, stereotypical hand movements, and motor abnormalities. Its prevalence is about 1 in 10,000 female births. Rett syndrome is caused by mutations within methyl CpG-binding protein 2 (MECP2) gene. Over 270 individual nucleotide changes which cause pathogenic mutations have been reported. However, eight most commonly occurring missense and nonsense mutations account for almost 70% of all patients. We screened 90 individuals with Rett syndrome phenotype. A total of 19 different MECP2 mutations and polymorphisms were identified in 27 patients. Of the 19 mutations, we identified 7 (37%) frameshift, 6 (31%) nonsense, 14 (74%) missense mutations and one duplication (5%). The most frequent pathogenic changes were: missense p.T158M (11%), p.R133C (7.4%), and p.R306C (7.4%) and nonsense p.R168X (11%), p.R255X (7.4%) mutations. We have identified two novel mutations namely p.385-388delPLPP present in atypical patients and p.Glu290AlafsX38 present in a classical patient of Rett syndrome. Sequence homology for p.385-388delPLPP mutation revealed that these 4 amino acids were conserved across mammalian species. This indicated the importance of these 4 amino acids in structure and function of the protein. A novel variant p.T479T has also been identified in a patient with atypical Rett syndrome. A total of 62 (69%) patients remained without molecular genetics diagnosis that necessitates further search for mutations in other genes like CDKL5 and FOXG1 that are known to cause Rett phenotype. The majority of mutations are detected in exon 4 and only one mutation was present in exon 3. Therefore, our study suggests the need for screening exon 4 of MECP2 as first line of diagnosis in these patients. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex

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    Rocco Piazza

    2013-05-01

    Full Text Available BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2 corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation.

  6. The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

    NARCIS (Netherlands)

    Schonewolf-Greulich, B.; Tejada, M.I.; Stephens, K.; Hadzsiev, K.; Gauthier, J.; Brondum-Nielsen, K.; Pfundt, R.P.; Ravn, K.; Maortua, H.; Gener, B.; Martinez-Bouzas, C.; Piton, A.; Rouleau, G.; Clayton-Smith, J.; Kleefstra, T.; Bisgaard, A.M.; Tumer, Z.

    2016-01-01

    Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair

  7. Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.

    Science.gov (United States)

    Ramírez-Alejo, Noé; Alcántara-Montiel, Julio C; Yamazaki-Nakashimada, Marco; Duran-McKinster, Carola; Valenzuela-León, Paola; Rivas-Larrauri, Francisco; Cedillo-Barrón, Leticia; Hernández-Rivas, Rosaura; Santos-Argumedo, Leopoldo

    2015-10-01

    NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections

    OpenAIRE

    Xu, Xiu; Xu, Qiong; Zhang, Ying; Zhang, Xiaodi; Cheng, Tianlin; Wu, Bingbing; Ding, Yanhua; Lu, Ping; Zheng, Jingjing; Zhang, Min; Qiu, Zilong; Yu, Xiang

    2012-01-01

    Abstract Background Autistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism. Case presentation Here, we identified a Chinese famil...

  9. Structural Effects of Some Relevant Missense Mutations on the MECP2-DNA Binding: A MD Study Analyzed by Rescore+, a Versatile Rescoring Tool of the VEGA ZZ Program.

    Science.gov (United States)

    Pedretti, Alessandro; Granito, Cinzia; Mazzolari, Angelica; Vistoli, Giulio

    2016-09-01

    DNA methylation plays key roles in mammalian cells and is modulated by a set of proteins which recognize symmetrically methylated nucleotides. Among them, the protein MECP2 shows multifunctional roles repressing and/or activating genes by binding to both methylated and unmethylated regions of the genome. The interest for this protein markedly increased from the observation that its mutations are the primary cause of Rett syndrome, a neurodevelopmental disorder which causes mental retardation in young females. Thus, the present study is aimed to investigate the effects of some of these known pathogenic missense mutations (i.e. R106Q, R106W, R111G, R133C and R133H) on the MECP2 folding and DNA binding by molecular dynamics simulations. The effects of the simulated mutations are also parameterized by using a here proposed new tool, named Rescore+, implemented in the VEGA ZZ suite of programs, which calculates a set of scoring functions on all frames of a trajectory or on all complexes contained in a database thus allowing an easy rescoring of results coming from MD or docking simulations. The obtained results revealed that the reported loss of the MECP2 function induced by the simulated mutations can be ascribed to both stabilizing and destabilizing effect on DNA binding. The study confirms that MD simulations are particularly useful to rationalize and predict the mutation effects offering insightful information for diagnostics and drug design. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Novel Hypomorphic Mutation in FANCD2 Gene Observed in a Fetus with Multiple Congenital Anomalies

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    Radoslava Vazharova

    2016-01-01

    Full Text Available Congenital anomalies affect 1% to 2% of the newborns. The urinary tract and the kidneys are involved in 4-5% of the cases while upper-extremities abnormalities are present in 10%. Certain anomalies occur in isolation, whereas others are associated with systemic conditions. The prenatal detection of fetal anomalies compatible with life is a challenge for both the parents and the physician. The prognosis for the fetus/newborn and the reproductive decisions of the family largely depend on the causes underlying the disease. The reported case is of a G2P1 pregnant woman referred for routine ultrasound scan at 24 weeks of gestation (w.g.. The fetus had growth retardation, right kidney agenesis, bilateral absence of radial bones and thumbs, radial deviation of the wrists, and short humeri. Nuchal fold thickness was 5 mm and there was a single umbilical artery. After termination of pregnancy, SNP array genotyping and next-generation sequencing of targeted candidate-genes were performed trying to clarify the etiology of the fetal polymalformative syndrome. A new hypomorphic mutation in FANCD2 gene was found to underlie this fetal anomaly. The case illustrates that patients/families affected by rare monogenic disorders may benefit from application of modern technologies like microarrays and NGS.

  11. The study on morphologic alteration of fetal mice and the change of MeCP2 in fetal brain induced by ionizing radiation

    International Nuclear Information System (INIS)

    Chen Feng; Zhang Fengxiang; Tu Yu

    2012-01-01

    Objective: In order to investigate the effect and the possible mechanism of γ-rays on neuro development of fetal brain tissue as bystander effect organ. Methods: pregnant kunming mice were randomly divided into blank control group, 0.5 Gy whole-body exposed group, 0.5 Gy head exposed group, 1.0 Gy whole-body exposed group, 1.0 Gy head exposed group, 2.0 Gy whole-body exposed group and 2.0 Gy head exposed group. The exposed mice were exposed with a vertical single acute dose using 60 Co therapy apparatus on the 9 th day of pregnancy, and cesarean operation were performed to gain fetal mice on the 18 th day of pregnancy. The number, the size, stillbirth, birth defects and abortion, and get fetal brains from live births were observed. Western-blot assay was used to detect the expression of MeCP2 protein. Results: Compared with the blank control group, the rates of stillbirth, birth defects and abortion ascended as the increase of doses; the expression of MeCP2 were upregulated except 0.5 Gy whole-body exposed group, there were no significant differences between groups. Conclusion: When the pregnant mice were exposed to ionizing radiation in the first trimester, bystander effect in fetal brain tissue was induced, within a certain range, the incidence of deterministic effects and stochastic effects ascended as the increase of doses. (authors)

  12. Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS).

    Science.gov (United States)

    KhorshidAhmad, Tina; Acosta, Crystal; Cortes, Claudia; Lakowski, Ted M; Gangadaran, Surendiran; Namaka, Michael

    2016-03-01

    Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.

  13. The expression of spinal methyl-CpG-binding protein 2, DNA methyltransferases and histone deacetylases is modulated in persistent pain states

    Directory of Open Access Journals (Sweden)

    Tochiki Keri K

    2012-02-01

    Full Text Available Abstract Background DNA CpG methylation is carried out by DNA methyltransferases and induces chromatin remodeling and gene silencing through a transcription repressor complex comprising the methyl-CpG-binding protein 2 (MeCP2 and a subset of histone deacetylases. Recently, we have found that MeCP2 activity had a crucial role in the pattern of gene expression seen in the superficial dorsal horn rapidly after injection of Complete Freund's Adjuvant (CFA in the rat ankle joint. The aim of the present study was to analyse the changes in expression of MeCP2, DNA methyltransferases and a subset of histone deacetylases in the superficial dorsal horn during the maintenance phase of persistent pain states. In this process, the cell specific expression of MeCP2 was also investigated. Results Using immunohistochemistry, we found that neurones, oligodendrocytes and astrocytes expressed MeCP2. Microglia, oligodendrocyte precursor cells and Schwann cells never showed any positive stain for MeCP2. Quantitative analyses showed that MeCP2 expression was increased in the superficial dorsal horn 7 days following CFA injection in the ankle joint but decreased 7 days following spared nerve injury. Overall, the expression of DNA methyltransferases and a subset of histone deacetylases followed the same pattern of expression. However, there were no significant changes in the expression of the MeCP2 targets that we had previously shown are regulated in the early time points following CFA injection in the ankle joint. Finally, the expression of MeCP2 was also down regulated in damaged dorsal root ganglion neurones following spared nerve injury. Conclusion Our results strongly suggest that changes in chromatin compaction, regulated by the binding of MeCP2 complexes to methylated DNA, are involved in the modulation of gene expression in the superficial dorsal horn and dorsal root ganglia during the maintenance of persistent pain states.

  14. EXO1 is critical for embryogenesis and the DNA damage response in mice with a hypomorphic Nbs1 allele.

    Science.gov (United States)

    Rein, Katrin; Yanez, Diana A; Terré, Berta; Palenzuela, Lluís; Aivio, Suvi; Wei, Kaichun; Edelmann, Winfried; Stark, Jeremy M; Stracker, Travis H

    2015-09-03

    The maintenance of genome stability is critical for the suppression of diverse human pathologies that include developmental disorders, premature aging, infertility and predisposition to cancer. The DNA damage response (DDR) orchestrates the appropriate cellular responses following the detection of lesions to prevent genomic instability. The MRE11 complex is a sensor of DNA double strand breaks (DSBs) and plays key roles in multiple aspects of the DDR, including DNA end resection that is critical for signaling and DNA repair. The MRE11 complex has been shown to function both upstream and in concert with the 5'-3' exonuclease EXO1 in DNA resection, but it remains unclear to what extent EXO1 influences DSB responses independently of the MRE11 complex. Here we examine the genetic relationship of the MRE11 complex and EXO1 during mammalian development and in response to DNA damage. Deletion of Exo1 in mice expressing a hypomorphic allele of Nbs1 leads to severe developmental impairment, embryonic death and chromosomal instability. While EXO1 plays a minimal role in normal cells, its loss strongly influences DNA replication, DNA repair, checkpoint signaling and damage sensitivity in NBS1 hypomorphic cells. Collectively, our results establish a key role for EXO1 in modulating the severity of hypomorphic MRE11 complex mutations. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. Astrocyte-specific regulation of hMeCP2 expression in Drosophila

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    David L. Hess-Homeier

    2014-10-01

    Full Text Available Alterations in the expression of Methyl-CpG-binding protein 2 (MeCP2 either by mutations or gene duplication leads to a wide spectrum of neurodevelopmental disorders including Rett Syndrome and MeCP2 duplication disorder. Common features of Rett Syndrome (RTT, MeCP2 duplication disorder, and neuropsychiatric disorders indicate that even moderate changes in MeCP2 protein levels result in functional and structural cell abnormalities. In this study, we investigated two areas of MeCP2 pathophysiology using Drosophila as a model system: the effects of MeCP2 glial gain-of-function activity on circuits controlling sleep behavior, and the cell-type specific regulation of MeCP2 expression. In this study, we first examined the effects of elevated MeCP2 levels on microcircuits by expressing human MeCP2 (hMeCP2 in astrocytes and distinct subsets of amine neurons including dopamine and octopamine (OA neurons. Depending on the cell-type, hMeCP2 expression reduced sleep levels, altered daytime/nighttime sleep patterns, and generated sleep maintenance deficits. Second, we identified a 498 base pair region of the MeCP2e2 isoform that is targeted for regulation in distinct subsets of astrocytes. Levels of the full-length hMeCP2e2 and mutant RTT R106W protein decreased in astrocytes in a temporally and spatially regulated manner. In contrast, expression of the deletion Δ166 hMeCP2 protein was not altered in the entire astrocyte population. qPCR experiments revealed a reduction in full-length hMeCP2e2 transcript levels suggesting transgenic hMeCP2 expression is regulated at the transcriptional level. Given the phenotypic complexities that are caused by alterations in MeCP2 levels, our results provide insight into distinct cellular mechanisms that control MeCP2 expression and link microcircuit abnormalities with defined behavioral deficits.

  16. Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure*

    Science.gov (United States)

    Becker, Annette; Zhang, Peng; Allmann, Lena; Meilinger, Daniela; Bertulat, Bianca; Eck, Daniel; Hofstaetter, Maria; Bartolomei, Giody; Hottiger, Michael O.; Schreiber, Valérie; Leonhardt, Heinrich; Cardoso, M. Cristina

    2016-01-01

    The epigenetic information encoded in the genomic DNA methylation pattern is translated by methylcytosine binding proteins like MeCP2 into chromatin topology and structure and gene activity states. We have shown previously that the MeCP2 level increases during differentiation and that it causes large-scale chromatin reorganization, which is disturbed by MeCP2 Rett syndrome mutations. Phosphorylation and other posttranslational modifications of MeCP2 have been described recently to modulate its function. Here we show poly(ADP-ribosyl)ation of endogenous MeCP2 in mouse brain tissue. Consequently, we found that MeCP2 induced aggregation of pericentric heterochromatin and that its chromatin accumulation was enhanced in poly(ADP-ribose) polymerase (PARP) 1−/− compared with wild-type cells. We mapped the poly(ADP-ribosyl)ation domains and engineered MeCP2 mutation constructs to further analyze potential effects on DNA binding affinity and large-scale chromatin remodeling. Single or double deletion of the poly(ADP-ribosyl)ated regions and PARP inhibition increased the heterochromatin clustering ability of MeCP2. Increased chromatin clustering may reflect increased binding affinity. In agreement with this hypothesis, we found that PARP-1 deficiency significantly increased the chromatin binding affinity of MeCP2 in vivo. These data provide novel mechanistic insights into the regulation of MeCP2-mediated, higher-order chromatin architecture and suggest therapeutic opportunities to manipulate MeCP2 function. PMID:26772194

  17. A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development.

    Directory of Open Access Journals (Sweden)

    Philip J Byrd

    2016-03-01

    Full Text Available Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi anaemia (FA-N, with a predisposition for developing embryonal-type tumours in infancy. Here we describe two unusual patients from a single family, carrying biallelic PALB2 mutations, one truncating, c.1676_1677delAAinsG;(p.Gln559ArgfsTer2, and the second, c.2586+1G>A; p.Thr839_Lys862del resulting in an in frame skip of exon 6 (24 amino acids. Strikingly, the affected individuals did not exhibit the severe developmental defects typical of FA-N patients and initially presented with B cell non-Hodgkin lymphoma. The expressed p.Thr839_Lys862del mutant PALB2 protein retained the ability to interact with BRCA2, previously unreported in FA-N patients. There was also a large increased chromosomal radiosensitivity following irradiation in G2 and increased sensitivity to mitomycin C. Although patient cells were unable to form Rad51 foci following exposure to either DNA damaging agent, U2OS cells, in which the mutant PALB2 with in frame skip of exon 6 was induced, did show recruitment of Rad51 to foci following damage. We conclude that a very mild form of FA-N exists arising from a hypomorphic PALB2 allele.

  18. Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: a hippocampal proteomic study in mice.

    Directory of Open Access Journals (Sweden)

    Jarrah R Spencer

    2013-02-01

    Full Text Available Neuregulin 1 (NRG1 is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for Nrg1 (Nrg1 HET mice display schizophrenia-relevant behavioural phenotypes and aberrant expression of serotonin and glutamate receptors. Nrg1 HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC. To gain traction on the molecular pathways disrupted by Nrg1 hypomorphism and Nrg1-cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT and Nrg1 HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and Nrg1 HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with Nrg1. These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and; proteins affecting growth factor expression. Nrg1 HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent Nrg1 HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover for the first time novel proteins altered in response to Nrg1 hypomorphism and Nrg1-cannabinoid interactions that improves our molecular understanding of Nrg1 signaling and Nrg1-mediated genetic vulnerability to the neurobehavioural effects

  19. Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei

    Energy Technology Data Exchange (ETDEWEB)

    Begley, Darren W.; Hartley, Robert C.; Davies, Douglas R.; Edwards, Thomas E.; Leonard, Jess T.; Abendroth, Jan; Burris, Courtney A.; Bhandari, Janhavi; Myler, Peter J.; Staker, Bart L.; Stewart, Lance J. (UWASH); (Emerald)

    2011-09-28

    As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification of several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme.

  20. Hypomorphic Smn knockdown C2C12 myoblasts reveal intrinsic defects in myoblast fusion and myotube morphology

    International Nuclear Information System (INIS)

    Shafey, Dina; Cote, Patrice D.; Kothary, Rashmi

    2005-01-01

    Dosage of the survival motor neuron (SMN) protein has been directly correlated with the severity of disease in patients diagnosed with spinal muscular atrophy (SMA). It is also clear that SMA is a neurodegenerative disorder characterized by the degeneration of the α-motor neurons in the anterior horn of the spinal cord and atrophy of the associated skeletal muscle. What is more controversial is whether it is neuronal and/or muscle-cell-autonomous defects that are responsible for the disease per se. Although motor neuron degeneration is generally accepted as the primary event in SMA, intrinsic muscle defects in this disease have not been ruled out. To gain a better understanding of the influence of SMN protein dosage in muscle, we have generated a hypomorphic series of myoblast (C2C12) stable cell lines with variable Smn knockdown. We show that depletion of Smn in these cells resulted in a decrease in the number of nuclear 'gems' (gemini of coiled bodies), reduced proliferation with no increase in cell death, defects in myoblast fusion, and malformed myotubes. Importantly, the severity of these abnormalities is directly correlated with the decrease in Smn dosage. Taken together, our work supports the view that there is an intrinsic defect in skeletal muscle cells of SMA patients and that this defect contributes to the overall pathogenesis in this devastating disease

  1. Tyr120Asp mutation alters domain flexibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: Atomistic characterization of a Rett syndrome causing mutation.

    Science.gov (United States)

    D'Annessa, Ilda; Gandaglia, Anna; Brivio, Elena; Stefanelli, Gilda; Frasca, Angelisa; Landsberger, Nicoletta; Di Marino, Daniele

    2018-05-01

    Mutations in the X-linked MECP2 gene represent the main origin of Rett syndrome, causing a profound intellectual disability in females. MeCP2 is an epigenetic transcriptional regulator containing two main functional domains: a methyl-CpG binding domain (MBD) and a transcription repression domain (TRD). Over 600 pathogenic mutations were reported to affect the whole protein; almost half of missense mutations affect the MBD. Understanding the impact of these mutations on the MBD structure and interaction with DNA will foster the comprehension of their pathogenicity and possibly genotype/phenotype correlation studies. Herein, we use molecular dynamics simulations to obtain a detailed view of the dynamics of WT and mutated MBD in the presence and absence of DNA. The pathogenic mutation Y120D is used as paradigm for our studies. Further, since the Y120 residue was previously found to be a phosphorylation site, we characterize the dynamic profile of the MBD also in the presence of Y120 phosphorylation (pY120). We found that addition of a phosphate group to Y120 or mutation in aspartic acid affect domain mobility that samples an alternative conformational space with respect to the WT, leading to impaired ability to interact with DNA. Experimental assays showing a significant reduction in the binding affinity between the mutated MBD and the DNA confirmed our predictions. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis.

    Science.gov (United States)

    Herrera, José A; Ward, Christopher S; Wehrens, Xander H T; Neul, Jeffrey L

    2016-11-15

    Sudden unexpected death occurs in one quarter of deaths in Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). People with RTT show a variety of autonomic nervous system (ANS) abnormalities and mouse models show similar problems including QTc interval prolongation and hypothermia. To explore the role of cardiac problems in sudden death in RTT, we characterized cardiac rhythm in mice lacking Mecp2 function. Male and female mutant mice exhibited spontaneous cardiac rhythm abnormalities including bradycardic events, sinus pauses, atrioventricular block, premature ventricular contractions, non-sustained ventricular arrhythmias, and increased heart rate variability. Death was associated with spontaneous cardiac arrhythmias and complete conduction block. Atropine treatment reduced cardiac arrhythmias in mutant mice, implicating overactive parasympathetic tone. To explore the role of MeCP2 within the parasympathetic neurons, we selectively removed MeCP2 function from cholinergic neurons (MeCP2 ChAT KO), which recapitulated the cardiac rhythm abnormalities, hypothermia, and early death seen in RTT male mice. Conversely, restoring MeCP2 only in cholinergic neurons rescued these phenotypes. Thus, MeCP2 in cholinergic neurons is necessary and sufficient for autonomic cardiac control, thermoregulation, and survival, and targeting the overactive parasympathetic system may be a useful therapeutic strategy to prevent sudden unexpected death in RTT.

  3. Progressive cerebellar degenerative changes in the severe mental retardation syndrome caused by duplication of MECP2 and adjacent loci on Xq28.

    LENUS (Irish Health Repository)

    Reardon, William

    2010-08-01

    Localised duplications, involving the MECP2 locus, at Xq28 have been associated with a syndrome comprising X-linked mental retardation, hypotonia and recurrent infections in males. We now present neuroradiological evidence that progressive cerebellar degenerative changes may also be a consistent feature of this syndrome, emerging in the second decade of life. We report seven affected males, from three different families who, in addition to the previously described clinical findings, have a reduction in the volume of the white matter and mild dilatation of the lateral ventricles. Three of the older patients show a consistent cerebellar degenerative phenotype. Furthermore, we describe the first female affected with the disorder. The female was mildly affected and shows X-inactivation in the ratio of 70:30, demonstrating that X-inactivation cannot be exclusively relied upon to spare the female carriers from symptoms. In conclusion, there is a radiological phenotype associated with Xq28 duplication which clearly demonstrates progressive degenerative cerebellar disease as part of the syndrome.

  4. [Relationship and interaction between folate and expression of methyl-CpG-binding protein 2 in cervical cancerization].

    Science.gov (United States)

    Li, Q L; Ding, L; Nan, J; Liu, C L; Yang, Z K; Chen, F; Liang, Y L; Wang, J T

    2016-07-01

    To explore the interaction between folate and the expression of methyl-CpG-binding protein 2(MeCP2)in cervical cancerization. Forty one patients diagnosed with cervical squamous cell carcinoma(SCC), 71 patients diagnosed with cervical intraepithelial neoplasm(CIN1, n=34; CIN2 +, n=37)and 61 women with normal cervix(NC)were recruited in this study. Microbiological assay was conducted to detect the levels of serum folate and RBC folate, Western blot assay and real-time PCR were performed to detect the expression levels of MeCP2 protein and mRNA, respectively. The data were analyzed by Kruskal-Wallis H test, χ(2) test, trend χ(2) test and Spearman correlation with SPSS statistical software(version 20.0), and the interaction were evaluated by using generalized multifactor dimensionality reduction(GMDR)model. The levels of serum folate(H=44.71, Pfolate(H=5.28, Pfolate level and RBC folate level(r=0.270, Pfolate level and the expression level of MeCP2 protein(serum folate: r=-0.226, P=0.003; RBC folate: r=-0.164, P=0.004). Moreover, the results by GMDR model revealed there were interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and MeCP2 mRNA high expression in SCC and CIN2 + patients. Folate deficiency and high expression of MeCP2 gene might increase the risk of cervical cancer and its precancerous lesions through interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and mRNA high expression in the progression of cervical cancerization.

  5. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.

    Science.gov (United States)

    Witteveen, Josefine S; Willemsen, Marjolein H; Dombroski, Thaís C D; van Bakel, Nick H M; Nillesen, Willy M; van Hulten, Josephus A; Jansen, Eric J R; Verkaik, Dave; Veenstra-Knol, Hermine E; van Ravenswaaij-Arts, Conny M A; Wassink-Ruiter, Jolien S Klein; Vincent, Marie; David, Albert; Le Caignec, Cedric; Schieving, Jolanda; Gilissen, Christian; Foulds, Nicola; Rump, Patrick; Strom, Tim; Cremer, Kirsten; Zink, Alexander M; Engels, Hartmut; de Munnik, Sonja A; Visser, Jasper E; Brunner, Han G; Martens, Gerard J M; Pfundt, Rolph; Kleefstra, Tjitske; Kolk, Sharon M

    2016-08-01

    Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.

  6. The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.

    Science.gov (United States)

    Schönewolf-Greulich, B; Tejada, M-I; Stephens, K; Hadzsiev, K; Gauthier, J; Brøndum-Nielsen, K; Pfundt, R; Ravn, K; Maortua, H; Gener, B; Martínez-Bouzas, C; Piton, A; Rouleau, G; Clayton-Smith, J; Kleefstra, T; Bisgaard, A-M; Tümer, Z

    2016-06-01

    Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/- mice, using liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Forrest, Caroline M; Kennedy, Peter G E; Rodgers, Jean; Dalton, R Neil; Turner, Charles; Darlington, L Gail; Cobb, Stuart R; Stone, Trevor W

    2016-11-01

    To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography - tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment. At 24 h there was also a strong trend to an increase in quinolinic acid levels (P = 0.055). No significant changes were observed in any of the other kynurenine metabolites. The results confirm the marked increase in the accumulation of some neuroactive kynurenines when KMO is inhibited, and re-emphasise the potential importance of changes in anthranilic acid. The prolonged duration of metabolite accumulation in the embryo brains indicates a trapping of compounds within the embryonic CNS independently of maternal levels. When brains were examined from young mice heterozygous for the meCP2 gene - a potential model for Rett syndrome - no differences were noted from control mice, suggesting that the proposed roles for kynurenines in autism spectrum disorder are not relevant to Rett syndrome, supporting its recognition as a distinct, independent, condition. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Reactivation of CDX2 in Gastric Cancer as Mark for Gene Silencing Memory

    International Nuclear Information System (INIS)

    Kameoka, Yuri; Kitazawa, Riko; Ariasu, Kanazu; Tachibana, Ryosuke; Mizuno, Yosuke; Haraguchi, Ryuma; Kitazawa, Sohei

    2015-01-01

    To explore the epigenetic mechanism that reactivates CDX2 (a homeobox transcription factor that serves as a tumor-suppressor gene) in intestinal-type gastric cancer during cancer progression, we examined the methylation status of the CDX2 gene promoter and the expression pattern of methyl-CpG binding protein-2 (MeCP2). From archives of the pathology records of surgically excised advanced stomach cancer cases in the Department of Molecular Pathology, Ehime University in a past decate (n=265), 10 cases of intestinal-type tubular adenocarcinoma, well-differentiated type (wel) with minor poorly-differentiated adenocarcinoma (por) components were selected. The expression pattern of CDX2, MUC2 and MeCP2 in these 10 cases was analyzed by immunohistochemistry. The cancerous and non-cancerous areas were selectively obtained by microdissection, and the methylation status of the CDX2 promoter of each area was assessed by methylation-specific polymerase chain reaction (MSP). In all 10 cases, CDX2 expression was clearly observed in the nucleus of the non-cancerous background of the intestinal metaplasic area, where the unmethylation pattern of the CDX2 gene promoter prevailed with reduced MeCP2 expression. In this metaplastic area, CDX2 expression was co-localized with its target gene, MUC2. CDX2 expression then disappeared from the deep invasive wel area. Reflecting the reduced CDX2 expression, microdissected samples from all the wel areas showed hypermethylation of the CDX2 gene promoter by MSP, with prominent MeCP2 expression. Interestingly, while hypermethylation of the CDX2 gene promoter was maintained in the por area in 8 of the 10 cases, CDX2 expression was restored in por areas where MeCP2 expression was markedly and selectively reduced. The other two cases, however, showed a constant MeCP2 expression level comparable to the surrounding deep invasive wel area with negative CDX2 expression. Therefore, gene silencing by hypermethylation may be overcome by the reduction of

  9. Downstream targets of methyl CpG binding protein 2 and their abnormal expression in the frontal cortex of the human Rett syndrome brain

    Directory of Open Access Journals (Sweden)

    Minchenko Dimitri

    2010-04-01

    Full Text Available Abstract Background The Rett Syndrome (RTT brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected. Results Using microarrays and quantitative PCR, the mRNA expression profiles of these two neuroanatomical regions were compared in postmortem brain tissue from RTT patients and normal controls. A subset of genes was differentially expressed in the frontal cortex of RTT brains, some of which are known to be associated with neurological disorders (clusterin and cytochrome c oxidase subunit 1 or are involved in synaptic vesicle cycling (dynamin 1. RNAi-mediated knockdown of MeCP2 in vitro, followed by further expression analysis demonstrated that the same direction of abnormal expression was recapitulated with MeCP2 knockdown, which for cytochrome c oxidase subunit 1 was associated with a functional respiratory chain defect. Chromatin immunoprecipitation (ChIP analysis showed that MeCP2 associated with the promoter regions of some of these genes suggesting that loss of MeCP2 function may be responsible for their overexpression. Conclusions This study has shed more light on the subset of aberrantly expressed genes that result from MECP2 mutations. The mitochondrion has long been implicated in the pathogenesis of RTT, however it has not been at the forefront of RTT research interest since the discovery of MECP2 mutations. The functional consequence of the underexpression of cytochrome c oxidase subunit 1 indicates that this is an area that should be revisited.

  10. PIF1 disruption or NBS1 hypomorphism does not affect chromosome healing or fusion resulting from double-strand breaks near telomeres in murine embryonic stem cells.

    Science.gov (United States)

    Reynolds, Gloria E; Gao, Qing; Miller, Douglas; Snow, Bryan E; Harrington, Lea A; Murnane, John P

    2011-11-10

    Telomerase serves to maintain telomeric repeat sequences at the ends of chromosomes. However, telomerase can also add telomeric repeat sequences at DNA double-strand breaks (DSBs), a process called chromosome healing. Here, we employed a method of inducing DSBs near telomeres to query the role of two proteins, PIF1 and NBS1, in chromosome healing in mammalian cells. PIF1 was investigated because the PIF1 homolog in Saccharomyces cerevisiae inhibits chromosome healing, as shown by a 1000-fold increase in chromosome in PIF1-deficient cells. NBS1 was investigated because the functional homolog of NBS1 in S. cerevisiae, Xrs2, is part of the Mre11/Rad50/Xrs2 complex that is required for chromosome healing due to its role in the processing of DSBs and recruitment of telomerase. We found that disruption of mPif1 had no detectable effect on the frequency of chromosome healing at DSBs near telomeres in murine embryonic stem cells. Moreover, the Nbs1(ΔB) hypomorph, which is defective in the processing of DSBs, also had no detectable effect on the frequency of chromosome healing, DNA degradation, or gross chromosome rearrangements (GCRs) that result from telomeric DSBs. Although we cannot rule out small changes in chromosome healing using this system, it is clear from our results that knockout of PIF1 or the Nbs1(ΔB) hypomorph does not result in large differences in chromosome healing in murine cells. These results represent the first genetic assessment of the role of these proteins in chromosome healing in mammals, and suggest that murine cells have evolved mechanisms to ensure the functional redundancy of Pif1 or Nbs1 in the regulation of chromosome healing. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Hypomorphic mutation in mouse Nppc gene causes retarded bone growth due to impaired endochondral ossification

    International Nuclear Information System (INIS)

    Tsuji, Takehito; Kondo, Eri; Yasoda, Akihiro; Inamoto, Masataka; Kiyosu, Chiyo; Nakao, Kazuwa; Kunieda, Tetsuo

    2008-01-01

    Long bone abnormality (lbab/lbab) is a spontaneous mutant mouse characterized by dwarfism with shorter long bones. A missense mutation was reported in the Nppc gene, which encodes C-type natriuretic peptide (CNP), but it has not been confirmed whether this mutation is responsible for the dwarf phenotype. To verify that the mutation causes the dwarfism of lbab/lbab mice, we first investigated the effect of CNP in lbab/lbab mice. By transgenic rescue with chondrocyte-specific expression of CNP, the dwarf phenotype in lbab/lbab mice was completely compensated. Next, we revealed that CNP derived from the lbab allele retained only slight activity to induce cGMP production through its receptor. Histological analysis showed that both proliferative and hypertrophic zones of chondrocytes in the growth plate of lbab/lbab mice were markedly reduced. Our results demonstrate that lbab/lbab mice have a hypomorphic mutation in the Nppc gene that is responsible for dwarfism caused by impaired endochondral ossification

  12. Feed efficiency of diets with different energy and protein concentrations supplemented with methionine in laying quails

    Science.gov (United States)

    Ratriyanto, A.; Indreswari, R.; Nuhriawangsa, A. M. P.; Purwanti, E.

    2018-03-01

    The study was conducted to evaluate the feed efficiency of quail diets containing different concentrations of metabolizable energy (ME) and crude protein (CP) with constant ratio and supplemented with methionine. Four hundred laying quails (Coturnix coturnix japonica) were randomly assigned to four experimental diets in a 2×2 factorial arrangement. Each dietary treatment used 5 replicates of 20 quails. Two basal diets were formulated to contain 2,800 kcal kg-1 ME and 18.7% CP (High ME-CP) and 2,600 kcal kg-1 ME and 17.3% CP (Low ME-CP). Each basal diet was supplemented with 0 and 0.12% methionine. The High ME-CP diets generated lower feed consumption but higher egg mass and feed efficiency (Pprotein efficiency ratio (PHigh ME-CP supplemented with methionine resulted the highest feed efficiency followed by the Low ME-CP supplemented with methionine, while both High ME-CP and Low ME-CP without methionine supplementation resulted the lowest feed efficiency (PHigh ME-CP supplemented with 0.12% methionine provided benefit to improve the feed efficiency in laying quails.

  13. Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.

    Directory of Open Access Journals (Sweden)

    Ronghui Li

    2016-06-01

    Full Text Available Mutations in the human MECP2 gene cause Rett syndrome (RTT, a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies.

  14. Compound heterozygosity of the functionally null Cdh23(v-ngt) and hypomorphic Cdh23(ahl) alleles leads to early-onset progressive hearing loss in mice.

    Science.gov (United States)

    Miyasaka, Yuki; Suzuki, Sari; Ohshiba, Yasuhiro; Watanabe, Kei; Sagara, Yoshihiko; Yasuda, Shumpei P; Matsuoka, Kunie; Shitara, Hiroshi; Yonekawa, Hiromichi; Kominami, Ryo; Kikkawa, Yoshiaki

    2013-01-01

    The waltzer (v) mouse mutant harbors a mutation in Cadherin 23 (Cdh23) and is a model for Usher syndrome type 1D, which is characterized by congenital deafness, vestibular dysfunction, and prepubertal onset of progressive retinitis pigmentosa. In mice, functionally null Cdh23 mutations affect stereociliary morphogenesis and the polarity of both cochlear and vestibular hair cells. In contrast, the murine Cdh23(ahl) allele, which harbors a hypomorphic mutation, causes an increase in susceptibility to age-related hearing loss in many inbred strains. We produced congenic mice by crossing mice carrying the v niigata (Cdh23(v-ngt)) null allele with mice carrying the hypomorphic Cdh23(ahl) allele on the C57BL/6J background, and we then analyzed the animals' balance and hearing phenotypes. Although the Cdh23(v-ngt/ahl) compound heterozygous mice exhibited normal vestibular function, their hearing ability was abnormal: the mice exhibited higher thresholds of auditory brainstem response (ABR) and rapid age-dependent elevation of ABR thresholds compared with Cdh23(ahl/ahl) homozygous mice. We found that the stereocilia developed normally but were progressively disrupted in Cdh23(v-ngt/ahl) mice. In hair cells, CDH23 localizes to the tip links of stereocilia, which are thought to gate the mechanoelectrical transduction channels in hair cells. We hypothesize that the reduction of Cdh23 gene dosage in Cdh23(v-ngt/ahl) mice leads to the degeneration of stereocilia, which consequently reduces tip link tension. These findings indicate that CDH23 plays an important role in the maintenance of tip links during the aging process.

  15. Altered poly(ADP-ribose) metabolism impairs cellular responses to genotoxic stress in a hypomorphic mutant of poly(ADP-ribose) glycohydrolase

    International Nuclear Information System (INIS)

    Gao Hong; Coyle, Donna L.; Meyer-Ficca, Mirella L.; Meyer, Ralph G.; Jacobson, Elaine L.; Wang, Zhao-Qi; Jacobson, Myron K.

    2007-01-01

    Genotoxic stress activates nuclear poly(ADP-ribose) (PAR) metabolism leading to PAR synthesis catalyzed by DNA damage activated poly(ADP-ribose) polymerases (PARPs) and rapid PAR turnover by action of nuclear poly(ADP-ribose) glycohydrolase (PARG). The involvement of PARP-1 and PARP-2 in responses to DNA damage has been well studied but the involvement of nuclear PARG is less well understood. To gain insights into the function of nuclear PARG in DNA damage responses, we have quantitatively studied PAR metabolism in cells derived from a hypomorphic mutant mouse model in which exons 2 and 3 of the PARG gene have been deleted (PARG-Δ2,3 cells), resulting in a nuclear PARG containing a catalytic domain but lacking the N-terminal region (A domain) of the protein. Following DNA damage induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we found that the activity of both PARG and PARPs in intact cells is increased in PARG-Δ2,3 cells. The increased PARG activity leads to decreased PARP-1 automodification with resulting increased PARP activity. The degree of PARG activation is greater than PARP, resulting in decreased PAR accumulation. Following MNNG treatment, PARG-Δ2,3 cells show reduced formation of XRCC1 foci, delayed H2AX phosphorylation, decreased DNA break intermediates during repair, and increased cell death. Our results show that a precise coordination of PARPs and PARG activities is important for normal cellular responses to DNA damage and that this coordination is defective in the absence of the PARG A domain

  16. Disease: H01211 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H01211 MECP2-related severe neonatal encephalopathy MECP2-related severe neonatal encephalopathy... is a rare disorder of males characterized by a static encephalopathy, severe developmental de...BC ... TITLE ... MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and

  17. Methyl CpG–binding proteins induce large-scale chromatin reorganization during terminal differentiation

    Science.gov (United States)

    Brero, Alessandro; Easwaran, Hariharan P.; Nowak, Danny; Grunewald, Ingrid; Cremer, Thomas; Leonhardt, Heinrich; Cardoso, M. Cristina

    2005-01-01

    Pericentric heterochromatin plays an important role in epigenetic gene regulation. We show that pericentric heterochromatin aggregates during myogenic differentiation. This clustering leads to the formation of large chromocenters and correlates with increased levels of the methyl CpG–binding protein MeCP2 and pericentric DNA methylation. Ectopic expression of fluorescently tagged MeCP2 mimicked this effect, causing a dose-dependent clustering of chromocenters in the absence of differentiation. MeCP2-induced rearrangement of heterochromatin occurred throughout interphase, did not depend on the H3K9 histone methylation pathway, and required the methyl CpG–binding domain (MBD) only. Similar to MeCP2, another methyl CpG–binding protein, MBD2, also increased during myogenic differentiation and could induce clustering of pericentric regions, arguing for functional redundancy. This MeCP2- and MBD2-mediated chromatin reorganization may thus represent a molecular link between nuclear genome topology and the epigenetic maintenance of cellular differentiation. PMID:15939760

  18. CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice

    Directory of Open Access Journals (Sweden)

    Shivakumar Subbanna

    2018-02-01

    Full Text Available Alcohol exposure can affect brain development, leading to long-lasting behavioral problems, including cognitive impairment, which together is defined as fetal alcohol spectrum disorder (FASD. However, the fundamental mechanisms through which this occurs are largely unknown. In this study, we report that the exposure of postnatal day 7 (P7 mice to ethanol activates caspase-3 via cannabinoid receptor type-1 (CB1R in neonatal mice and causes a reduction in methylated DNA binding protein (MeCP2 levels. The developmental expression of MeCP2 in mice is closely correlated with synaptogenesis and neuronal maturation. It was shown that ethanol treatment of P7 mice enhanced Mecp2 mRNA levels but reduced protein levels. The genetic deletion of CB1R prevented, and administration of a CB1R antagonist before ethanol treatment of P7 mice inhibited caspase-3 activation. Additionally, it reversed the loss of MeCP2 protein, cAMP response element binding protein (CREB activation, and activity-regulated cytoskeleton-associated protein (Arc expression. The inhibition of caspase-3 activity prior to ethanol administration prevented ethanol-induced loss of MeCP2, CREB activation, epigenetic regulation of Arc expression, long-term potentiation (LTP, spatial memory deficits and activity-dependent impairment of several signaling molecules, including MeCP2, in adult mice. Collectively, these results reveal that the ethanol-induced CB1R-mediated activation of caspase-3 degrades the MeCP2 protein in the P7 mouse brain and causes long-lasting neurobehavioral deficits in adult mice. This CB1R-mediated instability of MeCP2 during active synaptic maturation may disrupt synaptic circuit maturation and lead to neurobehavioral abnormalities, as observed in this animal model of FASD.

  19. Rett syndrome: a neurological disorder with metabolic components

    Science.gov (United States)

    Kyle, Stephanie M.

    2018-01-01

    Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome. PMID:29445033

  20. Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity.

    Science.gov (United States)

    Kondo, Mari A; Gray, Laura J; Pelka, Gregory J; Leang, Sook-Kwan; Christodoulou, John; Tam, Patrick P L; Hannan, Anthony J

    2016-02-01

    Rett syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) and consequent dysregulation of brain maturation. Patients suffer from a range of debilitating physical symptoms, however, behavioral and emotional symptoms also severely affect their quality of life. Here, we present previously unreported and clinically relevant affective dysfunction in the female heterozygous Mecp2(tm1Tam) mouse model of RTT (129sv and C57BL6 mixed background). The affective dysfunction and aberrant anxiety-related behavior of the Mecp2(+/-) mice were found to be reversible with environmental enrichment (EE) from 4 weeks of age. The effect of exercise alone (via wheel running) was also explored, providing the first evidence that increased voluntary physical activity in an animal model of RTT is beneficial for some phenotypes. Mecp2(+/-) mutants displayed elevated corticosterone despite decreased Crh expression, demonstrating hypothalamic-pituitary-adrenal axis dysregulation. EE of Mecp2(+/-) mice normalized basal serum corticosterone and hippocampal BDNF protein levels. The enrichment-induced rescue appears independent of the transcriptional regulation of the MeCP2 targets Bdnf exon 4 and Crh. These findings provide new insight into the neurodevelopmental role of MeCP2 and pathogenesis of RTT, in particular the affective dysfunction. The positive outcomes of environmental stimulation and physical exercise have implications for the development of therapies targeting the affective symptoms, as well as behavioral and cognitive dimensions, of this devastating neurodevelopmental disorder. © 2015 Wiley Periodicals, Inc.

  1. Experiment list: SRX669239 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available alance, and learn motor skills. 29340926,92.8,32.0,493 GSM1464567: MeCP2IP MeCP2 ChIP Cerebellum2; Mus muscu... cerebellar nuclei. Its function is to coordinate voluntary movements, maintain b

  2. Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes.

    Science.gov (United States)

    Challa, Anil K; Boitet, Evan R; Turner, Ashley N; Johnson, Larry W; Kennedy, Daniel; Downs, Ethan R; Hymel, Katherine M; Gross, Alecia K; Kesterson, Robert A

    2016-01-01

    Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr) cause oculocutaneous albinism (OCA1) in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ≈24% are spontaneous mutations, ≈60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA) as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray) and chandana (Sanskrit for sandalwood). These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in-frame deletions and helps gain further insights into structure-function of Tyr gene.

  3. Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes.

    Directory of Open Access Journals (Sweden)

    Anil K Challa

    Full Text Available Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr cause oculocutaneous albinism (OCA1 in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ≈24% are spontaneous mutations, ≈60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray and chandana (Sanskrit for sandalwood. These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in-frame deletions and helps gain further insights into structure-function of Tyr gene.

  4. Experiment list: SRX669237 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available alance, and learn motor skills. 25906192,97.9,24.0,451 GSM1464565: MeCP2IP MeCP2 ChIP Cerebellum1; Mus muscu... cerebellar nuclei. Its function is to coordinate voluntary movements, maintain b

  5. Exact 2-point function in Hermitian matrix model

    International Nuclear Information System (INIS)

    Morozov, A.; Shakirov, Sh.

    2009-01-01

    J. Harer and D. Zagier have found a strikingly simple generating function [1,2] for exact (all-genera) 1-point correlators in the Gaussian Hermitian matrix model. In this paper we generalize their result to 2-point correlators, using Toda integrability of the model. Remarkably, this exact 2-point correlation function turns out to be an elementary function - arctangent. Relation to the standard 2-point resolvents is pointed out. Some attempts of generalization to 3-point and higher functions are described.

  6. Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D

    Directory of Open Access Journals (Sweden)

    Paul Edgar Gray

    2017-08-01

    Full Text Available Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in UNC13D. The older sibling presented aged 11 with linear growth arrest and delayed puberty, 2 years prior to developing transient ischemic attacks secondary to neuroinflammation and hypogammaglobulinemia, but no FHL symptoms. Her geno-identical younger sister was initially asymptomatic but then presented at the same age with severe EBV-driven infectious mononucleosis, which was treated aggressively and did not progress to HLH. The sisters had similar natural killer cell degranulation; however, while cytotoxic activity was moderately reduced in the asymptomatic patient, it was completely absent in both siblings during active disease. Following allogeneic bone marrow transplantation at the age of 15, the older child has completely recovered NK cell cytotoxicity, is asymptomatic, and has experienced an exceptional compensatory growth spurt. Her younger sister was also successfully transplanted and is currently disease free. The current study reveals previously unappreciated manifestations of FHL in patients who inherited hypomorphic gene variants and also raises the important question of whether a threshold of minimum NK function can be defined that should protect a patient from serious disease manifestations such as HLH.

  7. A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Miriam Kron

    2014-09-01

    Full Text Available Reduced levels of brain-derived neurotrophic factor (BDNF are thought to contribute to the pathophysiology of Rett syndrome (RTT, a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2. In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to

  8. Two new Rett syndrome families and review of the literature

    DEFF Research Database (Denmark)

    Ravn, Kirstine; Roende, Gitte; Duno, Morten

    2011-01-01

    Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which is usually caused by de novo mutations in the MECP2 gene. More than 70% of the disease causing MECP2 mutations are eight recurrent C to T transitions, which almost exclusively arise on the paternally derived X chromosome...

  9. Unconventional transcriptional response to environmental enrichment in a mouse model of Rett syndrome.

    Directory of Open Access Journals (Sweden)

    Bredford Kerr

    Full Text Available BACKGROUND: Rett syndrome (RTT is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2 and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2(-/y. PRINCIPAL FINDINGS: We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. CONCLUSIONS/SIGNIFICANCE: We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.

  10. Duplication at Xq28 involving IKBKG is associated with progressive macrocephaly, recurrent infections, ectodermal dysplasia, benign tumors, and neuropathy

    NARCIS (Netherlands)

    Asbeck, E. Van; Ramalingam, A.; Dvorak, C.; Chen, T.J.; Morava, E.

    2014-01-01

    Duplications on Xq28 are common, although quite variable in size, but usually include the MECP2 gene. Here, we present a patient with a unique, small, 167-kb duplication at Xq28, not including MECP2. The most important gene in the duplicated region was IKBKG, mutations in which can cause a variety

  11. Pseudo-dynamic source modelling with 1-point and 2-point statistics of earthquake source parameters

    KAUST Repository

    Song, S. G.

    2013-12-24

    Ground motion prediction is an essential element in seismic hazard and risk analysis. Empirical ground motion prediction approaches have been widely used in the community, but efficient simulation-based ground motion prediction methods are needed to complement empirical approaches, especially in the regions with limited data constraints. Recently, dynamic rupture modelling has been successfully adopted in physics-based source and ground motion modelling, but it is still computationally demanding and many input parameters are not well constrained by observational data. Pseudo-dynamic source modelling keeps the form of kinematic modelling with its computational efficiency, but also tries to emulate the physics of source process. In this paper, we develop a statistical framework that governs the finite-fault rupture process with 1-point and 2-point statistics of source parameters in order to quantify the variability of finite source models for future scenario events. We test this method by extracting 1-point and 2-point statistics from dynamically derived source models and simulating a number of rupture scenarios, given target 1-point and 2-point statistics. We propose a new rupture model generator for stochastic source modelling with the covariance matrix constructed from target 2-point statistics, that is, auto- and cross-correlations. Our sensitivity analysis of near-source ground motions to 1-point and 2-point statistics of source parameters provides insights into relations between statistical rupture properties and ground motions. We observe that larger standard deviation and stronger correlation produce stronger peak ground motions in general. The proposed new source modelling approach will contribute to understanding the effect of earthquake source on near-source ground motion characteristics in a more quantitative and systematic way.

  12. L1 retrotransposition is activated by Ten-eleven-translocation protein 1 and repressed by methyl-CpG binding proteins.

    Science.gov (United States)

    Zhang, Peng; Ludwig, Anne K; Hastert, Florian D; Rausch, Cathia; Lehmkuhl, Anne; Hellmann, Ines; Smets, Martha; Leonhardt, Heinrich; Cardoso, M Cristina

    2017-09-03

    One of the major functions of DNA methylation is the repression of transposable elements, such as the long-interspersed nuclear element 1 (L1). The underlying mechanism(s), however, are unclear. Here, we addressed how retrotransposon activation and mobilization are regulated by methyl-cytosine modifying ten-eleven-translocation (Tet) proteins and how this is modulated by methyl-CpG binding domain (MBD) proteins. We show that Tet1 activates both, endogenous and engineered L1 retrotransposons. Furthermore, we found that Mecp2 and Mbd2 repress Tet1-mediated activation of L1 by preventing 5hmC formation at the L1 promoter. Finally, we demonstrate that the methyl-CpG binding domain, as well as the adjacent non-sequence specific DNA binding domain of Mecp2 are each sufficient to mediate repression of Tet1-induced L1 mobilization. Our study reveals a mechanism how L1 elements get activated in the absence of Mecp2 and suggests that Tet1 may contribute to Mecp2/Mbd2-deficiency phenotypes, such as the Rett syndrome. We propose that the balance between methylation "reader" and "eraser/writer" controls L1 retrotransposition.

  13. A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

    NARCIS (Netherlands)

    Kuijpers, Taco W.; van Leeuwen, Ester M. M.; Barendregt, Barbara H.; Klarenbeek, Paul; Aan de Kerk, Daan J.; Baars, Paul A.; Jansen, Machiel H.; de Vries, Niek; van Lier, René A. W.; van der Burg, Mirjam

    2013-01-01

    Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined

  14. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

    NARCIS (Netherlands)

    Shimelis, Hermela; Mesman, Romy L. S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne M. G. R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M.; Aittomäki, Kristiina; Andrulis, Irene; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching-Yu; Choi, Ji-Yeob; Collée, J. Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B.; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lai, Kah-Nyin; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olson, Janet E.; Olswold, Curtis; Oosterwijk, Jan J. C.; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D. P.; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad Usman; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha; Shu, Xiao-Ou; Slager, Susan; Southey, Melissa C.; Stram, Daniel O.; Swerdlow, Anthony; teo, Soo H.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van Asperen, Christi J.; van der Kolk, Lizet E.; Wang, Qin; Winqvist, Robert; Wu, Anna H.; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen B. M.; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F.; Spurdle, Amanda; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N. A.; Goldgar, David E.; Carreira, Aura; Vreeswijk, Maaike P. G.; Couch, Fergus J.

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk

  15. Pseudo-dynamic source modelling with 1-point and 2-point statistics of earthquake source parameters

    KAUST Repository

    Song, S. G.; Dalguer, L. A.; Mai, Paul Martin

    2013-01-01

    statistical framework that governs the finite-fault rupture process with 1-point and 2-point statistics of source parameters in order to quantify the variability of finite source models for future scenario events. We test this method by extracting 1-point

  16. Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

    Science.gov (United States)

    Weaving, Linda S.; Christodoulou, John; Williamson, Sarah L.; Friend, Kathie L.; McKenzie, Olivia L. D.; Archer, Hayley; Evans, Julie; Clarke, Angus; Pelka, Gregory J.; Tam, Patrick P. L.; Watson, Catherine; Lahooti, Hooshang; Ellaway, Carolyn J.; Bennetts, Bruce; Leonard, Helen; Gécz, Jozef

    2004-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G→A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps—but is not identical to—that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations. PMID:15492925

  17. Nav2 is necessary for cranial nerve development and blood pressure regulation

    OpenAIRE

    McNeill, Elizabeth M; Roos, Kenneth P; Moechars, Dieder; Clagett-Dame, Margaret

    2010-01-01

    Abstract Background All-trans retinoic acid (atRA) is required for nervous system development, including the developing hindbrain region. Neuron navigator 2 (Nav2) was first identified as an atRA-responsive gene in human neuroblastoma cells (retinoic acid-induced in neuroblastoma 1, Rainb1), and is required for atRA-mediated neurite outgrowth. In this paper, we explore the importance of Nav2 in nervous system development and function in vivo. Results Nav2 hypomorphic homozygous mutants show d...

  18. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

    OpenAIRE

    Shimelis, Hermela; Mesman, Romy LS; Von, Nicolai Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne MGR; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomäki, Kristiina; Andrulis, Irene

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the $\\textit{BRCA1}$ and $\\textit{BRCA2}$ genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine ...

  19. BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

    OpenAIRE

    Shimelis, Hermela; Mesman, Romy L.s.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calleja, Fabienne Mgr; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomaki, Kristiina; Andrulis, Irene L.

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ances...

  20. Boiling point measurements on liquid UO2

    International Nuclear Information System (INIS)

    Bober, M.; Singer, J.; Trapp, M.

    1986-01-01

    In analogy to the classic boiling point method, a quasi-stationary millisecond laser-heating technique was applied to measure the saturated-vapour pressure curve of liquid UO 2 in the temperature range of 3500 to 4500 K. The result is represented by log p(MPa) 5.049 -23042/T(K) according to an average heat of vaporization of 441 kJ/mol and a normal boiling point of 3808 K. Besides, spectral emissivities of liquid UO 2 were measured at the pyrometer wavelengths of 752 and 1064 nm. (author)

  1. Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance.

    Science.gov (United States)

    Payne, Felicity; Colnaghi, Rita; Rocha, Nuno; Seth, Asha; Harris, Julie; Carpenter, Gillian; Bottomley, William E; Wheeler, Eleanor; Wong, Stephen; Saudek, Vladimir; Savage, David; O'Rahilly, Stephen; Carel, Jean-Claude; Barroso, Inês; O'Driscoll, Mark; Semple, Robert

    2014-09-01

    Structural maintenance of chromosomes (SMC) complexes are essential for maintaining chromatin structure and regulating gene expression. Two the three known SMC complexes, cohesin and condensin, are important for sister chromatid cohesion and condensation, respectively; however, the function of the third complex, SMC5-6, which includes the E3 SUMO-ligase NSMCE2 (also widely known as MMS21) is less clear. Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2. Both mutations reduced NSMCE2 expression in patient cells. Primary cells from one patient showed increased micronucleus and nucleoplasmic bridge formation, delayed recovery of DNA synthesis, and reduced formation of foci containing Bloom syndrome helicase (BLM) after hydroxyurea-induced replication fork stalling. These nuclear abnormalities in patient dermal fibroblast were restored by expression of WT NSMCE2, but not a mutant form lacking SUMO-ligase activity. Furthermore, in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase-deficient NSMCE. Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress.

  2. The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Oliwia Alicja Janc

    2014-02-01

    Full Text Available Rett syndrome (RS causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2-deficient mouse (Mecp2-/y hippocampus, confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3-5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved short-term plasticity, and fully restored synaptic long-term potentiation. Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation.

  3. Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats

    Directory of Open Access Journals (Sweden)

    Pablo Muñoz

    2016-01-01

    Full Text Available Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2 to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS, the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA impaired hippocampal long-term potentiation (LTP. Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP.

  4. Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats.

    Science.gov (United States)

    Muñoz, Pablo; Estay, Carolina; Díaz, Paula; Elgueta, Claudio; Ardiles, Álvaro O; Lizana, Pablo A

    2016-01-01

    Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS), the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA) impaired hippocampal long-term potentiation (LTP). Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP.

  5. New insight on the Xq28 association with systemic sclerosis

    Science.gov (United States)

    Carmona, F David; Cénit, M Carmen; Diaz-Gallo, Lina-Marcela; Broen, Jasper C A; Simeón, Carmen P; Carreira, Patricia E; Callejas-Rubio, José-Luis; Fonollosa, Vicente; López-Longo, Francisco J; González-Gay, Miguel A; Hunzelmann, Nicolas; Riemekasten, Gabriela; Witte, Torsten; Kreuter, Alexander; Distler, Jörg H W; Madhok, Rajan; Shiels, Paul; van Laar, Jacob M; Schuerwegh, Annemie J; Vonk, Madelon C; Voskuyl, Alexandre E; Fonseca, Carmen; Denton, Christopher P; Herrick, Ariane; Worthington, Jane; Arnett, Frank C; Tan, Filemon K; Assassi, Shervin; Radstake, Timothy R D J; Mayes, Maureen D; Martín, Javier

    2013-01-01

    Objective To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). Methods We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. Results IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). Conclusions Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease. PMID:23444193

  6. ALICE makes a clean sweep at Point 2

    CERN Document Server

    2001-01-01

    Since the middle of June the ALICE collaboration has taken up residence at Point 2, previously occupied by L3, and is now preparing the cavern for the arrival of its detector. The last muon chambers of the L3 experiment were removed at the beginning of July. Anyone who knew L3 when it was in operation will be in for a shock if they go down to the cavern at Point 2, which looks as if it's been emptied of all its contents. The members of the ALICE collaboration would not quite share that point of view, however, as some components still have to be dismantled before the cavern can receive its new detector. The collaboration, which has inherited L3's huge red magnet, took over at Point 2 in the middle of June and is now getting down to work. This is the first major stage in the installation of the future detector, which has to be ready to observe its first LHC collisions on 1 April 2006. The first difficulty is to remove the support tube running through the magnet. This huge 32-metre long, 4.5-m diameter, 300-t...

  7. Stabilization of dendritic spine clusters and hyperactive Ras-MAPK signaling predict enhanced motor learning in an autistic savant mouse model

    Directory of Open Access Journals (Sweden)

    Ryan Thomas Ash

    2014-03-01

    Full Text Available That both prominent behavioral inflexibility and exceptional learning abilities are seen occasionally in autistic patients is a mystery. We hypothesize that these altered patterns of learning and memory can arise from a pathological imbalance between the stability and plasticity of internal neural representations. We evaluated this hypothesis in the mouse model of MECP2 duplication syndrome, which demonstrates enhanced motor learning, stereotyped behaviors, and social avoidance. Learning-associated structural plasticity was measured in the motor cortex of MECP2 duplication mice by 2-photon imaging (Fig. 1A. An increased stabilization rate of learning-associated dendritic spines was observed in mutants, and this correlated with rotarod performance. Analysis of the spatial distribution of stabilized spines revealed that the mutant’s increased spine stabilization was due to a specific increase in the stability of spines jointly formed in ~9-micron clusters. Clustered spine stabilization but not isolated spine stabilization predicted enhanced motor performance in MECP2 duplication mice (Fig. 1B. Biochemical assays of Ras-MAPK and mTOR pathway activation demonstrated profound hyperphosphorylation of MAPK in the motor cortex of MECP2 duplication mice with motor training (Fig. 1C. Taken together these data suggest that a pathological bias towards hyperstability of learning-associated dendritic spine clusters driven by hyperactive Ras-MAPK signaling could contribute to neurobehavioral phenotypes in this form of syndromic autism.

  8. Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Bianca De Filippis

    2015-01-01

    Full Text Available Rett syndrome (RTT is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2 cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task. A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

  9. Spin-k/2-spin-k/2 SU(2) two-point functions on the torus

    International Nuclear Information System (INIS)

    Kirsch, Ingo; Kucharski, Piotr

    2012-11-01

    We discuss a class of two-point functions on the torus of primary operators in the SU(2) Wess-Zumino-Witten model at integer level k. In particular, we construct an explicit expression for the current blocks of the spin-(k)/(2)-spin-(k)/(2) torus two-point functions for all k. We first examine the factorization limits of the proposed current blocks and test their monodromy properties. We then prove that the current blocks solve the corresponding Knizhnik-Zamolodchikov-like differential equations using the method of Mathur, Mukhi and Sen.

  10. Spin-k/2-spin-k/2 SU(2) two-point functions on the torus

    Energy Technology Data Exchange (ETDEWEB)

    Kirsch, Ingo [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Gruppe Theorie; Kucharski, Piotr [Warsaw Univ. (Poland). Inst. of Theoretical Physics

    2012-11-15

    We discuss a class of two-point functions on the torus of primary operators in the SU(2) Wess-Zumino-Witten model at integer level k. In particular, we construct an explicit expression for the current blocks of the spin-(k)/(2)-spin-(k)/(2) torus two-point functions for all k. We first examine the factorization limits of the proposed current blocks and test their monodromy properties. We then prove that the current blocks solve the corresponding Knizhnik-Zamolodchikov-like differential equations using the method of Mathur, Mukhi and Sen.

  11. Rett Syndrome: From Bed to Bench

    Directory of Open Access Journals (Sweden)

    Shih-Ming Weng

    2011-12-01

    Full Text Available Rett syndrome (RTT, a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse and thus potentially amenable to rational therapeutic intervention.

  12. 75 FR 16201 - FPL Energy Point Beach, LLC; Point Beach Nuclear Plant, Units 1 and 2; Exemption

    Science.gov (United States)

    2010-03-31

    ... NUCLEAR REGULATORY COMMISSION [Docket Nos. 50-266 and 50-301; NRC-2010-0123] FPL Energy Point Beach, LLC; Point Beach Nuclear Plant, Units 1 and 2; Exemption 1.0 Background FPL Energy Point Beach.... Borchardt (NRC) to M. S. Fertel (Nuclear Energy Institute) dated June 4, 2009. The licensee's request for an...

  13. Combination of hypomorphic mutations of the Drosophila homologues of aryl hydrocarbon receptor and nucleosome assembly protein family genes disrupts morphogenesis, memory and detoxification.

    Science.gov (United States)

    Kuzin, Boris A; Nikitina, Ekaterina A; Cherezov, Roman O; Vorontsova, Julia E; Slezinger, Mikhail S; Zatsepina, Olga G; Simonova, Olga B; Enikolopov, Grigori N; Savvateeva-Popova, Elena V

    2014-01-01

    Aryl hydrocarbon receptor is essential for biological responses to endogenous and exogenous toxins in mammals. Its Drosophila homolog spineless plays an important role in fly morphogenesis. We have previously shown that during morphogenesis spineless genetically interacts with CG5017 gene, which encodes a nucleosome assembly factor and may affect cognitive function of the fly. We now demonstrate synergistic interactions of spineless and CG5017 in pathways controlling oxidative stress response and long-term memory formation in Drosophila melanogaster. Oxidative stress was induced by low doses of X-ray irradiation of flies carrying hypomorphic mutation of spineless, mutation of CG5017, and their combination. To determine the sensitivity of these mutants to pharmacological modifiers of the irradiation effect, we irradiated flies growing on standard medium supplemented by radiosensitizer furazidin and radioprotector serotonin. The effects of irradiation were investigated by analyzing leg and antenna morphological structures and by using real-time PCR to measure mRNA expression levels for spineless, Cyp6g1 and Gst-theta genes. We also examined long-term memory in these mutants using conditioned courtship suppression paradigm. Our results show that the interaction of spineless and CG5017 is important for regulation of morphogenesis, long-term memory formation, and detoxification during oxidative stress. Since spineless and CG5017 are evolutionary conserved, these results must be considered when evaluating the risk of combining similar mutations in other organisms, including humans.

  14. Combination of hypomorphic mutations of the Drosophila homologues of aryl hydrocarbon receptor and nucleosome assembly protein family genes disrupts morphogenesis, memory and detoxification.

    Directory of Open Access Journals (Sweden)

    Boris A Kuzin

    Full Text Available Aryl hydrocarbon receptor is essential for biological responses to endogenous and exogenous toxins in mammals. Its Drosophila homolog spineless plays an important role in fly morphogenesis. We have previously shown that during morphogenesis spineless genetically interacts with CG5017 gene, which encodes a nucleosome assembly factor and may affect cognitive function of the fly. We now demonstrate synergistic interactions of spineless and CG5017 in pathways controlling oxidative stress response and long-term memory formation in Drosophila melanogaster. Oxidative stress was induced by low doses of X-ray irradiation of flies carrying hypomorphic mutation of spineless, mutation of CG5017, and their combination. To determine the sensitivity of these mutants to pharmacological modifiers of the irradiation effect, we irradiated flies growing on standard medium supplemented by radiosensitizer furazidin and radioprotector serotonin. The effects of irradiation were investigated by analyzing leg and antenna morphological structures and by using real-time PCR to measure mRNA expression levels for spineless, Cyp6g1 and Gst-theta genes. We also examined long-term memory in these mutants using conditioned courtship suppression paradigm. Our results show that the interaction of spineless and CG5017 is important for regulation of morphogenesis, long-term memory formation, and detoxification during oxidative stress. Since spineless and CG5017 are evolutionary conserved, these results must be considered when evaluating the risk of combining similar mutations in other organisms, including humans.

  15. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

    DEFF Research Database (Denmark)

    Shimelis, Hermela; Mesman, Romy L S; Von Nicolai, Catharina

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk ......, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR....... were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA...... of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant...

  16. Promoter- and cell-specific epigenetic regulation of CD44, Cyclin D2, GLIPR1 and PTEN by Methyl-CpG binding proteins and histone modifications

    International Nuclear Information System (INIS)

    Müller, Imke; Wischnewski, Frank; Pantel, Klaus; Schwarzenbach, Heidi

    2010-01-01

    The aim of the current study was to analyze the involvement of methyl-CpG binding proteins (MBDs) and histone modifications on the regulation of CD44, Cyclin D2, GLIPR1 and PTEN in different cellular contexts such as the prostate cancer cells DU145 and LNCaP, and the breast cancer cells MCF-7. Since global chromatin changes have been shown to occur in tumours and regions of tumour-associated genes are affected by epigenetic modifications, these may constitute important regulatory mechanisms for the pathogenesis of malignant transformation. In DU145, LNCaP and MCF-7 cells mRNA expression levels of CD44, Cyclin D2, GLIPR1 and PTEN were determined by quantitative RT-PCR at the basal status as well as after treatment with demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor Trichostatin A. Furthermore, genomic DNA was bisulfite-converted and sequenced. Chromatin immunoprecipitation was performed with the stimulated and unstimulated cells using antibodies for MBD1, MBD2 and MeCP2 as well as 17 different histone antibodies. Comparison of the different promoters showed that MeCP2 and MBD2a repressed promoter-specifically Cyclin D2 in all cell lines, whereas in MCF-7 cells MeCP2 repressed cell-specifically all methylated promoters. Chromatin immunoprecipitation showed that all methylated promoters associated with at least one MBD. Treatment of the cells by the demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) caused dissociation of the MBDs from the promoters. Only MBD1v1 bound and repressed methylation-independently all promoters. Real-time amplification of DNA immunoprecipitated by 17 different antibodies showed a preferential enrichment for methylated lysine of histone H3 (H3K4me1, H3K4me2 and H3K4me3) at the particular promoters. Notably, the silent promoters were associated with unmodified histones which were acetylated following treatment by 5-aza-CdR. This study is one of the first to reveal the histone code and MBD profile

  17. Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects.

    Science.gov (United States)

    Zhubi, Adrian; Chen, Ying; Guidotti, Alessandro; Grayson, Dennis R

    2017-11-01

    Both Reelin (RELN) and glutamate decarboxylase 67 (GAD1) have been implicated in the pathophysiology of Autism Spectrum Disorders (ASD). We have previously shown that both mRNAs are reduced in the cerebella (CB) of ASD subjects through a mechanism that involves increases in the amounts of MECP2 binding to the corresponding promoters. In the current study, we examined the expression of RELN, GAD1, GAD2, and several other mRNAs implicated in this disorder in the frontal cortices (FC) of ASD and CON subjects. We also focused on the role that epigenetic processes play in the regulation of these genes in ASD brain. Our goal is to better understand the molecular basis for the down-regulation of genes expressed in GABAergic neurons in ASD brains. We measured mRNA levels corresponding to selected GABAergic genes using qRT-PCR in RNA isolated from both ASD and CON groups. We determined the extent of binding of MECP2 and DNMT1 repressor proteins by chromatin immunoprecipitation (ChIP) assays. The amount of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) present in the promoters of the target genes was quantified by methyl DNA immunoprecipitation (MeDIP) and hydroxyl MeDIP (hMeDIP). We detected significant reductions in the mRNAs associated with RELN and GAD1 and significant increases in mRNAs encoding the Ten-eleven Translocation (TET) enzymes 1, 2, and 3. We also detected increased MECP2 and DNMT1 binding to the corresponding promoter regions of GAD1, RELN, and GAD2. Interestingly, there were decreased amounts of 5mC at both promoters and little change in 5hmC content in these same DNA fragments. Our data demonstrate that RELN, GAD1, and several other genes selectively expressed in GABAergic neurons, are down-regulated in post-mortem ASD FC. In addition, we observed increased DNMT1 and MECP2 binding at the corresponding promoters of these genes. The finding of increased MECP2 binding to the RELN, GAD1 and GAD2 promoters, with reduced amounts of 5mC and unchanged

  18. CAGE-defined promoter regions of the genes implicated in Rett Syndrome

    DEFF Research Database (Denmark)

    Vitezic, Morana; Bertin, Nicolas; Andersson, Robin

    2014-01-01

    BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other...... reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers...

  19. Evaluation of 2-point, 3-point, and 6-point Dixon magnetic resonance imaging with flexible echo timing for muscle fat quantification.

    Science.gov (United States)

    Grimm, Alexandra; Meyer, Heiko; Nickel, Marcel D; Nittka, Mathias; Raithel, Esther; Chaudry, Oliver; Friedberger, Andreas; Uder, Michael; Kemmler, Wolfgang; Quick, Harald H; Engelke, Klaus

    2018-06-01

    The purpose of this study is to evaluate and compare 2-point (2pt), 3-point (3pt), and 6-point (6pt) Dixon magnetic resonance imaging (MRI) sequences with flexible echo times (TE) to measure proton density fat fraction (PDFF) within muscles. Two subject groups were recruited (G1: 23 young and healthy men, 31 ± 6 years; G2: 50 elderly men, sarcopenic, 77 ± 5 years). A 3-T MRI system was used to perform Dixon imaging on the left thigh. PDFF was measured with six Dixon prototype sequences: 2pt, 3pt, and 6pt sequences once with optimal TEs (in- and opposed-phase echo times), lower resolution, and higher bandwidth (optTE sequences) and once with higher image resolution (highRes sequences) and shortest possible TE, respectively. Intra-fascia PDFF content was determined. To evaluate the comparability among the sequences, Bland-Altman analysis was performed. The highRes 6pt Dixon sequences served as reference as a high correlation of this sequence to magnetic resonance spectroscopy has been shown before. The PDFF difference between the highRes 6pt Dixon sequence and the optTE 6pt, both 3pt, and the optTE 2pt was low (between 2.2% and 4.4%), however, not to the highRes 2pt Dixon sequence (33%). For the optTE sequences, difference decreased with the number of echoes used. In conclusion, for Dixon sequences with more than two echoes, the fat fraction measurement was reliable with arbitrary echo times, while for 2pt Dixon sequences, it was reliable with dedicated in- and opposed-phase echo timing. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Genetics Home Reference: MECP2 duplication syndrome

    Science.gov (United States)

    ... and Stroke: Seizures and Epilepsy National Institute of Neurological Disorders and Stroke: Spasticity Information Page Educational Resources (6 links) Boston Children's Hospital: Respiratory Distress Boston Children's Hospital: Seizures Centers ...

  1. 76 FR 40945 - Entergy Nuclear Indian Point 2, LLC, Entergy Nuclear Indian Point 3, LLC, Entergy Nuclear...

    Science.gov (United States)

    2011-07-12

    ... NUCLEAR REGULATORY COMMISSION [NRC-2011-0150; Docket Nos. 50-003, 50-247, and 50-286; License Nos. DPR-5, DPR-26, and DPR-64] Entergy Nuclear Indian Point 2, LLC, Entergy Nuclear Indian Point 3, LLC, Entergy Nuclear Operations, Inc.; Receipt of Request for Action Notice is hereby given that by petition...

  2. Elliptic Curve Integral Points on y2 = x3 + 3x ‑ 14

    Science.gov (United States)

    Zhao, Jianhong

    2018-03-01

    The positive integer points and integral points of elliptic curves are very important in the theory of number and arithmetic algebra, it has a wide range of applications in cryptography and other fields. There are some results of positive integer points of elliptic curve y 2 = x 3 + ax + b, a, b ∈ Z In 1987, D. Zagier submit the question of the integer points on y 2 = x 3 ‑ 27x + 62, it count a great deal to the study of the arithmetic properties of elliptic curves. In 2009, Zhu H L and Chen J H solved the problem of the integer points on y 2 = x 3 ‑ 27x + 62 by using algebraic number theory and P-adic analysis method. In 2010, By using the elementary method, Wu H M obtain all the integral points of elliptic curves y 2 = x 3 ‑ 27x ‑ 62. In 2015, Li Y Z and Cui B J solved the problem of the integer points on y 2 = x 3 ‑ 21x ‑ 90 By using the elementary method. In 2016, Guo J solved the problem of the integer points on y 2 = x 3 + 27x + 62 by using the elementary method. In 2017, Guo J proved that y 2 = x 3 ‑ 21x + 90 has no integer points by using the elementary method. Up to now, there is no relevant conclusions on the integral points of elliptic curves y 2 = x 3 + 3x ‑ 14, which is the subject of this paper. By using congruence and Legendre Symbol, it can be proved that elliptic curve y 2 = x 3 + 3x ‑ 14 has only one integer point: (x, y) = (2, 0).

  3. Evaluation of melting point of UO2 by molecular dynamics simulation

    International Nuclear Information System (INIS)

    Arima, Tatsumi; Idemitsu, Kazuya; Inagaki, Yaohiro; Tsujita, Yuichi; Kinoshita, Motoyasu; Yakub, Eugene

    2009-01-01

    The melting point of UO 2 has been evaluated by molecular dynamics simulation (MD) in terms of interatomic potential, pressure and Schottky defect concentration. The Born-Mayer-Huggins potentials with or without a Morse potential were explored in the present study. Two-phase simulation whose supercell at the initial state consisted of solid and liquid phases gave the melting point comparable to the experimental data using the potential proposed by Yakub. The heat of fusion was determined by the difference in enthalpy at the melting point. In addition, MD calculations showed that the melting point increased with pressure applied to the system. Thus, the Clausius-Clapeyron equation was verified. Furthermore, MD calculations clarified that an addition of Schottky defects, which generated the local disorder in the UO 2 crystal, lowered the melting point.

  4. 75 FR 14206 - FPL Energy Point Beach, LLC; Point Beach Nuclear Plant, Units 1 and 2; Environmental Assessment...

    Science.gov (United States)

    2010-03-24

    ... NUCLEAR REGULATORY COMMISSION [Docket Nos. 50-266 And 50-301; NRC-2010-0123 FPL Energy Point Beach, LLC; Point Beach Nuclear Plant, Units 1 and 2; Environmental Assessment and Finding of No Significant Impact The U.S. Nuclear Regulatory Commission (NRC) is considering issuance of an Exemption, pursuant to...

  5. Four point functions in the SL(2,R) WZW model

    Energy Technology Data Exchange (ETDEWEB)

    Minces, Pablo [Instituto de Astronomia y Fisica del Espacio (IAFE), C.C. 67 Suc. 28, 1428 Buenos Aires (Argentina)]. E-mail: minces@iafe.uba.ar; Nunez, Carmen [Instituto de Astronomia y Fisica del Espacio (IAFE), C.C. 67 Suc. 28, 1428 Buenos Aires (Argentina) and Physics Department, University of Buenos Aires, Ciudad Universitaria, Pab. I, 1428 Buenos Aires (Argentina)]. E-mail: carmen@iafe.uba.ar

    2007-04-19

    We consider winding conserving four point functions in the SL(2,R) WZW model for states in arbitrary spectral flow sectors. We compute the leading order contribution to the expansion of the amplitudes in powers of the cross ratio of the four points on the worldsheet, both in the m- and x-basis, with at least one state in the spectral flow image of the highest weight discrete representation. We also perform certain consistency check on the winding conserving three point functions.

  6. Four point functions in the SL(2,R) WZW model

    International Nuclear Information System (INIS)

    Minces, Pablo; Nunez, Carmen

    2007-01-01

    We consider winding conserving four point functions in the SL(2,R) WZW model for states in arbitrary spectral flow sectors. We compute the leading order contribution to the expansion of the amplitudes in powers of the cross ratio of the four points on the worldsheet, both in the m- and x-basis, with at least one state in the spectral flow image of the highest weight discrete representation. We also perform certain consistency check on the winding conserving three point functions

  7. H-point exciton transitions in bulk MoS2

    International Nuclear Information System (INIS)

    Saigal, Nihit; Ghosh, Sandip

    2015-01-01

    Reflectance and photoreflectance spectrum of bulk MoS 2 around its direct bandgap energy have been measured at 12 K. Apart from spectral features due to the A and B ground state exciton transitions at the K-point of the Brillouin zone, one observes additional features at nearby energies. Through lineshape analysis the character of two prominent additional features are shown to be quite different from that of A and B. By comparing with reported electronic band structure calculations, these two additional features are identified as ground state exciton transitions at the H-point of the Brillouin zone involving two spin-orbit split valance bands. The excitonic energy gap at the H-point is 1.965 eV with a valance bands splitting of 185 meV. While at the K-point, the corresponding values are 1.920 eV and 205 meV, respectively

  8. Validating the Rett Syndrome Gross Motor Scale

    DEFF Research Database (Denmark)

    Downs, Jenny; Stahlhut, Michelle; Wong, Kingsley

    2016-01-01

    .93-0.98). The standard error of measurement for the total score was 2 points and we would be 95% confident that a change 4 points in the 45-point scale would be greater than within-subject measurement error. The Rett Syndrome Gross Motor Scale could be an appropriate measure of gross motor skills in clinical practice......Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale was developed to measure gross motor abilities in this population. The current study investigated...... the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age...

  9. Promoter- and cell-specific epigenetic regulation of CD44, Cyclin D2, GLIPR1 and PTEN by Methyl-CpG binding proteins and histone modifications

    Directory of Open Access Journals (Sweden)

    Schwarzenbach Heidi

    2010-06-01

    Full Text Available Abstract Background The aim of the current study was to analyze the involvement of methyl-CpG binding proteins (MBDs and histone modifications on the regulation of CD44, Cyclin D2, GLIPR1 and PTEN in different cellular contexts such as the prostate cancer cells DU145 and LNCaP, and the breast cancer cells MCF-7. Since global chromatin changes have been shown to occur in tumours and regions of tumour-associated genes are affected by epigenetic modifications, these may constitute important regulatory mechanisms for the pathogenesis of malignant transformation. Methods In DU145, LNCaP and MCF-7 cells mRNA expression levels of CD44, Cyclin D2, GLIPR1 and PTEN were determined by quantitative RT-PCR at the basal status as well as after treatment with demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor Trichostatin A. Furthermore, genomic DNA was bisulfite-converted and sequenced. Chromatin immunoprecipitation was performed with the stimulated and unstimulated cells using antibodies for MBD1, MBD2 and MeCP2 as well as 17 different histone antibodies. Results Comparison of the different promoters showed that MeCP2 and MBD2a repressed promoter-specifically Cyclin D2 in all cell lines, whereas in MCF-7 cells MeCP2 repressed cell-specifically all methylated promoters. Chromatin immunoprecipitation showed that all methylated promoters associated with at least one MBD. Treatment of the cells by the demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR caused dissociation of the MBDs from the promoters. Only MBD1v1 bound and repressed methylation-independently all promoters. Real-time amplification of DNA immunoprecipitated by 17 different antibodies showed a preferential enrichment for methylated lysine of histone H3 (H3K4me1, H3K4me2 and H3K4me3 at the particular promoters. Notably, the silent promoters were associated with unmodified histones which were acetylated following treatment by 5-aza-CdR. Conclusions This study is one

  10. Effects of hypo-O-GlcNAcylation on Drosophila development.

    Science.gov (United States)

    Mariappa, Daniel; Ferenbach, Andrew T; van Aalten, Daan M F

    2018-05-11

    Post-translational modification of serine/threonine residues in nucleocytoplasmic proteins with GlcNAc ( O -GlcNAcylation) is an essential regulatory mechanism in many cellular processes. In Drosophila , null mutants of the Polycomb gene O -GlcNAc transferase ( OGT ; also known as super sex combs ( sxc )) display homeotic phenotypes. To dissect the requirement for O -GlcNAc signaling in Drosophila development, we used CRISPR/Cas9 gene editing to generate rationally designed sxc catalytically hypomorphic or null point mutants. Of the fertile males derived from embryos injected with the CRISPR/Cas9 reagents, 25% produced progeny carrying precise point mutations with no detectable off-target effects. One of these mutants, the catalytically inactive sxc K872M , was recessive lethal, whereas a second mutant, the hypomorphic sxc H537A , was homozygous viable. We observed that reduced total protein O -GlcNAcylation in the sxc H537A mutant is associated with a wing vein phenotype and temperature-dependent lethality. Genetic interaction between sxc H537A and a null allele of Drosophila host cell factor ( dHcf ), encoding an extensively O -GlcNAcylated transcriptional coactivator, resulted in abnormal scutellar bristle numbers. A similar phenotype was also observed in sxc H537A flies lacking a copy of skuld ( skd ), a Mediator complex gene known to affect scutellar bristle formation. Interestingly, this phenotype was independent of OGT Polycomb function or dHcf downstream targets. In conclusion, the generation of the endogenous OGT hypomorphic mutant sxc H537A enabled us to identify pleiotropic effects of globally reduced protein O -GlcNAc during Drosophila development. The mutants generated and phenotypes observed in this study provide a platform for discovery of OGT substrates that are critical for Drosophila development. © 2018 Mariappa et al.

  11. 2-filteredness and the point of every Galois topos

    OpenAIRE

    Dubuc, Eduardo J.

    2007-01-01

    A locally connected topos is a Galois topos if the Galois objects generate the topos. We show that the full subcategory of Galois objects in any connected locally connected topos is an inversely 2-filtered 2-category, and as an application of the construction of 2-filtered bi-limits of topoi, we show that every Galois topos has a point.

  12. 3D reconstruction of laser projective point with projection invariant generated from five points on 2D target.

    Science.gov (United States)

    Xu, Guan; Yuan, Jing; Li, Xiaotao; Su, Jian

    2017-08-01

    Vision measurement on the basis of structured light plays a significant role in the optical inspection research. The 2D target fixed with a line laser projector is designed to realize the transformations among the world coordinate system, the camera coordinate system and the image coordinate system. The laser projective point and five non-collinear points that are randomly selected from the target are adopted to construct a projection invariant. The closed form solutions of the 3D laser points are solved by the homogeneous linear equations generated from the projection invariants. The optimization function is created by the parameterized re-projection errors of the laser points and the target points in the image coordinate system. Furthermore, the nonlinear optimization solutions of the world coordinates of the projection points, the camera parameters and the lens distortion coefficients are contributed by minimizing the optimization function. The accuracy of the 3D reconstruction is evaluated by comparing the displacements of the reconstructed laser points with the actual displacements. The effects of the image quantity, the lens distortion and the noises are investigated in the experiments, which demonstrate that the reconstruction approach is effective to contribute the accurate test in the measurement system.

  13. Mitochondrial Pyruvate Carrier 2 Hypomorphism in Mice Leads to Defects in Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Patrick A. Vigueira

    2014-06-01

    Full Text Available Carrier-facilitated pyruvate transport across the inner mitochondrial membrane plays an essential role in anabolic and catabolic intermediary metabolism. Mitochondrial pyruvate carrier 2 (Mpc2 is believed to be a component of the complex that facilitates mitochondrial pyruvate import. Complete MPC2 deficiency resulted in embryonic lethality in mice. However, a second mouse line expressing an N-terminal truncated MPC2 protein (Mpc2Δ16 was viable but exhibited a reduced capacity for mitochondrial pyruvate oxidation. Metabolic studies demonstrated exaggerated blood lactate concentrations after pyruvate, glucose, or insulin challenge in Mpc2Δ16 mice. Additionally, compared with wild-type controls, Mpc2Δ16 mice exhibited normal insulin sensitivity but elevated blood glucose after bolus pyruvate or glucose injection. This was attributable to reduced glucose-stimulated insulin secretion and was corrected by sulfonylurea KATP channel inhibitor administration. Collectively, these data are consistent with a role for MPC2 in mitochondrial pyruvate import and suggest that Mpc2 deficiency results in defective pancreatic β cell glucose sensing.

  14. Freezing Point Depressions of Phase Change CO2 Solvents

    DEFF Research Database (Denmark)

    Arshad, Muhammad Waseem; Fosbøl, Philip Loldrup; von Solms, Nicolas

    2013-01-01

    Freezing point depressions (FPD) in phase change solvents containing 2-(diethylamino)ethanol (DEEA) and 3-(methylamino)propylamine (MAPA) were measured using a modified Beckmann apparatus. The measurements were performed for the binary aqueous DEEA and MAPA solutions, respectively...

  15. Condensates near the Argyres-Douglas point in SU (2) gauge theory with broken Ν = 2 supersymmetry

    International Nuclear Information System (INIS)

    Gorsky, A.

    2002-01-01

    The behaviour of the chiral condensates in the SU(2) gauge theory with broken N = 2 supersymmetry is reviewed. The calculation of monopole, dyon, and charge condensates is described. It is shown that the monopole and charge condensates vanish at the Argyres-Douglas point where the monopole and charge vacua collide. This phenomenon is interpreted as a deconfinement of electric and magnetic charges at the Argyres-Douglas point. (authors)

  16. Fixed Points of Expansive Type Mappings in 2-Banach Spaces

    Directory of Open Access Journals (Sweden)

    Prabha Chouhan

    2013-08-01

    Full Text Available In present paper, we define expansive mappings in 2-Banach space and prove some common unique fixed point theorems which are the extension of results of Wang et al. [12] and Rhoades [9] in 2-Banach space.

  17. PointCloudExplore 2: Visual exploration of 3D gene expression

    Energy Technology Data Exchange (ETDEWEB)

    International Research Training Group Visualization of Large and Unstructured Data Sets, University of Kaiserslautern, Germany; Institute for Data Analysis and Visualization, University of California, Davis, CA; Computational Research Division, Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA; Genomics Division, LBNL; Computer Science Department, University of California, Irvine, CA; Computer Science Division,University of California, Berkeley, CA; Life Sciences Division, LBNL; Department of Molecular and Cellular Biology and the Center for Integrative Genomics, University of California, Berkeley, CA; Ruebel, Oliver; Rubel, Oliver; Weber, Gunther H.; Huang, Min-Yu; Bethel, E. Wes; Keranen, Soile V.E.; Fowlkes, Charless C.; Hendriks, Cris L. Luengo; DePace, Angela H.; Simirenko, L.; Eisen, Michael B.; Biggin, Mark D.; Hagen, Hand; Malik, Jitendra; Knowles, David W.; Hamann, Bernd

    2008-03-31

    To better understand how developmental regulatory networks are defined inthe genome sequence, the Berkeley Drosophila Transcription Network Project (BDNTP)has developed a suite of methods to describe 3D gene expression data, i.e.,the output of the network at cellular resolution for multiple time points. To allow researchersto explore these novel data sets we have developed PointCloudXplore (PCX).In PCX we have linked physical and information visualization views via the concept ofbrushing (cell selection). For each view dedicated operations for performing selectionof cells are available. In PCX, all cell selections are stored in a central managementsystem. Cells selected in one view can in this way be highlighted in any view allowingfurther cell subset properties to be determined. Complex cell queries can be definedby combining different cell selections using logical operations such as AND, OR, andNOT. Here we are going to provide an overview of PointCloudXplore 2 (PCX2), thelatest publicly available version of PCX. PCX2 has shown to be an effective tool forvisual exploration of 3D gene expression data. We discuss (i) all views available inPCX2, (ii) different strategies to perform cell selection, (iii) the basic architecture ofPCX2., and (iv) illustrate the usefulness of PCX2 using selected examples.

  18. Point-contact spectroscopic studies on normal and superconducting AFe2As2-type iron pnictide single crystals

    International Nuclear Information System (INIS)

    Lu Xin; Park, W K; Greene, L H; Yuan, H Q; Chen, G F; Luo, G L; Wang, N L; Sefat, A S; McGuire, M A; Jin, R; Sales, B C; Mandrus, D; Gillett, J; Sebastian, Suchitra E

    2010-01-01

    Point-contact Andreev reflection spectroscopy is applied to investigate the gap structure in iron pnictide single-crystal superconductors of the AFe 2 As 2 (A = Ba, Sr) family ('Fe-122'). The observed point-contact junction conductance curves, G(V), can be divided into two categories: one where Andreev reflection is present for both (Ba 0.6 K 0.4 )Fe 2 As 2 and Ba(Fe 0.9 Co 0.1 ) 2 As 2 , and the other with a V 2/3 background conductance universally observed, extending even up to 100 meV for Sr 0.6 Na 0.4 Fe 2 As 2 and Sr(Fe 0.9 Co 0.1 ) 2 As 2 . The latter is also observed in point-contact junctions on the nonsuperconducting parent compound BaFe 2 As 2 and superconducting (Ba 0.6 K 0.4 )Fe 2 As 2 crystals. Mesoscopic phase-separated coexistence of magnetic and superconducting orders is considered to explain distinct behaviors in the superconducting samples. For Ba 0.6 K 0.4 Fe 2 As 2 , double peaks due to Andreev reflection with a strongly sloping background are frequently observed for point contacts on freshly cleaved c-axis surfaces. If normalized using a background baseline and analyzed using the Blonder-Tinkham-Klapwijk model, the data show a gap size of ∼ 3.0-4.0 meV with 2Δ 0 /k B T c ∼ 2.0-2.6, consistent with the smaller gap size reported for the LnFeAsO family ('Fe-1111'). For the Ba(Fe 0.9 Co 0.1 ) 2 As 2 , the G(V) curves typically display a zero-bias conductance peak.

  19. Color point tuning for (Sr,Ca,Ba)Si2O2N2:Eu2+ for white light LEDs

    NARCIS (Netherlands)

    Bachmann, V.M.; Ronda, R.C.; Meijerink, A.; Oeckler, O.; Schnick, W.

    2009-01-01

    Color point tuning is an important challenge for improving white light LEDs. In this paper, the possibilities of color tuning with the efficient LED phosphor Sr1-x-y-zCaxBaySi2O2N2:Euz 2+ (0 e x, y e 1; 0.005 e z e 0.16) are investigated. The emission color can be tuned in two ways: by changing Eu2+

  20. Double Dirac point semimetal in 2D material: Ta2Se3

    Science.gov (United States)

    Ma, Yandong; Jing, Yu; Heine, Thomas

    2017-06-01

    Here, we report by first-principles calculations one new stable 2D Dirac material, Ta2Se3 monolayer. For this system, stable layered bulk phase exists, and exfoliation should be possible. Ta2Se3 monolayer is demonstrated to support two Dirac points close to the Fermi level, achieving the exotic 2D double Dirac semimetal. And like 2D single Dirac and 2D node-line semimetals, spin-orbit coupling could introduce an insulating state in this new class of 2D Dirac semimetals. Moreover, the Dirac feature in this system is layer-dependent and a metal-to-insulator transition is identified in Ta2Se3 when reducing the layer-thickness from bilayer to monolayer. These findings are of fundamental interests and of great importance for nanoscale device applications.

  1. CO2 point sources and subsurface storage capacities for CO2 in aquifers in Norway

    International Nuclear Information System (INIS)

    Boee, Reidulv; Magnus, Christian; Osmundsen, Per Terje; Rindstad, Bjoern Ivar

    2002-01-01

    The GESTCO project comprises a study of the distribution and coincidence of thermal CO 2 emission sources and location/quality of geological storage capacity in Europe. Four of the most promising types of geological storage are being studied. 1. Onshore/offshore saline aquifers with or without lateral seal. 2. Low entalpy geothermal reservoirs. 3. Deep methane-bearing coal beds and abandoned coal and salt mines. 4. Exhausted or near exhausted hydrocarbon structures. In this report we present an inventory of CO 2 point sources in Norway (1999) and the results of the work within Study Area C: Deep saline aquifers offshore/near shore Northern and Central Norway. Also offshore/near shore Southern Norway has been included while the Barents Sea is not described in any detail. The most detailed studies are on the Tilje and Aare Formations on the Troendelag Platform off Mid-Norway and on the Sognefjord, Fensfjord and Krossfjord Formations, southeast of the Troll Field off Western Norway. The Tilje Formation has been chosen as one of the cases to be studied in greater detail (numerical modelling) in the project. This report shows that offshore Norway, there are concentrations of large CO 2 point sources in the Haltenbanken, the Viking Graben/Tampen Spur area, the Southern Viking Graben and the central Trough, while onshore Norway there are concentrations of point sources in the Oslofjord/Porsgrund area, along the coast of western Norway and in the Troendelag. A number of aquifers with large theoretical CO 2 storage potential are pointed out in the North Sea, the Norwegian Sea and in the Southern Barents Sea. The storage capacity in the depth interval 0.8 - 4 km below sea level is estimated to be ca. 13 Gt (13000000000 tonnes) CO 2 in geological traps (outside hydrocarbon fields), while the storage capacity in aquifers not confined to traps is estimated to be at least 280 Gt CO 2 . (Author)

  2. ClinicalKey 2.0: Upgrades in a Point-of-Care Search Engine.

    Science.gov (United States)

    Huslig, Mary Ann; Vardell, Emily

    2015-01-01

    ClinicalKey 2.0, launched September 23, 2014, offers a mobile-friendly design with a search history feature for targeting point-of-care resources for health care professionals. Browsing is improved with searchable, filterable listings of sources highlighting new resources. ClinicalKey 2.0 improvements include more than 1,400 new Topic Pages for quick access to point-of-care content. A sample search details some of the upgrades and content options.

  3. Weak ferrimagnetism, compensation point and magnetization reversal in Ni(HCOO)2x2H2O

    International Nuclear Information System (INIS)

    Kageyama, H.; Khomskii, D.I.; Levitin, R.Z.; Vasiliev, A.N.

    2003-01-01

    Nickel (II) format dihydrate Ni(HCOO) 2 x2H 2 O shows peculiar magnetic response at T N =15.5 K. The magnitude of weak magnetic moment increases initially below T N , equals zero at T*=8.5 K and increases again at lowering temperature. The sign of low field magnetization at any given temperature is determined by the sample's magnetic prehistory and the signs are opposite to each other at T N . This behavior suggests that Ni(HCOO) 2 x2H 2 O is a weak ferrimagnet and T* is a compensation point

  4. Rational Points on Curves of Genus 2: Experiments and Speculations

    OpenAIRE

    Stoll, Michael

    2009-01-01

    I will present results of computations providing statistics on rational points on (small) curves of genus 2 and use them to present several conjectures. Some of them are based on heuristic considerations, others are not.

  5. Silent angels the genetic and clinical aspects of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Dziwota Ewelina

    2016-12-01

    Full Text Available Rett syndrome is a neurodevelopmental genetic disorder and, because of some behavioral characteristics, individuals affected by the disease are known as silent angels. Girls with Rett syndrome perform stereotyped movements, they have learning difficulties, their reaction time is prolonged, and they seem alienated in the environment. These children require constant pediatric, neurological and orthopedic care. In the treatment of Rett syndrome physical therapy, music therapy, hydrotherapy, hippotherapy, behavioral methods, speech therapy and diet, are also used. In turn, psychological therapy of the syndrome is based on the sensory integration method, using two or more senses simultaneously. In 80% of cases, the syndrome is related to mutations of the MECP2 gene, located on chromosome X. The pathogenesis of Rett syndrome is caused by the occurrence of a non-functional MeCP2 protein, which is a transcription factor of many genes, i.e. Bdnf, mef2c, Sgk1, Uqcrc1. Abnormal expression of these genes reveals a characteristic disease phenotype. Clinical symptoms relate mainly to the nervous, respiratory, skeletal and gastrointestinal systems. Currently causal treatment is not possible. However, researchers are developing methods by which, perhaps in the near future, it will be possible to eliminate the mutations in the MECP2 gene, and this will give a chance to the patient for normal functioning.

  6. Worldsheet four-point functions in AdS{sub 3}/CFT{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Cardona, Carlos A. [Instituto de Astronomia y Fisica del Espacio (CONICET-UBA), Buenos Aires (Argentina); Kirsch, Ingo [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2010-07-15

    We calculate some extremal and non-extremal four-point functions on the sphere of certain chiral primary operators for strings on AdS{sub 3} x S{sup 3} x T{sup 4}. The computation is done for small values of the spacetime cross-ratio where global SL(2) and SU(2) descendants may be neglected in the intermediate channel. Ignoring also current algebra descendants, we find that in the non-extremal case the integrated worldsheet correlators factorize into spacetime three-point functions, which is non-trivial due to the integration over the moduli space. We then restrict to the extremal case and compare our results with the four-point correlators recently computed in the dual boundary theory. We also discuss a particular non-extremal correlator involving two chiral and two anti-chiral operators. (orig)

  7. Subclinical Inflammatory Status in Rett Syndrome

    Directory of Open Access Journals (Sweden)

    Alessio Cortelazzo

    2014-01-01

    Full Text Available Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR in stage II (i.e., “pseudo-autistic” RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions. Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P<0.0001 were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63. The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6 spots or negative (n=9 spots, and to a lesser extent as proteins involved in the immune system (n=2 spots, with some proteins having overlapping functions on metabolism (n=7 spots. The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by the MECP2 gene mutation.

  8. 2.5D Multi-View Gait Recognition Based on Point Cloud Registration

    Science.gov (United States)

    Tang, Jin; Luo, Jian; Tjahjadi, Tardi; Gao, Yan

    2014-01-01

    This paper presents a method for modeling a 2.5-dimensional (2.5D) human body and extracting the gait features for identifying the human subject. To achieve view-invariant gait recognition, a multi-view synthesizing method based on point cloud registration (MVSM) to generate multi-view training galleries is proposed. The concept of a density and curvature-based Color Gait Curvature Image is introduced to map 2.5D data onto a 2D space to enable data dimension reduction by discrete cosine transform and 2D principle component analysis. Gait recognition is achieved via a 2.5D view-invariant gait recognition method based on point cloud registration. Experimental results on the in-house database captured by a Microsoft Kinect camera show a significant performance gain when using MVSM. PMID:24686727

  9. Minimum energy consumption process synthesis for energy saving

    Energy Technology Data Exchange (ETDEWEB)

    Xiao-Ping, Jia [Institute for Petroleum and Chemical Industry, Qingdao University of Science and Technology, Qingdao 266042, Shandong (China); Department of Environmental Science and Engineering, Tsinghua University, Beijing 100084 (China); Fang, Wang; Shu-Guang, Xiang; Xin-Sun, Tan; Fang-Yu, Han [Institute for Petroleum and Chemical Industry, Qingdao University of Science and Technology, Qingdao 266042, Shandong (China)

    2008-05-15

    The paper presents a synthesis strategy for the chemical processes with energy saving. The concept of minimum energy consumption process (MECP) is proposed. Three characteristics of MECP are introduced, including thermodynamic minimum energy demand, energy consumption efficiency and integration degree. These characteristics are evaluated according to quantitative thermodynamic analysis and qualitative knowledge rules. The procedure of synthesis strategy is proposed to support the generation of MECP alternatives, which combine flowsheet integration and heat integration. The cases studies will focus on how integration degrees of a process affect the energy-saving results. The separation sequences of the hydrodealkylation of toluene (HDA) process and ethanol distillation process as case studies are used to illustrate. (author)

  10. Point group invariants in the Uqp(u(2)) quantum algebra picture

    International Nuclear Information System (INIS)

    Kibler, M.

    1993-07-01

    Some consequences of a qp-quantization of a point group invariant developed in the enveloping algebra of SU(2) are examined. A set of open problems concerning such invariants in the U qp (u(2)) quantum algebra picture is briefly discussed. (author) 18 refs

  11. Effects of the second X-point on hot VDE in HL-2M

    Science.gov (United States)

    Xue, L.; Duan, X. R.; Zheng, G. Y.; Liu, Y. Q.; Dokuka, V. N.; Lukash, V. E.; Khayrutdinov, R. R.

    2017-05-01

    Study of the hot-plasma vertical displacement event (VDE) in advanced divertor configurations is of significant importance for ITER and for future fusion reactors. The newly designed, medium-sized copper-conductor machine HL-2M has the capability of generating the second X-point for various advanced divertor configurations. In this paper, effects of the second X-point on the hot VDE in HL-2M are numerically investigated by utilizing the non-linear time-dependent DINA code. The simulation results show that the existence of the second X-point at certain special locations appears to have a better stability in the vertical direction, compared to the standard configuration with the same main plasma parameters. Meanwhile, the peak halo current during the current quench tends to increase as the second X-point changes in the horizontal direction. The same quantity decreases as the second X-point changes in the vertical direction away from the dominant X-point. From the view point of minimizing the halo current, the tripod is better than the standard configuration, followed by the snowflake-plus and the exact snowflake (SF) configuration. The SF-minus is the worst scenario. On the other hand, the tripod configuration, as well as the SF minus configurations, results in relatively higher peak electromagnetic force acting on the vacuum vessel, when compared to other aforementioned configurations.

  12. Infrared fixed point of SU(2) gauge theory with six flavors

    Science.gov (United States)

    Leino, Viljami; Rummukainen, Kari; Suorsa, Joni; Tuominen, Kimmo; Tähtinen, Sara

    2018-06-01

    We compute the running of the coupling in SU(2) gauge theory with six fermions in the fundamental representation of the gauge group. We find strong evidence that this theory has an infrared stable fixed point at strong coupling and measure also the anomalous dimension of the fermion mass operator at the fixed point. This theory therefore likely lies close to the boundary of the conformal window and will display novel infrared dynamics if coupled with the electroweak sector of the Standard Model.

  13. A review on the effects of TiO2 surface point defects on CO2 photoreduction with H2O

    Directory of Open Access Journals (Sweden)

    Huilei Zhao

    2017-03-01

    Full Text Available Photocatalytic reduction of CO2 with water by photocatalysts such as TiO2 to produce solar fuels is an attractive approach to alleviate the environmental influences of greenhouse gases and in the meantime produce valuable carbon-neutral fuels. Among the materials properties that affect catalytic activity of CO2 photoreduction, the point defect on TiO2 is one of the most important but not frequently addressed and well understood in the literature. In this review, we have examined the major influences of TiO2 point defects on CO2 photoreduction with H2O, by changing the catalysts' gas adsorption capabilities, optical properties, and electronic structures. In addition, the performances of various defective TiO2 toward CO2 photoreduction are summarized and compared in terms of productivity, selectivity, and stability. We hope this review can contribute to understanding the mechanism of CO2 photoreduction on defective TiO2 and provide insights to the design of highly efficient defect-rich TiO2 to boost the CO2 utilization.

  14. Point-point and point-line moving-window correlation spectroscopy and its applications

    Science.gov (United States)

    Zhou, Qun; Sun, Suqin; Zhan, Daqi; Yu, Zhiwu

    2008-07-01

    In this paper, we present a new extension of generalized two-dimensional (2D) correlation spectroscopy. Two new algorithms, namely point-point (P-P) correlation and point-line (P-L) correlation, have been introduced to do the moving-window 2D correlation (MW2D) analysis. The new method has been applied to a spectral model consisting of two different processes. The results indicate that P-P correlation spectroscopy can unveil the details and re-constitute the entire process, whilst the P-L can provide general feature of the concerned processes. Phase transition behavior of dimyristoylphosphotidylethanolamine (DMPE) has been studied using MW2D correlation spectroscopy. The newly proposed method verifies that the phase transition temperature is 56 °C, same as the result got from a differential scanning calorimeter. To illustrate the new method further, a lysine and lactose mixture has been studied under thermo perturbation. Using the P-P MW2D, the Maillard reaction of the mixture was clearly monitored, which has been very difficult using conventional display of FTIR spectra.

  15. Visualizing Robustness of Critical Points for 2D Time-Varying Vector Fields

    KAUST Repository

    Wang, B.

    2013-06-01

    Analyzing critical points and their temporal evolutions plays a crucial role in understanding the behavior of vector fields. A key challenge is to quantify the stability of critical points: more stable points may represent more important phenomena or vice versa. The topological notion of robustness is a tool which allows us to quantify rigorously the stability of each critical point. Intuitively, the robustness of a critical point is the minimum amount of perturbation necessary to cancel it within a local neighborhood, measured under an appropriate metric. In this paper, we introduce a new analysis and visualization framework which enables interactive exploration of robustness of critical points for both stationary and time-varying 2D vector fields. This framework allows the end-users, for the first time, to investigate how the stability of a critical point evolves over time. We show that this depends heavily on the global properties of the vector field and that structural changes can correspond to interesting behavior. We demonstrate the practicality of our theories and techniques on several datasets involving combustion and oceanic eddy simulations and obtain some key insights regarding their stable and unstable features. © 2013 The Author(s) Computer Graphics Forum © 2013 The Eurographics Association and Blackwell Publishing Ltd.

  16. Visualizing Robustness of Critical Points for 2D Time-Varying Vector Fields

    KAUST Repository

    Wang, B.; Rosen, P.; Skraba, P.; Bhatia, H.; Pascucci, V.

    2013-01-01

    Analyzing critical points and their temporal evolutions plays a crucial role in understanding the behavior of vector fields. A key challenge is to quantify the stability of critical points: more stable points may represent more important phenomena or vice versa. The topological notion of robustness is a tool which allows us to quantify rigorously the stability of each critical point. Intuitively, the robustness of a critical point is the minimum amount of perturbation necessary to cancel it within a local neighborhood, measured under an appropriate metric. In this paper, we introduce a new analysis and visualization framework which enables interactive exploration of robustness of critical points for both stationary and time-varying 2D vector fields. This framework allows the end-users, for the first time, to investigate how the stability of a critical point evolves over time. We show that this depends heavily on the global properties of the vector field and that structural changes can correspond to interesting behavior. We demonstrate the practicality of our theories and techniques on several datasets involving combustion and oceanic eddy simulations and obtain some key insights regarding their stable and unstable features. © 2013 The Author(s) Computer Graphics Forum © 2013 The Eurographics Association and Blackwell Publishing Ltd.

  17. Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder.

    Science.gov (United States)

    Pecorelli, Alessandra; Belmonte, Giuseppe; Meloni, Ilaria; Cervellati, Franco; Gardi, Concetta; Sticozzi, Claudia; De Felice, Claudio; Signorini, Cinzia; Cortelazzo, Alessio; Leoncini, Silvia; Ciccoli, Lucia; Renieri, Alessandra; Jay Forman, Henry; Hayek, Joussef; Valacchi, Giuseppe

    2015-09-01

    CDKL5 mutation is associated with an atypical Rett syndrome (RTT) variant. Recently, cholesterol homeostasis perturbation and oxidative-mediated loss of the high-density lipoprotein receptor SRB1 in typical RTT have been suggested. Here, we demonstrate an altered lipid serum profile also in CDKL5 patients with decreased levels of SRB1 and impaired activation of the defensive system Nrf2. In addition, CDKL5 fibroblasts showed an increase in 4-hydroxy-2-nonenal- and nitrotyrosine-SRB1 adducts that lead to its ubiquitination and probable degradation. This study highlights a possible common denominator between two different RTT variants (MECP2 and CDKL5) and a possible common future therapeutic target. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. (0,2) SCFTs from the Leigh-Strassler fixed point

    Energy Technology Data Exchange (ETDEWEB)

    Bobev, Nikolay [Perimeter Institute for Theoretical Physics, 31 Caroline Street North, Waterloo, ON N2L 2Y5 (Canada); Pilch, Krzysztof; Vasilakis, Orestis [Department of Physics and Astronomy, University of Southern California, Los Angeles, CA 90089 (United States)

    2014-06-17

    We show that there is a family of two-dimensional (0,2) SCFTs associated with twisted compactifications of the four-dimensional N=1 Leigh-Strassler fixed point on a closed hyperbolic Riemann surface. We calculate the central charges for this class of theories using anomalies and c-extremization. In a suitable truncation of the five-dimensional maximal supergravity, we construct supersymmetric AdS{sub 3} solutions that are holographic duals of those two-dimensional (0,2) SCFTs. We also exhibit supersymmetric domain wall solutions that are holographically dual to the RG flows between the four-dimensional and two-dimensional theories.

  19. (0,2) SCFTs from the Leigh-Strassler fixed point

    International Nuclear Information System (INIS)

    Bobev, Nikolay; Pilch, Krzysztof; Vasilakis, Orestis

    2014-01-01

    We show that there is a family of two-dimensional (0,2) SCFTs associated with twisted compactifications of the four-dimensional N=1 Leigh-Strassler fixed point on a closed hyperbolic Riemann surface. We calculate the central charges for this class of theories using anomalies and c-extremization. In a suitable truncation of the five-dimensional maximal supergravity, we construct supersymmetric AdS 3 solutions that are holographic duals of those two-dimensional (0,2) SCFTs. We also exhibit supersymmetric domain wall solutions that are holographically dual to the RG flows between the four-dimensional and two-dimensional theories.

  20. The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

    Directory of Open Access Journals (Sweden)

    Xin Xu

    2017-07-01

    Full Text Available Brain-derived neurotrophic factor (Bdnf has been implicated in several neurological disorders including Rett syndrome (RTT, an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2. The human BDNF gene has a single nucleotide polymorphism (SNP—a methionine (met substitution for valine (val at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT and Mecp2 knockout (KO mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.

  1. FIND: Douglas Point Nuclear Generating Station, Units 1 and 2

    International Nuclear Information System (INIS)

    Moore, M.M.

    1975-12-01

    This index is presented as a guide to microfiche items 1 through 136 in Docket 50448, which was assigned to Potomac Electric Power Company's Application for Licenses to construct and operate Douglas Point Nuclear Generating Station, Units 1 and 2. Information received from August, 1973 through July, 1975 is included

  2. Potential Improvements of Supercritical Recompression CO2 Brayton Cycle Coupled with KALIMER-600 by Modifying Critical Point of CO2

    International Nuclear Information System (INIS)

    Jeong, Woo Seok; Lee, Jeong Ik; Jeong, Yong Hoon; No, Hee Cheon

    2010-01-01

    Most of the existing designs of a Sodium cooled Fast Reactor (SFR) have a Rankine cycle as an electric power generation cycle. This has the risk of a sodium water reaction. To prevent any hazards from a sodium water reaction, an indirect Brayton cycle using Supercritical Carbon dioxide (S-CO 2 ) as the working fluids for a SFR is an alternative approach to improve the current SFR design. The supercritical Brayton cycle is defined as a cycle with operating conditions above the critical point and the main compressor inlet condition located slightly above the critical point of working fluid. This is because the main advantage of the cycle comes from significantly decreased compressor work just above the critical point due to high density near boundary between supercritical state and subcritical state. For this reason, the minimum temperature and pressure of cycle are just above the CO 2 critical point. In other words, the critical point acts as a limitation of the lowest operating condition of the cycle. In general, lowering the minimum temperature of a thermodynamic cycle can increase the efficiency and the minimum temperature can be decreased by shifting the critical point of CO 2 as mixed with other gases. In this paper, potential enhancement of S-CO 2 cycle coupled with KALIMER-600, which has been developed at KAERI, was investigated using a developed cycle code with a gas mixture property program

  3. Wrox SharePoint 2010 SharePoint911 three-pack

    CERN Document Server

    Klindt, Todd; Mason, Jennifer; Rogers, Laura; Drisgill, Randy; Ross, John; Riemann, Larry; Perran, Amanda; Perran, Shane; Sanford, Jacob J; Stubbs, Paul; Caravajal, Steve

    2012-01-01

    The Wrox SharePoint 2010 SharePoint911 Three-Pack combines the contents of three full e-books written by the experts from SharePoint911.  That's over 1800 pages of hands-on advice from Todd Klindt, Shane Young, Laura Rogers, Randy Drisgill, Jennifer Mason, John Ross, and Larry Riemann, among others. In Beginning SharePoint 2010: Building Business Solutions with SharePoint (ISBN 978-0-470-61789-2) by Amanda Perran, Shane Perran, Jennifer Mason, and Laura Rogers, readers learn the core concepts, terminology, and features of SharePoint 2010. In Professiona

  4. Genetics Home Reference: MECP2-related severe neonatal encephalopathy

    Science.gov (United States)

    ... and Stroke: Encephalopathy Information Page National Institute of Neurological Disorders and Stroke: Microcephaly Information Page Educational Resources (8 links) Boston Children's Hospital: Seizures Centers for Disease Control and Prevention: ...

  5. Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late.

    Directory of Open Access Journals (Sweden)

    Suzan M Hammond

    Full Text Available Spinal muscular atrophy (SMA is caused by low survival motor neuron (SMN levels and patients represent a clinical spectrum due primarily to varying copies of the survival motor neuron-2 (SMN2 gene. Patient and animals studies show that disease severity is abrogated as SMN levels increase. Since therapies currently being pursued target the induction of SMN, it will be important to understand the dosage, timing and cellular requirements of SMN for disease etiology and potential therapeutic intervention. This requires new mouse models that can induce SMN temporally and/or spatially. Here we describe the generation of two hypomorphic Smn alleles, Smn(C-T-Neo and Smn(2B-Neo. These alleles mimic SMN2 exon 7 splicing, titre Smn levels and are inducible. They were specifically designed so that up to three independent lines of mice could be generated, herein we describe two. In a homozygous state each allele results in embryonic lethality. Analysis of these mutants indicates that greater than 5% of Smn protein is required for normal development. The severe hypomorphic nature of these alleles is caused by inclusion of a loxP-flanked neomycin gene selection cassette in Smn intron 7, which can be removed with Cre recombinase. In vitro and in vivo experiments demonstrate these as inducible Smn alleles. When combined with an inducible Cre mouse, embryonic lethality caused by low Smn levels can be rescued early in gestation but not late. This provides direct genetic evidence that a therapeutic window for SMN inductive therapies may exist. Importantly, these lines fill a void for inducible Smn alleles. They also provide a base from which to generate a large repertoire of SMA models of varying disease severities when combined with other Smn alleles or SMN2-containing mice.

  6. Self-diffusion at the melting point: From H2 and N2 to liquid metals

    International Nuclear Information System (INIS)

    Armstrong, B.H.

    1992-01-01

    A nominal lower bound to the mean free diffusion time at the melting point T m was obtained earlier which provided a factor-two type estimate for self-diffusion coefficients of the alkali halides, alkali metals, eight other metals, and Ar. The argument was based on the classical Uncertainty Principle applied to the solid crystal, whereby maximum-frequency phonons lose validity as collective excitations and degenerate into aperiodic, single-particle diffusive motion at the melting point. Because of the short time scale of this motion, the perfect-gas diffusion equation and true mass can be used to obtain the self-diffusion coefficient in the Debye approximation to the phonon spectrum. This result for the self-diffusion coefficient also yields the scale factor that determines the order of magnitude of liquid self-diffusion coefficients, which has long been an open question. The earlier theory is summarized and clarified, and the results extended to the more complex molecular liquids H 2 and N 2 . It is also demonstrated that combining Lindemann's melting law with the perfect-gas diffusion equation estimate yields a well-known empirical expression for liquid-metal self-diffusion at T m . Validity of the self-diffusion estimate over a melting temperature range from 14 to more than 1,300 K and over a wide variety of crystals provides strong confirmation for the existence of the specialized diffusive motion at the melting point, as well as confirmation of a relation between the phonon spectrum of the solid crystal and diffusive motion in the melt. 21 refs., 2 tabs

  7. Differential operators associated with Gegenbauer polynomials - 2: The limit-point case

    International Nuclear Information System (INIS)

    Onyango Otieno, V.P.

    1987-10-01

    In this paper we study the limit-point case of the Gegenbauer differential equation -((1-x 2 ) υ+1/2 y'(x)) 1 +υ 2 (1-x 2 ) υ-1/2 y(x)=λ(1-x 2 ) υ-1/2 y(x), (x ε (-1,1), λ ε C) in both the so-called right-definite and left-definite cases based partially on a classical approach due to E.C. Titchmarsh. We then link the Titchmarsh approach with operator theoretic results in the spaces L 2 w (-1,1) and H 2 p,q (-1,1). (author). 19 refs

  8. Deconfinement at the Argyres-Douglas point in SU(2) gauge theory with broken N=2 supersymmetry

    International Nuclear Information System (INIS)

    Gorsky, A.; Vainshtein, A.; Yung, A.

    2000-01-01

    We consider chiral condensates in SU(2) gauge theory with broken N=2 supersymmetry. The matter sector contains an adjoint multiplet and one fundamental flavor. Matter and gaugino condensates are determined by integrating out the adjoint field. The only nonperturbative input is the Affleck-Dine-Seiberg (ADS) superpotential generated by one instanton plus the Konishi anomaly. These results are consistent with those obtained by the 'integrating in' procedure, including a reproduction of the Seiberg-Witten curve from the ADS superpotential. We then calculate monopole, dyon, and charge condensates using the Seiberg-Witten approach. We show that the monopole and charge condensates vanish at the Argyres-Douglas point where the monopole and charge vacua collide. We interpret this phenomenon as a deconfinement of electric and magnetic charges at the Argyres-Douglas point

  9. Gluon 2- and 3-Point Correlation Functions on the Lattice

    OpenAIRE

    Parrinello, Claudio

    1993-01-01

    I present some preliminary results, obtained in collaboration with C. Bernard and A. Soni, for the lattice evaluation of 2- and 3-point gluon correlation functions in momentum space, with emphasis on the amputated 3-gluon vertex function. The final goal of this approach is the study of the running QCD coupling constant as defined from the amputated 3-gluon vertex.

  10. 2- and 3-point gluon correlation functions on the lattice

    Energy Technology Data Exchange (ETDEWEB)

    Parrinello, C. (Dept. of Physics, Univ. of Edinburgh (United Kingdom))

    1994-04-01

    I present some preliminary results, obtained in collaboration with C. Bernard and A. Soni, for the lattice evaluation of 2- and 3-point gluon correlation functions in momentum space, with emphasis on the amputated 3-gluon vertex function. The final goal of this approach is the study of the running QCD coupling constant as defined from the amputated 3-gluon vertex. (orig.)

  11. Supercritical CO2 Brayton cycle compression and control near the critical point

    International Nuclear Information System (INIS)

    Wright, S. A.; Fuller, R.; Noall, J.; Radel, R.; Vernon, M. E.; Pickard, P. S.

    2008-01-01

    This report describes the supercritical compression and control issues, the analysis, and the measured test results of a small-scale supercritical CO 2 (S-CO 2 ) compression test-loop. The test loop was developed by Sandia and is described in a companion paper in this conference. The results of these experiments will for the first time evaluate and experimentally demonstrate supercritical compression and the required compressor inlet control approaches on an appropriate scale in a series of test loops at Sandia National Laboratories. The Sandia effort is focused on the main compressor of a supercritical Brayton loop while a separate DOE Gen lV program focus is on studying similar behavior in re-compression Brayton cycles that have dual compressors. One of the main goals of this program is to develop and demonstrate the ability to design, operate, and control the supercritical compression process near the critical point due to highly non-linear behavior near this point. This Sandia supercritical test-loop uses a 50 kW radial compressor to pump supercritical CO 2 (S-CO 2 ) through an orifice and through a water-cooled gas-chiller. At the design point the compressor flow rate is 3.5 kg/s, the inlet pressure is 7, 690 kPa, the pressure ratio is 1.8, the inlet temperature is 305 K, and the shaft speed is 75, 000 rpm. The purpose of the loop is to study the compression and control issues near the critical point. To study compression we intend to compare the design code predictions for efficiency and change in enthalpy (or pressure ratio / head) of the radial compressor with the measured results from actual tests. In the tests the inlet flow, temperature, and pressure, will be varied around the critical point of CO 2 (Tc=304.2 K, and Pc=7.377 MPa). To study control, the test loop will use a variety of methods including inventory control, shaft speed control, and cooling water flow rate, and cooling water temperature control methods to set the compressor inlet temperature

  12. Optimum BMI cut points to screen asian americans for type 2 diabetes.

    Science.gov (United States)

    Araneta, Maria Rosario G; Kanaya, Alka M; Hsu, William C; Chang, Healani K; Grandinetti, Andrew; Boyko, Edward J; Hayashi, Tomoshige; Kahn, Steven E; Leonetti, Donna L; McNeely, Marguerite J; Onishi, Yukiko; Sato, Kyoko K; Fujimoto, Wilfred Y

    2015-05-01

    Asian Americans manifest type 2 diabetes at low BMI levels but may not undergo diagnostic testing for diabetes if the currently recommended BMI screening cut point of ≥25 kg/m(2) is followed. We aimed to ascertain an appropriate lower BMI cut point among Asian-American adults without a prior diabetes diagnosis. We consolidated data from 1,663 participants, ages ≥45 years, without a prior diabetes diagnosis, from population- and community-based studies, including the Mediators of Atherosclerosis in South Asians Living in America study, the North Kohala Study, the Seattle Japanese American Community Diabetes Study, and the University of California San Diego Filipino Health Study. Clinical measures included a 2-h 75-g oral glucose tolerance test, BMI, and glycosylated hemoglobin (HbA1c). Mean age was 59.7 years, mean BMI was 25.4 kg/m(2), 58% were women, and type 2 diabetes prevalence (American Diabetes Association 2010 criteria) was 16.9%. At BMI ≥25 kg/m(2), sensitivity (63.7%), specificity (52.8%), and Youden index (0.16) values were low; limiting screening to BMI ≥25 kg/m(2) would miss 36% of Asian Americans with type 2 diabetes. For screening purposes, higher sensitivity is desirable to minimize missing cases, especially if the diagnostic test is relatively simple and inexpensive. At BMI ≥23 kg/m(2), sensitivity (84.7%) was high in the total sample and by sex and Asian-American subgroup and would miss only ∼15% of Asian Americans with diabetes. The BMI cut point for identifying Asian Americans who should be screened for undiagnosed type 2 diabetes should be <25 kg/m(2), and ≥23 kg/m(2) may be the most practical. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  13. Leaky RAG Deficiency in Adult Patients with Impaired Antibody Production against Bacterial Polysaccharide Antigens.

    Directory of Open Access Journals (Sweden)

    Christoph B Geier

    Full Text Available Loss of function mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause a T-B-NK+ type of severe combined immunodeficiency. In addition identification of hypomorphic mutations in RAG1 and RAG2 has led to an expansion of the spectrum of disease to include Omenn syndrome, early onset autoimmunity, granuloma, chronic cytomegalovirus- or EBV-infection with expansion of gamma/delta T-cells, idiophatic CD4 lymphopenia and a phenotype resembling common variable immunodeficiency. Herein we describe a novel presentation of leaky RAG1 and RAG2 deficiency in two unrelated adult patients with impaired antibody production against bacterial polysaccharide antigens. Clinical manifestation included recurrent pneumonia, sinusitis, otitis media and in one patient recurrent cutaneous vasculitis. Both patients harbored a combination of a null mutation on one allele with a novel hypomorphic RAG1/2 mutation on the other allele. One of these novel mutations affected the start codon of RAG1 and resulted in an aberrant gene and protein expression. The second novel RAG2 mutation leads to a truncated RAG2 protein, lacking the C-terminus with intact core RAG2 and reduced VDJ recombination capacity as previously described in a mouse model. Both patients presented with severely decreased numbers of naïve CD4+ T cells and defective T independent IgG responses to bacterial polysaccharide antigens, while T cell-dependent IgG antibody formation e.g. after tetanus or TBEV vaccination was intact. In conclusion, hypomorphic mutations in genes responsible for SCID should be considered in adults with predominantly antibody deficiency.

  14. Indian Point 2 steam generator tube rupture analyses

    International Nuclear Information System (INIS)

    Dayan, A.

    1985-01-01

    Analyses were conducted with RETRAN-02 to study consequences of steam generator tube rupture (SGTR) events. The Indian Point, Unit 2, power plant (IP2, PWR) was modeled as a two asymmetric loops, consisting of 27 volumes and 37 junctions. The break section was modeled once, conservatively, as a 150% flow area opening at the wall of the steam generator cold leg plenum, and once as a 200% double-ended tube break. Results revealed 60% overprediction of breakflow rates by the traditional conservative model. Two SGTR transients were studied, one with low-pressure reactor trip and one with an earlier reactor trip via over temperature ΔT. The former is more typical to a plant with low reactor average temperature such as IP2. Transient analyses for a single tube break event over 500 seconds indicated continued primary subcooling and no need for steam line pressure relief. In addition, SGTR transients with reactor trip while the pressurizer still contains water were found to favorably reduce depressurization rates. Comparison of the conservative results with independent LOFTRAN predictions showed good agreement

  15. How do ligands influence the quantum yields of cyclometalated platinum(ii) complexes, a theoretical research study.

    Science.gov (United States)

    Yang, Baozhu; Huang, Shuang; Wang, Jianhao

    2017-08-30

    A series of cyclometalated platinum(ii) complexes have been investigated with the TDDFT method. These complexes have similar structures but distinct phosphorescence quantum yields. Theoretical calculations were carried out to explain the differences in quantum yields from the conjugation effect of the cyclometalated ligand, molecular rigidity and ligand-field strength of the monodentate ligand. The radiative decay rate constants (k r ) have been discussed with the oscillator strength (f n ), the strength of the spin-orbit coupling (SOC) interaction between the lowest energy triplet excited state (T 1 ) and singlet excited states (S n ), and the energy gaps between E(T 1 ) and E(S n ). To illustrate the nonradiative decay processes, the transition states (TS) between the triplet metal-centered state ( 3 MC) and T 1 states have been optimized. In addition, the minimum energy crossing points (MECPs) between 3 MC and the ground states (S 0 ) were optimized. Finally, the potential energy curves along the nonradiative decay pathways are simulated. To obtain a phosphorescent complex with a high quantum yield, the complex should retain molecular rigidity well in the S 1 and T 1 states, while showing significant structural distortion at the MECP structure.

  16. Vapor pressure determination of liquid UO/sub 2/ using a boiling point technique

    International Nuclear Information System (INIS)

    Bober, M.; Singer, J.

    1987-01-01

    By analogy with the classic boiling point method, a quasi-stationary millisecond laser-heating technique was applied to measure the saturated vapor pressure curve of liquid UO/sub 2/ in the temperature range of 3500 to 4500 K. The results are represented by log rho (MPa)=5.049 - 23 042/T (K), which gives an average heat of vaporization of 441 kJ/mol and a normal boiling point of 3808 K. In addition, spectral emissivities of liquid UO/sub 2/ were determined as a function of the temperature at the pyrometer wavelengths of 752 and 1064 nm

  17. IAU 2015 Resolution B2 on Recommended Zero Points for the Absolute and Apparent Bolometric Magnitude Scales

    DEFF Research Database (Denmark)

    Mamajek, E. E.; Torres, G.; Prsa, A.

    2015-01-01

    The XXIXth IAU General Assembly in Honolulu adopted IAU 2015 Resolution B2 on recommended zero points for the absolute and apparent bolometric magnitude scales. The resolution was proposed by the IAU Inter-Division A-G Working Group on Nominal Units for Stellar and Planetary Astronomy after...... consulting with a broad spectrum of researchers from the astronomical community. Resolution B2 resolves the long-standing absence of an internationally-adopted zero point for the absolute and apparent bolometric magnitude scales. Resolution B2 defines the zero point of the absolute bolometric magnitude scale...... such that a radiation source with $M_{\\rm Bol}$ = 0 has luminosity L$_{\\circ}$ = 3.0128e28 W. The zero point of the apparent bolometric magnitude scale ($m_{\\rm Bol}$ = 0) corresponds to irradiance $f_{\\circ}$ = 2.518021002e-8 W/m$^2$. The zero points were chosen so that the nominal solar luminosity (3.828e26 W...

  18. Point of care testing of phospholipase A2 group IIA for serological diagnosis of rheumatoid arthritis

    Science.gov (United States)

    Liu, Nathan J.; Chapman, Robert; Lin, Yiyang; Mmesi, Jonas; Bentham, Andrew; Tyreman, Matthew; Abraham, Sonya; Stevens, Molly M.

    2016-02-01

    Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08423g

  19. Gentilly-2 and Point Lepreau divider plate replacement

    International Nuclear Information System (INIS)

    Schneider, W.; McClellan, G.; Weston, S.

    1996-01-01

    The steam generators at Hydro Quebec's Gentilly-2 and New Brunswick Power's Point Lepreau Nuclear Plants have been in operation since 1983, and were built with primary divider plates of a bolted panel configuration. During a routine outage inspection at Gentilly-2, it was noted that two bolts had dislodged from the divider plate and were located lying in the primary head. Subsequent inspections revealed erosion damage to a a substantial number of divider plate bolts and to a lesser extent, to the divider plate itself. After further inspection and repair the units were returned to operation, however, it was determined that a permanent replacement of the primary divider plates was going to be necessary. Upon evaluation of various options, it was decided that the panel type divider plates would be replaced with a single piece floating design. The divider plate itself was to be of one piece all-welded arrangement to be constructed from individual panels to be brought in through the manways. In view of the strength limitations of the bolted attachment of the upper seat bar to the tubesheet, a new welded seat was was provided. To counteract erosion concerns, the new divider plate is fitted with erosion resistant inserts of weld buildup and with improved sealing features in order to minimize leakage and erosion. At an advanced stage in the design and manufacture of the components, the issue of divider plate strength during loss of coolant accident (LOCA) conditions came into focus. Analysis was performed to determine the strength and/or failure characteristics of the divider plate to a variety of small and large LOCA conditions. Subsequently, Point Lepreau decided to replace their divider plates to address LOCA concerns. The paper describes the diagnosis of the original divider plates and the design. manufacture, field mobilization, installation and subsequent operation of the replacement divider plates. (author)

  20. Lessons Learned from OMI Observations of Point Source SO2 Pollution

    Science.gov (United States)

    Krotkov, N.; Fioletov, V.; McLinden, Chris

    2011-01-01

    The Ozone Monitoring Instrument (OMI) on NASA Aura satellite makes global daily measurements of the total column of sulfur dioxide (SO2), a short-lived trace gas produced by fossil fuel combustion, smelting, and volcanoes. Although anthropogenic SO2 signals may not be detectable in a single OMI pixel, it is possible to see the source and determine its exact location by averaging a large number of individual measurements. We describe new techniques for spatial and temporal averaging that have been applied to the OMI SO2 data to determine the spatial distributions or "fingerprints" of SO2 burdens from top 100 pollution sources in North America. The technique requires averaging of several years of OMI daily measurements to observe SO2 pollution from typical anthropogenic sources. We found that the largest point sources of SO2 in the U.S. produce elevated SO2 values over a relatively small area - within 20-30 km radius. Therefore, one needs higher than OMI spatial resolution to monitor typical SO2 sources. TROPOMI instrument on the ESA Sentinel 5 precursor mission will have improved ground resolution (approximately 7 km at nadir), but is limited to once a day measurement. A pointable geostationary UVB spectrometer with variable spatial resolution and flexible sampling frequency could potentially achieve the goal of daily monitoring of SO2 point sources and resolve downwind plumes. This concept of taking the measurements at high frequency to enhance weak signals needs to be demonstrated with a GEOCAPE precursor mission before 2020, which will help formulating GEOCAPE measurement requirements.

  1. Investigating genotype-phenotype relationships in Rett syndrome using an international data set.

    Science.gov (United States)

    Bebbington, A; Anderson, A; Ravine, D; Fyfe, S; Pineda, M; de Klerk, N; Ben-Zeev, B; Yatawara, N; Percy, A; Kaufmann, W E; Leonard, H

    2008-03-11

    Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype-phenotype relationships and compares these with previous findings in a population-based cohort. The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272). Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language. This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype-phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.

  2. Genetics Home Reference: Rett syndrome

    Science.gov (United States)

    ... Genetic Testing Registry: Rett syndrome Other Diagnosis and Management Resources (4 links) Boston Children's Hospital GeneReview: MECP2-Related Disorders MedlinePlus Encyclopedia: Rett Syndrome RettSyndrome.org: Rett Syndrome Clinics General Information from MedlinePlus (5 links) Diagnostic Tests ...

  3. Síndrome de Rett: 50 años de historia de un trastorno aun no bien conocido Rett syndrome: 50 years' history of a still not well known condition

    Directory of Open Access Journals (Sweden)

    Jaime Campos-Castello

    2007-01-01

    Full Text Available Desde que fue descrito por primera vez por Andreas Rett hace 50 años, el síndrome de Rett (SR ha sido objeto de muchas investigaciones, sin embargo continúa siendo un trastorno aún no bien conocido. Presentamos nuestra propia experiencia y una revisión de la literatura sobre el SR. Se trata de un trastorno del neurodesarrollo, dominante ligado a X, que afecta casi siempre a mujeres, la mayoría de los casos de forma esporádica. El diagnóstico de SR debe hacerse en base a la observación clínica. Las principales características son la aparición de un retraso mental, cambios conductuales, estereotipias, pérdida del lenguaje y, sobre todo, del uso propositivo de las manos, aparición de una apraxia de la marcha, presencia de alteraciones de la respiración y, frecuentemente, crisis epilépticas. Los criterios diagnósticos consensuados internacionalmente son aquí revisados. El SR se debe en la mayoría de casos a mutaciones del gen MECP2, si bien una proporción de casos atípicos puede estar causada por mutaciones de CDKL5, particularmente la variante con epilepsia precoz. Sin embargo, los mecanismos patogénicos moleculares no son bien conocidos, así como la relación entre las mutaciones de MECP2 y otros trastornos del desarrollo. Revisamos también los hallazgos de neuroimagen, neuropatológicos y neurobioquímicos descritos en el SR. Respecto al tratamiento, aparte del sintomático, no hay ninguno que se haya mostrado eficaz. Un trabajo reciente abre perspectivas terapéuticas futuras al haber demostrado mediante un modelo animal de ratón la reversión de los síntomas neurológicos mediante la activación de la expresión de MeCP2.Since it was first described by Andrea Rett 50 years ago, Rett syndrome (RS has been the subject of further investigations, nonetheless it continues to be a not well known condition. Our own experience and an updated literature review on RS is presented. RS is a severe dominant X chromosome

  4. Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses

    Directory of Open Access Journals (Sweden)

    Haowen Liu

    2018-02-01

    Full Text Available The locomotion of C. elegans is balanced by excitatory and inhibitory neurotransmitter release at neuromuscular junctions. However, the molecular mechanisms that maintain the balance of synaptic transmission remain enigmatic. Here, we investigated the function of voltage-gated Ca2+ channels in triggering spontaneous release at cholinergic and GABAergic synapses. Recordings of the miniature excitatory/inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively showed that UNC-2/CaV2 and EGL-19/CaV1 channels are the two major triggers for spontaneous release. Notably, however, Ca2+-independent spontaneous release was observed at GABAergic but not cholinergic synapses. Functional screening led to the identification of hypomorphic unc-64/Syntaxin-1A and snb-1/VAMP2 mutants in which mEPSCs are severely impaired, whereas mIPSCs remain unaltered, indicating differential regulation of these currents at cholinergic and GABAergic synapses. Moreover, Ca2+-independent spontaneous GABA release was nearly abolished in the hypomorphic unc-64 and snb-1 mutants, suggesting distinct mechanisms for Ca2+-dependent and Ca2+-independent spontaneous release.

  5. Infrared conformality and bulk critical points: SU(2) with heavy adjoint quarks

    CERN Document Server

    Lucini, Biagio; Rago, Antonio; Rinaldi, Enrico

    2013-01-01

    The lattice phase structure of a gauge theory can be a serious obstruction to Monte Carlo studies of its continuum behaviour. This issue is particularly delicate when numerical studies are performed to determine whether a theory is in a (near-)conformal phase. In this work we investigate the heavy mass limit of the SU(2) gauge theory with Nf=2 adjoint fermions and its lattice phase diagram, showing the presence of a critical point ending a line of first order bulk phase transition. The relevant gauge observables and the low-lying spectrum are monitored in the vicinity of the critical point with very good control over different systematic effects. The scaling properties of masses and susceptibilities open the possibility that the effective theory at criticality is a scalar theory in the universality class of the four-dimensional Gaussian model. This behaviour is clearly different from what is observed for SU(2) gauge theory with two dynamical adjoint fermions, whose (near-)conformal numerical signature is henc...

  6. Fixed point and anomaly mediation in partial {\\boldsymbol{N}}=2 supersymmetric standard models

    Science.gov (United States)

    Yin, Wen

    2018-01-01

    Motivated by the simple toroidal compactification of extra-dimensional SUSY theories, we investigate a partial N = 2 supersymmetric (SUSY) extension of the standard model which has an N = 2 SUSY sector and an N = 1 SUSY sector. We point out that below the scale of the partial breaking of N = 2 to N = 1, the ratio of Yukawa to gauge couplings embedded in the original N = 2 gauge interaction in the N = 2 sector becomes greater due to a fixed point. Since at the partial breaking scale the sfermion masses in the N = 2 sector are suppressed due to the N = 2 non-renormalization theorem, the anomaly mediation effect becomes important. If dominant, the anomaly-induced masses for the sfermions in the N = 2 sector are almost UV-insensitive due to the fixed point. Interestingly, these masses are always positive, i.e. there is no tachyonic slepton problem. From an example model, we show interesting phenomena differing from ordinary MSSM. In particular, the dark matter particle can be a sbino, i.e. the scalar component of the N = 2 vector multiplet of {{U}}{(1)}Y. To obtain the correct dark matter abundance, the mass of the sbino, as well as the MSSM sparticles in the N = 2 sector which have a typical mass pattern of anomaly mediation, is required to be small. Therefore, this scenario can be tested and confirmed in the LHC and may be further confirmed by the measurement of the N = 2 Yukawa couplings in future colliders. This model can explain dark matter, the muon g-2 anomaly, and gauge coupling unification, and relaxes some ordinary problems within the MSSM. It is also compatible with thermal leptogenesis.

  7. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

    DEFF Research Database (Denmark)

    Hansen, Lars; Tawamie, Hasan; Murakami, Yoshiko

    2013-01-01

    PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline...... mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated...... alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous...

  8. Double Dirac Point Semimetal in Two-Dimensional Material: Ta2Se3

    OpenAIRE

    Ma, Yandong; Jing, Yu; Heine, Thomas

    2017-01-01

    Here, we report by first-principles calculations one new stable 2D Dirac material, Ta2Se3 monolayer. For this system, stable layered bulk phase exists, and exfoliation should be possible. Ta2Se3 monolayer is demonstrated to support two Dirac points close to the Fermi level, achieving the exotic 2D double Dirac semimetal. And like 2D single Dirac and 2D node-line semimetals, spin-orbit coupling could introduce an insulating state in this new class of 2D Dirac semimetals. Moreover, the Dirac fe...

  9. Radar Image Simulation: Validation of the Point Scattering Method. Volume 2

    Science.gov (United States)

    1977-09-01

    the Engineer Topographic Labor - atory (ETL), Fort Belvoir, Virginia. This Radar Simulation Study was performed to validate the point tcattering radar...e.n For radar, the number of Independent samples in a given re.-olution cell is given by 5 ,: N L 2w (16) L Acoso where: 0 Radar incidence angle; w

  10. Stable Weyl points, trivial surface states, and particle-hole compensation in WP2

    Science.gov (United States)

    Razzoli, E.; Zwartsenberg, B.; Michiardi, M.; Boschini, F.; Day, R. P.; Elfimov, I. S.; Denlinger, J. D.; Süss, V.; Felser, C.; Damascelli, A.

    2018-05-01

    A possible connection between extremely large magnetoresistance and the presence of Weyl points has garnered much attention in the study of topological semimetals. Exploration of these concepts in transition-metal diphosphides WP2 has been complicated by conflicting experimental reports. Here we combine angle-resolved photoemission spectroscopy (ARPES) and density functional theory (DFT) calculations to disentangle surface and bulk contributions to the ARPES intensity, the superposition of which has plagued the determination of the band structure in WP2. Our results show that while the hole- and electronlike Fermi surface sheets originating from surface states have different areas, the bulk-band structure of WP2 is electron-hole compensated in agreement with DFT. Furthermore, the ARPES band structure is compatible with the presence of at least four temperature-independent Weyl points, confirming the topological nature of WP2 and its stability against lattice distortions.

  11. DXA measurements in rett syndrome reveal small bones with low bone mass

    DEFF Research Database (Denmark)

    Roende, Gitte; Ravn, Kirstine; Fuglsang, Kathrine

    2011-01-01

    Low bone mass is reported in growth-retarded patients harboring mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients...

  12. Modulation of DNA methylation machineries in Japanese rice fish (Oryzias latipes) embryogenesis by ethanol and 5-azacytidine.

    Science.gov (United States)

    Dasmahapatra, Asok K; Khan, Ikhlas A

    2016-01-01

    As a sequel of our investigations on the impact of epigenome in inducing fetal alcohol spectrum disorder (FASD) phenotypes in Japanese rice fish, we have investigated on several DNA methylation machinery genes including DNA methyl transferase 3ba (dnmt3ba) and methyl binding proteins (MBPs), namely, mbd1b, mbd3a, mbd3b, and mecp2 at the transcription level. Studies were made during normal development, from 0day post fertilization (dpf) to hatching, and also exposing the fertilized eggs to ethanol or a DNMT inhibitor, 5-azacytidine (5-azaC). We observed that during development, all these genes followed distinct expression patterns, generally high mRNA copies in early phases (0-1dpf) and significantly low mRNA copies prior to or after hatching. Ethanol (100-500mM, 0-2dpf) was unable to alter any of these mRNAs in 2dpf; additional four day (2-6dpf) maintenance of these embryos in ethanol-free environment, on 6dpf, was also unable to establish any significant difference in these mRNA levels in comparison with the corresponding controls. However, continuous exposure of fertilized eggs in 300mM ethanol, 0-6dpf, showed significantly high mRNA copies only in MBPs (mbd1b, mbd3a, mbd3b, mecp2). 5-azaC (2mM) on 2dpf was able to enhance only mbd3b mRNA. Removal of 5-azaC and maintenance of these embryos in clean medium, 2-6dpf, showed significantly enhanced mbd3b and mecp2 mRNAs compared to corresponding controls on 6dpf. Our studies showed that in Japanese rice fish embryogenesis both ethanol and 5-azaC have the potential to specifically modulate the developmental rhythm of DNA methylation machineries. Published by Elsevier Inc.

  13. Quasiparticle mass enhancement close to the quantum critical point in BaFe2(As(1-x)P(x))2.

    Science.gov (United States)

    Walmsley, P; Putzke, C; Malone, L; Guillamón, I; Vignolles, D; Proust, C; Badoux, S; Coldea, A I; Watson, M D; Kasahara, S; Mizukami, Y; Shibauchi, T; Matsuda, Y; Carrington, A

    2013-06-21

    We report a combined study of the specific heat and de Haas-van Alphen effect in the iron-pnictide superconductor BaFe2(As(1-x)P(x))2. Our data when combined with results for the magnetic penetration depth give compelling evidence for the existence of a quantum critical point close to x=0.30 which affects the majority of the Fermi surface by enhancing the quasiparticle mass. The results show that the sharp peak in the inverse superfluid density seen in this system results from a strong increase in the quasiparticle mass at the quantum critical point.

  14. Demerit points systems.

    NARCIS (Netherlands)

    2006-01-01

    In 2012, 21 of the 27 EU Member States had some form of demerit points system. In theory, demerit points systems contribute to road safety through three mechanisms: 1) prevention of unsafe behaviour through the risk of receiving penalty points, 2) selection and suspension of the most frequent

  15. Recent advances in understanding synaptic abnormalities in Rett syndrome [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Michael Johnston

    2015-12-01

    Full Text Available Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2 transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory synapses. In fact, it can be argued that Rett syndrome is primarily a disorder of synaptic plasticity and that agents that can correct this imbalance may have beneficial effects on brain development. This review briefly summarizes the link between disrupted synaptic plasticity mechanisms and Rett syndrome and early clinical trials that aim to target these abnormalities to improve the outcome for these severely disabled children.

  16. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy.

    Science.gov (United States)

    Fehr, Stephanie; Wilson, Meredith; Downs, Jenny; Williams, Simon; Murgia, Alessandra; Sartori, Stefano; Vecchi, Marilena; Ho, Gladys; Polli, Roberta; Psoni, Stavroula; Bao, Xinhua; de Klerk, Nick; Leonard, Helen; Christodoulou, John

    2013-03-01

    The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.

  17. ICSW2AN : An Inter-vehicle Communication System Using Mobile Access Point over Wireless Wide Area Networks

    Science.gov (United States)

    Byun, Tae-Young

    This paper presents a prototype of inter-vehicle communication system using mobile access point that internetworks wired or wireless LAN and wireless WAN anywhere. Implemented mobile access point can be equipped with various wireless WAN interfaces such as WCDMA and HSDPA. Mobile access point in the IP mechanism has to process connection setup procedure to one wireless WAN. To show the applicability of the mobile access point to inter-vehicle communication, a simplified V2I2V-based car communication system called ICSW2AN is implemented to evaluate major performance metrics by road test. In addition, results of road test for traffic information service are investigated in view of RTT, latency and server processing time. The experimental result indicates that V2I2V-based car communication system sufficiently can provide time-tolerant traffic information to moving vehicles while more than two mobile devices in restricted spaces such as car, train and ship access wireless Internet simultaneously.

  18. Point-to-point people with purpose—Exploring the possibility of a commercial traveler market for point-to-point suborbital space transportation

    Science.gov (United States)

    Webber, Derek

    2013-12-01

    An argument was made at the First Arcachon Conference on Private Human Access to Space in 2008 [1] that some systematic market research should be conducted into potential market segments for point-to-point suborbital space transportation (PtP), in order to understand whether a commercial market exists which might augment possible government use for such a vehicle. The cargo market potential was subsequently addressed via desk research, and the results, which resulted in a pessimistic business case outlook, were presented in [2]. The same desk research approach is now used in this paper to address the potential business and wealthy individual passenger traveler market segment ("point-to-point people with purpose"). The results, with the assumed ticket pricing, are not encouraging.

  19. S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid in Rett syndrome and the effect of folinic acid supplementation

    NARCIS (Netherlands)

    Hagebeuk, Eveline E. O.; Duran, Marinus; Abeling, Nico G. G. M.; Vyth, Arno; Poll-The, Bwee Tien

    2013-01-01

    Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate

  20. Strategies for satellite-based monitoring of CO2 from distributed area and point sources

    Science.gov (United States)

    Schwandner, Florian M.; Miller, Charles E.; Duren, Riley M.; Natraj, Vijay; Eldering, Annmarie; Gunson, Michael R.; Crisp, David

    2014-05-01

    Atmospheric CO2 budgets are controlled by the strengths, as well as the spatial and temporal variabilities of CO2 sources and sinks. Natural CO2 sources and sinks are dominated by the vast areas of the oceans and the terrestrial biosphere. In contrast, anthropogenic and geogenic CO2 sources are dominated by distributed area and point sources, which may constitute as much as 70% of anthropogenic (e.g., Duren & Miller, 2012), and over 80% of geogenic emissions (Burton et al., 2013). Comprehensive assessments of CO2 budgets necessitate robust and highly accurate satellite remote sensing strategies that address the competing and often conflicting requirements for sampling over disparate space and time scales. Spatial variability: The spatial distribution of anthropogenic sources is dominated by patterns of production, storage, transport and use. In contrast, geogenic variability is almost entirely controlled by endogenic geological processes, except where surface gas permeability is modulated by soil moisture. Satellite remote sensing solutions will thus have to vary greatly in spatial coverage and resolution to address distributed area sources and point sources alike. Temporal variability: While biogenic sources are dominated by diurnal and seasonal patterns, anthropogenic sources fluctuate over a greater variety of time scales from diurnal, weekly and seasonal cycles, driven by both economic and climatic factors. Geogenic sources typically vary in time scales of days to months (geogenic sources sensu stricto are not fossil fuels but volcanoes, hydrothermal and metamorphic sources). Current ground-based monitoring networks for anthropogenic and geogenic sources record data on minute- to weekly temporal scales. Satellite remote sensing solutions would have to capture temporal variability through revisit frequency or point-and-stare strategies. Space-based remote sensing offers the potential of global coverage by a single sensor. However, no single combination of orbit

  1. Performance of supercritical Brayton cycle using CO2-based binary mixture at varying critical points for SFR applications

    International Nuclear Information System (INIS)

    Jeong, Woo Seok; Jeong, Yong Hoon

    2013-01-01

    Highlights: • Supercritical CO 2 -based gas mixture Brayton cycles were investigated for a SFR. • The critical point of CO 2 is the lowest cycle operating limit of the S-CO 2 cycles. • Mixing additives with CO 2 changes the CO 2 critical point. • CO 2 –Xe and CO 2 –Kr cycles achieve higher cycle efficiencies than the S-CO 2 cycles. • CO 2 –H 2 S and CO 2 –cyclohexane cycles perform better at higher heat sink temperatures. -- Abstract: The supercritical carbon dioxide Brayton cycle (S-CO 2 cycle) has attracted much attention as an alternative to the Rankine cycle for sodium-cooled fast reactors (SFRs). The higher cycle efficiency of the S-CO 2 cycle results from the considerably decreased compressor work because the compressor behaves as a pump in the proximity of the CO 2 vapor–liquid critical point. In order to fully utilize this feature, the main compressor inlet condition should be controlled to be close to the critical point of CO 2 . This indicates that the critical point of CO 2 is a constraint on the minimum cycle condition for S-CO 2 cycles. Modifying the CO 2 critical point by mixing additive gases could be considered as a method of enhancing the performance and broadening the applicability of the S-CO 2 cycle. Due to the drastic fluctuations of the thermo-physical properties of fluids near the critical point, an in-house cycle analysis code using the NIST REFPROP database was implemented. Several gases were selected as potential additives considering their thermal stability and chemical interaction with sodium in the temperature range of interest and the availability of the mixture property database: xenon, krypton, hydrogen sulfide, and cyclohexane. The performances of the optimized CO 2 -containing binary mixture cycles with simple recuperated and recompression layouts were compared with the reference S-CO 2 , CO 2 –Ar, CO 2 –N 2 , and CO 2 –O 2 cycles. For the decreased critical temperatures, the CO 2 –Xe and CO 2

  2. Matter fields near quantum critical point in (2+1)-dimensional U(1) gauge theory

    International Nuclear Information System (INIS)

    Liu Guozhu; Li Wei; Cheng Geng

    2010-01-01

    We study chiral phase transition and confinement of matter fields in (2+1)-dimensional U(1) gauge theory of massless Dirac fermions and scalar bosons. The vanishing scalar boson mass, r=0, defines a quantum critical point between the Higgs phase and the Coulomb phase. We consider only the critical point r=0 and the Coulomb phase with r>0. The Dirac fermion acquires a dynamical mass when its flavor is less than certain critical value N f c , which depends quantitatively on the flavor N b and the scalar boson mass r. When N f f c , the matter fields carrying internal gauge charge are all confined if r≠0 but are deconfined at the quantum critical point r=0. The system has distinct low-energy elementary excitations at the critical point r=0 and in the Coulomb phase with r≠0. We calculate the specific heat and susceptibility of the system at r=0 and r≠0, which can help to detect the quantum critical point and to judge whether dynamical fermion mass generation takes place.

  3. Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alternations in CNS Development

    Science.gov (United States)

    2009-10-01

    2004. MECP2 structural and 3’-UTR variants in schizophrenia , autism and other psychiatric diseases: a possible association with autism. Am J Med...inhibition, thus potentially enabling enhancement of remyelination. Role: PI Award letter dated 12/11/06 Noble (PI) Cure Autism Now Foundation 02/05

  4. Klinisk og molekylærgenetisk diagnostik af Retts syndrom i Danmark

    DEFF Research Database (Denmark)

    Schönewolf-Greulich, Bitten; Dunø, Morten; Ravn, Kirstine

    2015-01-01

    The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene MECP2. However, the basis of the diagnosis...

  5. Two Siblings With a CDKL5 Mutation: Genotype and Phenotype Evaluation

    NARCIS (Netherlands)

    Hagebeuk, Eveline E. O.; Marcelis, Carlo L.; Alders, Mariëlle; Kaspers, Ageeth; de Weerd, Al W.

    2015-01-01

    This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who

  6. Ppargamma2 is a key driver of longevity in the mouse.

    Directory of Open Access Journals (Sweden)

    Carmen Argmann

    2009-12-01

    Full Text Available Aging involves a progressive physiological remodeling that is controlled by both genetic and environmental factors. Many of these factors impact also on white adipose tissue (WAT, which has been shown to be a determinant of lifespan. Interrogating a transcriptional network for predicted causal regulatory interactions in a collection of mouse WAT from F2 crosses with a seed set of 60 known longevity genes, we identified a novel transcriptional subnetwork of 742 genes which represent thus-far-unknown longevity genes. Within this subnetwork, one gene was Pparg (Nr1c3, an adipose-enriched nuclear receptor previously not associated with longevity. In silico, both the PPAR signaling pathway and the transcriptional signature of Ppargamma agonist rosiglitazone overlapped with the longevity subnetwork, while in vivo, lowered expression of Pparg reduced lifespan in both the lipodystrophic Pparg1/2-hypomorphic and the Pparg2-deficient mice. These results establish Ppargamma2 as one of the determinants of longevity and suggest that lifespan may be rather determined by a purposeful genetic program than a random process.

  7. A global reference model of Curie-point depths based on EMAG2

    Science.gov (United States)

    Li, Chun-Feng; Lu, Yu; Wang, Jian

    2017-03-01

    In this paper, we use a robust inversion algorithm, which we have tested in many regional studies, to obtain the first global model of Curie-point depth (GCDM) from magnetic anomaly inversion based on fractal magnetization. Statistically, the oceanic Curie depth mean is smaller than the continental one, but continental Curie depths are almost bimodal, showing shallow Curie points in some old cratons. Oceanic Curie depths show modifications by hydrothermal circulations in young oceanic lithosphere and thermal perturbations in old oceanic lithosphere. Oceanic Curie depths also show strong dependence on the spreading rate along active spreading centers. Curie depths and heat flow are correlated, following optimal theoretical curves of average thermal conductivities K = ~2.0 W(m°C)-1 for the ocean and K = ~2.5 W(m°C)-1 for the continent. The calculated heat flow from Curie depths and large-interval gridding of measured heat flow all indicate that the global heat flow average is about 70.0 mW/m2, leading to a global heat loss ranging from ~34.6 to 36.6 TW.

  8. Brd2 disruption in mice causes severe obesity without Type 2 diabetes.

    Science.gov (United States)

    Wang, Fangnian; Liu, Hongsheng; Blanton, Wanda P; Belkina, Anna; Lebrasseur, Nathan K; Denis, Gerald V

    2009-12-14

    Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that wholebody disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated pro-inflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic beta-cells, where it normally inhibits beta-cell mitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-alpha (tumour necrosis factor-alpha)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.

  9. Third harmonic generation imaging of intact human cerebral organoids to assess key components of early neurogenesis in Rett Syndrome (Conference Presentation)

    Science.gov (United States)

    Yildirim, Murat; Feldman, Danielle; Wang, Tianyu; Ouzounov, Dimitre G.; Chou, Stephanie; Swaney, Justin; Chung, Kwanghun; Xu, Chris; So, Peter T. C.; Sur, Mriganka

    2017-02-01

    Rett Syndrome (RTT) is a pervasive, X-linked neurodevelopmental disorder that predominantly affects girls. It is mostly caused by a sporadic mutation in the gene encoding methyl CpG-binding protein 2 (MeCP2).The clinical features of RTT are most commonly reported to emerge between the ages of 6-18 months and implicating RTT as a disorder of postnatal development. However, a variety of recent evidence from our lab and others demonstrates that RTT phenotypes are present at the earliest stages of brain development including neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. We have used RTT patient-derived induced pluripotent stem cells to generate 3D human cerebral organoids that can serve as a model for human neurogenesis in vitro. We aim to expand on our existing findings in order to determine aberrancies at individual stages of neurogenesis by performing structural and immunocytochemical staining in isogenic control and MeCP2-deficient organoids. In addition, we aim to use Third Harmonic Generation (THG) microscopy as a label-free, nondestructive 3D tissue visualization method in order to gain a complete understanding of the structural complexity that underlies human neurogenesis. As a proof of concept, we have performed THG imaging in healthy intact human cerebral organoids cleared with SWITCH. We acquired an intrinsic THG signal with the following laser configurations: 400 kHz repetition rate, 65 fs pulse width laser at 1350 nm wavelength. In these THG images, nuclei are clearly delineated and cross sections demonstrate the depth penetration capacity (< 1mm) that extends throughout the organoid. Imaging control and MeCP2-deficient human cerebral organoids in 2D sections reveals structural and protein expression-based alterations that we expect will be clearly elucidated via both THG and three-photon fluorescence microscopy.

  10. Polymerization of methyl methacrylate by diphenylamido bis (methylcyclopentadienyl) ytterbium complex

    Institute of Scientific and Technical Information of China (English)

    WANG, Yao-Rong(王耀荣); SHEN, Qi(沈琪); MA, Jia-Le(马家乐); ZHAO, Qun(赵群)

    2000-01-01

    Methyl methacrylate (MMA) was effectively polymerized by diphenylamido bis(methyicyclopentadienyl) ytterbium complex (MeCp)2YbNPh2(THF). Tne reaction can be carried out over a range of polymerization temperature from - 40℃ to 40℃ and gives the polyMMA with high molecular weights.The initiation mechanism was demonstrated by diphenylamidoterminated methyl methacrylate oligomer.

  11. Teaching Molecular Symmetry of Dihedral Point Groups by Drawing Useful 2D Projections

    Science.gov (United States)

    Chen, Lan; Sun, Hongwei; Lai, Chengming

    2015-01-01

    There are two main difficulties in studying molecular symmetry of dihedral point groups. One is locating the C[subscript 2] axes perpendicular to the C[subscript n] axis, while the other is finding the s[subscript]d planes which pass through the C[subscript n] axis and bisect the angles formed by adjacent C[subscript 2] axes. In this paper, a…

  12. Tricritical point of a ferromagnetic transition in UGe2

    International Nuclear Information System (INIS)

    Kabeya, N; Iijima, R; Osaki, E; Ban, S; Imura, K; Deguchi, K; Sato, N K; Aso, N; Homma, Y; Shiokawa, Y

    2010-01-01

    Thermal expansion and magnetostriction measurements of the superconducting ferromagnet UGe 2 under pressure were carried out. The temperature dependence of the thermal expansion coefficient shows a peak at the Curie temperature. When pressure is varied, the peak exhibits a maximum in the vicinity of a tricritical point (TCP), which separates the second-order phase transition from the first-order transition. From results of these measurements, we first construct the magnetic phase diagram including the TCP (P TCP ∼ 12.5 kbar). We also show that two lines characterizing the metamagnetism and the magnetic susceptibility emerge from the TCP. We argue that these magnetic properties in the vicinity of the TCP can be understood within a phenomenological frame of spin fluctuations.

  13. Critical points in magnetic systems

    International Nuclear Information System (INIS)

    Bongaarts, A.L.M.

    1975-01-01

    The magnetical phase transitions of CsCoCl 3 .2H 2 O and CsCoCl 3 .2D 2 O are investigated by neutron diffraction techniques with special attention to the critical points in the phase diagrams. CsCoCl 3 .2H 2 O turned out to be a one-dimentional magnetic antiferromagnet with ferromagnetic and antiferromagnetic interactions. In the vicinity of the Neel point, the critical behavior in zero magnetic field could be described as a three-dimentional long range ordering, while the fluctuations in the system are one-dimensional. In the presence of a magnetic field, the behavior of the system in the critical region of the magnetic phase diagram between the Neel temperature at zero field (3.3degK) and 1.85degK, was in good agreement with the theory. Below 1.85degK, the phase transition in a magnetic field changes into a line of triple points whose end point could be identified as a tricritical point, i.e., an intersection of three critical lines. The parameters derived from observations in the neighborhood of this tricritical point obey the scaling laws but are not in numerical agreement with theoretical predictions

  14. Throughput analysis of point-to-multi-point hybric FSO/RF network

    KAUST Repository

    Rakia, Tamer; Gebali, Fayez; Yang, Hong-Chuan; Alouini, Mohamed-Slim

    2017-01-01

    This paper presents and analyzes a point-to-multi-point (P2MP) network that uses a number of free-space optical (FSO) links for data transmission from the central node to the different remote nodes. A common backup radio-frequency (RF) link is used

  15. H-Ransac a Hybrid Point Cloud Segmentation Combining 2d and 3d Data

    Science.gov (United States)

    Adam, A.; Chatzilari, E.; Nikolopoulos, S.; Kompatsiaris, I.

    2018-05-01

    In this paper, we present a novel 3D segmentation approach operating on point clouds generated from overlapping images. The aim of the proposed hybrid approach is to effectively segment co-planar objects, by leveraging the structural information originating from the 3D point cloud and the visual information from the 2D images, without resorting to learning based procedures. More specifically, the proposed hybrid approach, H-RANSAC, is an extension of the well-known RANSAC plane-fitting algorithm, incorporating an additional consistency criterion based on the results of 2D segmentation. Our expectation that the integration of 2D data into 3D segmentation will achieve more accurate results, is validated experimentally in the domain of 3D city models. Results show that HRANSAC can successfully delineate building components like main facades and windows, and provide more accurate segmentation results compared to the typical RANSAC plane-fitting algorithm.

  16. 2-point functions in quantum cosmology

    International Nuclear Information System (INIS)

    Gielen, Steffen

    2012-01-01

    We discuss the path-integral formulation of quantum cosmology with a massless scalar field as a sum-over-histories, with particular reference to loop quantum cosmology. Exploiting the analogy with the relativistic particle, we give a complete overview of the possible two-point functions, deriving vertex expansions and composition laws they satisfy. We clarify the tie between definitions using a group averaging procedure and those in a deparametrised framework. We draw some conclusions about the physics of a single quantum universe and multiverse field theories where the role of these sectors and the inner product are reinterpreted.

  17. BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs

    Directory of Open Access Journals (Sweden)

    Finnson Kenneth

    2010-02-01

    Full Text Available Abstract Background Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas in axolotl limbs as in other tetrapods. It has been suggested that BMP-2 may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since BMP-2 expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether BMP-2 expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration. Results The expression of BMP-2 and SOX-9 in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration but did not affect the expression of BMP-2 and SOX-9. Overexpression of BMP-2 in regenerating limbs caused a loss of digits. Overexpression of Noggin (BMP inhibitor in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to BMP-2 overexpression was the result of increased cell condensation and apoptosis while the loss caused by Noggin was due to a decrease in cell division. Conclusion The expression of BMP-2 and its target SOX-9 was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has

  18. Standardized End Point Definitions for Coronary Intervention Trials: The Academic Research Consortium-2 Consensus Document.

    Science.gov (United States)

    Garcia-Garcia, Hector M; McFadden, Eugène P; Farb, Andrew; Mehran, Roxana; Stone, Gregg W; Spertus, John; Onuma, Yoshinobu; Morel, Marie-Angèle; van Es, Gerrit-Anne; Zuckerman, Bram; Fearon, William F; Taggart, David; Kappetein, Arie-Pieter; Krucoff, Mitchell W; Vranckx, Pascal; Windecker, Stephan; Cutlip, Donald; Serruys, Patrick W

    2018-06-14

    The Academic Research Consortium (ARC)-2 initiative revisited the clinical and angiographic end point definitions in coronary device trials, proposed in 2007, to make them more suitable for use in clinical trials that include increasingly complex lesion and patient populations and incorporate novel devices such as bioresorbable vascular scaffolds. In addition, recommendations for the incorporation of patient-related outcomes in clinical trials are proposed. Academic Research Consortium-2 is a collaborative effort between academic research organizations in the United States and Europe, device manufacturers, and European, US, and Asian regulatory bodies. Several in-person meetings were held to discuss the changes that have occurred in the device landscape and in clinical trials and regulatory pathways in the last decade. The consensus-based end point definitions in this document are endorsed by the stakeholders of this document and strongly advocated for clinical trial purposes. This Academic Research Consortium-2 document provides further standardization of end point definitions for coronary device trials, incorporating advances in technology and knowledge. Their use will aid interpretation of trial outcomes and comparison among studies, thus facilitating the evaluation of the safety and effectiveness of these devices.

  19. The Potential for Electrofuels Production in Sweden Utilizing Fossil and Biogenic CO2 Point Sources

    International Nuclear Information System (INIS)

    Hansson, Julia; Hackl, Roman; Taljegard, Maria; Brynolf, Selma; Grahn, Maria

    2017-01-01

    This paper maps, categorizes, and quantifies all major point sources of carbon dioxide (CO 2 ) emissions from industrial and combustion processes in Sweden. The paper also estimates the Swedish technical potential for electrofuels (power-to-gas/fuels) based on carbon capture and utilization. With our bottom-up approach using European databases, we find that Sweden emits approximately 50 million metric tons of CO 2 per year from different types of point sources, with 65% (or about 32 million tons) from biogenic sources. The major sources are the pulp and paper industry (46%), heat and power production (23%), and waste treatment and incineration (8%). Most of the CO 2 is emitted at low concentrations (<15%) from sources in the southern part of Sweden where power demand generally exceeds in-region supply. The potentially recoverable emissions from all the included point sources amount to 45 million tons. If all the recoverable CO 2 were used to produce electrofuels, the yield would correspond to 2–3 times the current Swedish demand for transportation fuels. The electricity required would correspond to about 3 times the current Swedish electricity supply. The current relatively few emission sources with high concentrations of CO 2 (>90%, biofuel operations) would yield electrofuels corresponding to approximately 2% of the current demand for transportation fuels (corresponding to 1.5–2 TWh/year). In a 2030 scenario with large-scale biofuels operations based on lignocellulosic feedstocks, the potential for electrofuels production from high-concentration sources increases to 8–11 TWh/year. Finally, renewable electricity and production costs, rather than CO 2 supply, limit the potential for production of electrofuels in Sweden.

  20. The four point correlations of all primary operators of the d=2 conformally invariant SU(2) sigma-model with Wess-Zumino term

    International Nuclear Information System (INIS)

    Christe, P.; Flume, R.

    1986-05-01

    We derive a contour integral representation for the four point correlations of all primary operators in the conformally invariant two-dimensional SU(2) sigma-model with Wess-Zumino term. The four point functions are identical in structure with those found in some special degenerate operator algebras with central Virasoro charge smaller than one. Using methods of Dotsenko and Fateev we evaluate for irrational values of the central SU(2) Kac-Moody charge the expansion coefficients of the algebra of Lorentz scalar operators. The conformal bootstrap provides in this case a unique determination. All SU(2) representations are non-trivially realised in the operator algebra. (orig.)

  1. Pb induces superconductivity in Bi2Se3 analyzed by point contact spectroscopy

    OpenAIRE

    Arevalo-López, P.; López-Romero, R. E.; Escudero, R.

    2015-01-01

    Some topological insulators become superconducting when doped with Cu and Pd. Superconductivity in a non-superconductor may be induced by proximity effect: i.e. Contacting a non-superconductor with a superconductor. The superconducting macroscopic wave function will induce electronic pairing into the normal compound. In the simplest topological insulator, Bi$_2$Se$_3$, superconductivity may be induced with Pb. We studied with point contact junctions formed by contacting Bi$_2$Se$_3$ crystals ...

  2. Critical-point nuclei

    International Nuclear Information System (INIS)

    Clark, R.M.

    2004-01-01

    It has been suggested that a change of nuclear shape may be described in terms of a phase transition and that specific nuclei may lie close to the critical point of the transition. Analytical descriptions of such critical-point nuclei have been introduced recently and they are described briefly. The results of extensive searches for possible examples of critical-point behavior are presented. Alternative pictures, such as describing bands in the candidate nuclei using simple ΔK = 0 and ΔK = 2 rotational-coupling models, are discussed, and the limitations of the different approaches highlighted. A possible critical-point description of the transition from a vibrational to rotational pairing phase is suggested

  3. C-point and V-point singularity lattice formation and index sign conversion methods

    Science.gov (United States)

    Kumar Pal, Sushanta; Ruchi; Senthilkumaran, P.

    2017-06-01

    The generic singularities in an ellipse field are C-points namely stars, lemons and monstars in a polarization distribution with C-point indices (-1/2), (+1/2) and (+1/2) respectively. Similar to C-point singularities, there are V-point singularities that occur in a vector field and are characterized by Poincare-Hopf index of integer values. In this paper we show that the superposition of three homogenously polarized beams in different linear states leads to the formation of polarization singularity lattice. Three point sources at the focal plane of the lens are used to create three interfering plane waves. A radial/azimuthal polarization converter (S-wave plate) placed near the focal plane modulates the polarization states of the three beams. The interference pattern is found to host C-points and V-points in a hexagonal lattice. The C-points occur at intensity maxima and V-points occur at intensity minima. Modulating the state of polarization (SOP) of three plane waves from radial to azimuthal does not essentially change the nature of polarization singularity lattice as the Poincare-Hopf index for both radial and azimuthal polarization distributions is (+1). Hence a transformation from a star to a lemon is not trivial, as such a transformation requires not a single SOP change, but a change in whole spatial SOP distribution. Further there is no change in the lattice structure and the C- and V-points appear at locations where they were present earlier. Hence to convert an interlacing star and V-point lattice into an interlacing lemon and V-point lattice, the interferometer requires modification. We show for the first time a method to change the polarity of C-point and V-point indices. This means that lemons can be converted into stars and stars can be converted into lemons. Similarly the positive V-point can be converted to negative V-point and vice versa. The intensity distribution in all these lattices is invariant as the SOPs of the three beams are changed in an

  4. A systematic analysis of the Braitenberg vehicle 2b for point-like stimulus sources

    International Nuclear Information System (INIS)

    Rañó, Iñaki

    2012-01-01

    Braitenberg vehicles have been used experimentally for decades in robotics with limited empirical understanding. This paper presents the first mathematical model of the vehicle 2b, displaying so-called aggression behaviour, and analyses the possible trajectories for point-like smooth stimulus sources. This sensory-motor steering control mechanism is used to implement biologically grounded target approach, target-seeking or obstacle-avoidance behaviour. However, the analysis of the resulting model reveals that complex and unexpected trajectories can result even for point-like stimuli. We also prove how the implementation of the controller and the vehicle morphology interact to affect the behaviour of the vehicle. This work provides a better understanding of Braitenberg vehicle 2b, explains experimental results and paves the way for a formally grounded application on robotics as well as for a new way of understanding target seeking in biology. (paper)

  5. Numerical Analysis of S-CO{sub 2} Test Loop Transient Conditions near the Critical Point of CO{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Seong Jun; Oh, Bongseong; Ahn, Yoonhan; Baik, Seongjoon; Lee, Jekyoung; Lee, Jeong Ik [KAIST, Daejeon (Korea, Republic of)

    2016-05-15

    It was identified that controlling CO{sub 2} compressor operation near the critical point is one of the most important issues to operate a S-CO{sub 2} Brayton cycle with a high efficiency. Despite the growing interest in the S-CO{sub 2} Brayton cycle, a few previous research on the transient analysis of the S-CO{sub 2} system has been conducted previously. Moreover, previous studies have some limitation in the modelled test facility, and the experiment was not performed to observe specific scenario. The KAIST research team has conducted S-CO{sub 2} system transient experiments with the CO{sub 2} compressing test facility called SCO{sub 2}PE (Supercritical CO{sub 2} Pressurizing Experiment) at KAIST In this study, authors use the transient analysis code GAMMA (Gas Multidimensional Multicomponent mixture Analysis) code for analyzing the experiment. Two transient scenarios were selected in this study; over cooling and under cooling situations. The selected transient situation is of particular interest since the compressor inlet conditions start to drift away from the critical point of CO{sub 2}. The results represent that the GAMMA code can simulate the S-CO{sub 2} test facility, SCO{sub 2}PE. However, as shown in the cooling water flow rate increasing scenario, the GAMMA code shows calculation error when the phase change occurs. Furthermore, although the results of the cooling water flow rate decrease case shows reasonable agreement with the experimental data, there are still some unexplained differences between the experimental data and the GAMMA code prediction.

  6. Gene expression analysis in lymphoblasts derived from patients with autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    Yasuda Yuka

    2011-05-01

    Full Text Available Abstract Background The autism spectrum disorders (ASDs are complex neurodevelopmental disorders that result in severe and pervasive impairment in the development of reciprocal social interaction and verbal and nonverbal communication skills. In addition, individuals with ASD have stereotypical behavior, interests and activities. Rare mutations of some genes, such as neuroligin (NLGN 3/4, neurexin (NRXN 1, SHANK3, MeCP2 and NHE9, have been reported to be associated with ASD. In the present study, we investigated whether alterations in mRNA expression levels of these genes could be found in lymphoblastoid cell lines derived from patients with ASD. Methods We measured mRNA expression levels of NLGN3/4, NRXN1, SHANK3, MeCP2, NHE9 and AKT1 in lymphoblastoid cells from 35 patients with ASD and 35 healthy controls, as well as from 45 patients with schizophrenia and 45 healthy controls, using real-time quantitative reverse transcriptase polymerase chain reaction assays. Results The mRNA expression levels of NLGN3 and SHANK3 normalized by β-actin or TBP were significantly decreased in the individuals with ASD compared to controls, whereas no difference was found in the mRNA expression level of MeCP2, NHE9 or AKT1. However, normalized NLGN3 and SHANK3 gene expression levels were not altered in patients with schizophrenia, and expression levels of NLGN4 and NRXN1 mRNA were not quantitatively measurable in lymphoblastoid cells. Conclusions Our results provide evidence that the NLGN3 and SHANK3 genes may be differentially expressed in lymphoblastoid cell lines from individuals with ASD compared to those from controls. These findings suggest the possibility that decreased mRNA expression levels of these genes might be involved in the pathophysiology of ASD in a substantial population of ASD patients.

  7. Browse Title Index

    African Journals Online (AJOL)

    Items 301 - 350 of 462 ... Vol 13, No 1 (2012), Molecular analysis of MECP2 gene in ... MA Shaheen, SM Zaki, AA El-Sayed, NM Sayed, AA Abdel Aziz, ... Vol 18, No 3 (2017), Molecular genetic analysis of Type II diabetes associated m.3243A>G mitochondrial ... syndrome pregnancy: An updated meta-analysis, Abstract PDF.

  8. GUI2QAD, Graphical Interface for QAD-CGPIC, Point Kernel for Shielding Calculations

    International Nuclear Information System (INIS)

    2001-01-01

    1 - Description of program or function: GUI2QAD is an aid in preparation of input for the included QAD-CGPIC program, which is based on CCC-493/QAD-CGGP and PICTURE. QAD-CGPIC, which is included in this distribution, is a Fortran code for neutron and gamma-ray shielding calculations by the point kernel method. Provision is available to interactively view the geometry of the system. QAD-CG calculates fast-neutron and gamma-ray penetration through various shield configurations defined by combinatorial geometry specifications. The code can use the ANS-6.4.3 1990 buildup factor compilation (26 materials). 2 - Methods:The code QAD-CGPIC is based on point kernel method and has a provision to select either GP or Capo's build up factors. 3 - Restrictions on the complexity of the problem: Details on restrictions and limitations are available in the RSICC code manual CCC-493/QAD-CGGP. Because CCC-493 was obsoleted by CCC-645/QAD-CGGP-A, the CCC-493 documentation is not online but is included with this package. This package includes a Graphical User Interface to facilitate use

  9. Vitamin D Deficiency is Prevalent in Females with Rett Syndrome

    Science.gov (United States)

    Motil, Kathleen J.; Barrish, Judy O.; Lane, Jane; Geerts, Suzanne P.; Annese, Fran; McNair, Lauren; Percy, Alan K.; Skinner, Steven A; Neul, Jeffrey L.; Glaze, Daniel G.

    2013-01-01

    Objectives To determine the prevalence of vitamin D deficiency and identify the relation between 25-hydroxyvitamin D [25(OH)D] levels and the consumption of dietary sources of vitamin D or exposure to anticonvulsants in females with Rett syndrome (RTT). Study design Retrospective review of the medical records of 284 females with RTT to determine serum 25(OH)D and parathyroid hormone levels, nutritional status, dietary sources of vitamin D, exposure to anticonvulsants, degree of mobility, and MECP2 status. Results Twenty percent of females who were tested (n=157) had 25(OH)D levels Anticonvulsants were used by 57% and 39% ambulated independently. Median 25(OH)D levels were lower in individuals who did not receive multivitamin supplements (panticonvulsants, degree of mobility, and MECP2 status did not influence 25(OH)D levels. Conclusion Vitamin D deficiency is prevalent in females with RTT. The use of multivitamin supplements or commercial formulas is associated with improved vitamin D levels. Attention to vitamin D may enhance bone mineral deposition and reduce the frequency of bone fractures in these individuals. PMID:21637127

  10. A dissipated energy comparison to evaluate fatigue resistance using 2-point bending

    Directory of Open Access Journals (Sweden)

    Cinzia Maggiore

    2014-02-01

    Full Text Available Fatigue is the main failure mode in pavement engineering. Typically, micro-cracks originate at the bottom of asphalt concrete layer due to horizontal tensile strains. Micro-cracks start to propagate towards the upper layers under repeated loading which can lead to pavement failure. Different methods are usually used to describe fatigue behavior in asphalt materials such as: phenomenological approach, fracture mechanics approach and dissipated energy approach. This paper presents a comparison of fatigue resistances calculated for different dissipated energy models using 2-point bending (2PB at IFSTTAR in Nantes. 2PB tests have been undertaken under different loading and environmental conditions in order to evaluate the properties of the mixtures (stiffness, dissipated energy, fatigue life and healing effect.

  11. Molecular analysis of MECP2 gene in Egyptian patients with Rett ...

    African Journals Online (AJOL)

    Maha S. Zaki

    2011-12-28

    Dec 28, 2011 ... criteria of the classic form and can be milder or more severe. The milder .... 4. Discussion. RTT is one of the most common causes of mental retardation .... social withdraw. 1. 1. 1. 1. 1. 1. 1 .... J Child Neurol 2010;25(7):842–8.

  12. Pressure-induced unconventional superconductivity near a quantum critical point in CaFe2As2

    International Nuclear Information System (INIS)

    Kawasaki, S; Tabuchi, T; Zheng Guoqing; Wang, X F; Chen, X H

    2010-01-01

    75 As-zero-field nuclear magnetic resonance (NMR) and nuclear quadrupole resonance (NQR) measurements are performed on CaFe 2 As 2 under pressure. At P = 4.7 and 10.8 kbar, the temperature dependencies of nuclear-spin-lattice relaxation rate (1/T 1 ) measured in the tetragonal phase show no coherence peak just below T c (P) and decrease with decreasing temperature. The superconductivity is gapless at P = 4.7 kbar but evolves to that with multiple gaps at P = 10.8 kbar. We find that the superconductivity appears near a quantum critical point under pressures in the range 4.7 kbar ≤ P ≤ 10.8 kbar. Both electron correlation and superconductivity disappear in the collapsed tetragonal phase. A systematic study under pressure indicates that electron correlations play a vital role in forming Cooper pairs in this compound.

  13. Mapping glaucoma patients' 30-2 and 10-2 visual fields reveals clusters of test points damaged in the 10-2 grid that are not sampled in the sparse 30-2 grid.

    Directory of Open Access Journals (Sweden)

    Ryo Asaoka

    Full Text Available PURPOSE: To cluster test points in glaucoma patients' 30-2 and 10-2 visual field (VF (Humphrey Field Analyzer: HFA, Carl Zeiss Meditec, Dublin, CA in order to map the different regions damaged by the disease. METHOD: This retrospective study included 128 eyes from 128 patients. 142 total deviation (TD values (74 from the 30-2 VF and 68 from the 10-2 VF were clustered using the 'Hierarchical Ordered Partitioning And Collapsing Hybrid-Partitioning Around Medoids' algorithm. The stability of the identified clusters was evaluated using bootstrapping. RESULTS: 65 sectors were identified in total: 38 sectors were located outside the 10-2 VF whereas 29 sectors were located inside the 10-2 VF (two sectors overlap in both grids. The mapping of many sectors appeared to follow the distribution of retinal nerve fiber bundles. The results of bootstrapping suggested clusters were stable whether they were outside or inside the 10-2 VF. CONCLUSION: A considerable number of sectors were identified in the 10-2 VF area, despite the fact that clustering was carried out on all points in both the 30-2 VF and 10-2 VF simultaneously. These findings suggest that glaucomatous central VF deterioration cannot be picked up by the 30-2 test grid alone, because of poor spatial sampling; denser estimation of the central ten degrees, than offered by the 30-2 test grid alone, is needed. It may be beneficial to develop a new VF test grid that combines test points from 30-2 and 10-2 VFs--the results of this study could help to devise this test grid.

  14. Brief Report: Systematic Review of Rett Syndrome in Males

    Science.gov (United States)

    Reichow, Brian; George-Puskar, Annie; Lutz, Tara; Smith, Isaac C.; Volkmar, Fred R.

    2015-01-01

    Rett syndrome (RTT) is a neurogenetic disorder in which a period of typical development is followed by loss of previously acquired skills. Once thought to occur exclusively in females, increasing numbers of male cases of RTT have been reported. This systematic review included 36 articles describing 57 cases of RTT in males. Mutations of the MECP2

  15. The Potential for Electrofuels Production in Sweden Utilizing Fossil and Biogenic CO{sub 2} Point Sources

    Energy Technology Data Exchange (ETDEWEB)

    Hansson, Julia, E-mail: julia.hansson@ivl.se [Climate and Sustainable Cities, IVL Swedish Environmental Research Institute, Stockholm (Sweden); Division of Physical Resource Theory, Department of Energy and Environment, Chalmers University of Technology, Göteborg (Sweden); Hackl, Roman [Climate and Sustainable Cities, IVL Swedish Environmental Research Institute, Stockholm (Sweden); Taljegard, Maria [Division of Energy Technology, Department of Energy and Environment, Chalmers University of Technology, Göteborg (Sweden); Brynolf, Selma; Grahn, Maria [Division of Physical Resource Theory, Department of Energy and Environment, Chalmers University of Technology, Göteborg (Sweden)

    2017-03-13

    This paper maps, categorizes, and quantifies all major point sources of carbon dioxide (CO{sub 2}) emissions from industrial and combustion processes in Sweden. The paper also estimates the Swedish technical potential for electrofuels (power-to-gas/fuels) based on carbon capture and utilization. With our bottom-up approach using European databases, we find that Sweden emits approximately 50 million metric tons of CO{sub 2} per year from different types of point sources, with 65% (or about 32 million tons) from biogenic sources. The major sources are the pulp and paper industry (46%), heat and power production (23%), and waste treatment and incineration (8%). Most of the CO{sub 2} is emitted at low concentrations (<15%) from sources in the southern part of Sweden where power demand generally exceeds in-region supply. The potentially recoverable emissions from all the included point sources amount to 45 million tons. If all the recoverable CO{sub 2} were used to produce electrofuels, the yield would correspond to 2–3 times the current Swedish demand for transportation fuels. The electricity required would correspond to about 3 times the current Swedish electricity supply. The current relatively few emission sources with high concentrations of CO{sub 2} (>90%, biofuel operations) would yield electrofuels corresponding to approximately 2% of the current demand for transportation fuels (corresponding to 1.5–2 TWh/year). In a 2030 scenario with large-scale biofuels operations based on lignocellulosic feedstocks, the potential for electrofuels production from high-concentration sources increases to 8–11 TWh/year. Finally, renewable electricity and production costs, rather than CO{sub 2} supply, limit the potential for production of electrofuels in Sweden.

  16. Throughput analysis of point-to-multi-point hybric FSO/RF network

    KAUST Repository

    Rakia, Tamer

    2017-07-31

    This paper presents and analyzes a point-to-multi-point (P2MP) network that uses a number of free-space optical (FSO) links for data transmission from the central node to the different remote nodes. A common backup radio-frequency (RF) link is used by the central node for data transmission to any remote node in case of the failure of any one of FSO links. We develop a cross-layer Markov chain model to study the throughput from central node to a tagged remote node. Numerical examples are presented to compare the performance of the proposed P2MP hybrid FSO/RF network with that of a P2MP FSO-only network and show that the P2MP Hybrid FSO/RF network achieves considerable performance improvement over the P2MP FSO-only network.

  17. Test Operations Procedure (TOP) 08-2-188 Chemical Point Detector Vapor Testing

    Science.gov (United States)

    2018-04-27

    Final 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Test Operations Procedure (TOP) 08-2-188 Chemical Point Detector Vapor Testing 5a. CONTRACT...NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING...ORGANIZATION NAME(S) AND ADDRESS(ES) US Army Dugway Proving Ground West Desert Test Center (TEDT-DPW) Dugway, UT 84022-5000 8. PERFORMING ORGANIZATION

  18. Laser Dew-Point Hygrometer

    Science.gov (United States)

    Matsumoto, Shigeaki; Toyooka, Satoru

    1995-01-01

    A rough-surface-type automatic dew-point hygrometer was developed using a laser diode and an optical fiber cable. A gold plate with 0.8 µ m average surface roughness was used as a surface for deposition of dew to facilitate dew deposition and prevent supersaturation of water vapor at the dew point. It was shown experimentally that the quantity of dew deposited can be controlled to be constant at any predetermined level, and is independent of the dew point to be measured. The dew points were measured in the range from -15° C to 54° C in which the temperature ranged from 0° C to 60° C. The measurement error of the dew point was ±0.5° C which was equal to below ±2% in relative humidity in the above dew-point range.

  19. Hierarchy of exactly solvable spin-1/2 chains with so (N)_I critical points

    NARCIS (Netherlands)

    Lahtinen, V.; Mansson, T.; Ardonne, E.

    2014-01-01

    We construct a hierarchy of exactly solvable spin-1/2 chains with so(N)1 critical points. Our construction is based on the framework of condensate-induced transitions between topological phases. We employ this framework to construct a Hamiltonian term that couples N transverse field Ising chains

  20. Aqueous Solubility of Piperazine and 2-Amino-2-methyl-1-propanol plus Their Mixtures Using an Improved Freezing-Point Depression Method

    DEFF Research Database (Denmark)

    Fosbøl, Philip Loldrup; Neerup, Randi; Waseem Arshad, Muhammad

    2011-01-01

    In this work the solid–liquid equilibrium (SLE) and freezing-point depression (FPD) in the electrolytic binary aqueous systems piperazine (PZ, CAS No. 110-85-0) and aqueous 2-amino-2-methyl-1-propanol (AMP, CAS No. 124-68-5) were measured. The FPD and solubility were also determined in the ternary...

  1. Dual time point 2-deoxy-2-[18F]fluoro-D-glucose PET/CT: nodal staging in locally advanced breast cancer.

    Science.gov (United States)

    García Vicente, A M; Soriano Castrejón, A; Cruz Mora, M Á; Ortega Ruiperez, C; Espinosa Aunión, R; León Martín, A; González Ageitos, A; Van Gómez López, O

    2014-01-01

    To assess dual time point 2-deoxy-2-[(18)F]fluoro-D-glucose (18)(F)FDG PET-CT accuracy in nodal staging and in detection of extra-axillary involvement. Dual time point [(18)F] FDG PET/CT scan was performed in 75 patients. Visual and semiquantitative assessment of lymph nodes was performed. Semiquantitative measurement of SUV and ROC-analysis were carried out to calculate SUV(max) cut-off value with the best diagnostic performance. Axillary and extra-axillary lymph node chains were evaluated. Sensitivity and specificity of visual assessment was 87.3% and 75%, respectively. SUV(max) values with the best sensitivity were 0.90 and 0.95 for early and delayed PET, respectively. SUV(max) values with the best specificity were 1.95 and 2.75, respectively. Extra-axillary lymph node involvement was detected in 26.7%. FDG PET/CT detected extra-axillary lymph node involvement in one-fourth of the patients. Semiquantitative lymph node analysis did not show any advantage over the visual evaluation. Copyright © 2013 Elsevier España, S.L. and SEMNIM. All rights reserved.

  2. DXA measurements in Rett syndrome reveal small bones with low bone mass.

    Science.gov (United States)

    Roende, Gitte; Ravn, Kirstine; Fuglsang, Kathrine; Andersen, Henrik; Nielsen, Jytte Bieber; Brøndum-Nielsen, Karen; Jensen, Jens-Erik Beck

    2011-09-01

    Low bone mass is reported in growth-retarded patients harboring mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients with RTT do have low BMD when correcting for smaller bones by examination with dual-energy X-ray absorptiometry (DXA). We compared areal BMD (aBMD(spine) and aBMD(total hip) ) and volumetric bone mineral apparent density (vBMAD(spine) and vBMAD(neck) ) in 61 patients and 122 matched healthy controls. Further, spine and hip aBMD and vBMAD of patients were associated with clinical risk factors of low BMD, low-energy fractures, MECP2 mutation groups, and X chromosome inactivation (XCI). Patients with RTT had reduced bone size on the order of 10% and showed lower values of spine and hip aBMD and vBMAD (p bone mass and small bones are evident in RTT, indicating an apparent low-bone-formation phenotype. Copyright © 2011 American Society for Bone and Mineral Research.

  3. Cdc20 is critical for meiosis I and fertility of female mice.

    Directory of Open Access Journals (Sweden)

    Fang Jin

    2010-09-01

    Full Text Available Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C, initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.

  4. Confinement near Argyres-Douglas point in N=2 QCD and low energy version of AdS/CFT correspondence

    International Nuclear Information System (INIS)

    Yung, Alexei

    2002-01-01

    We study Abrikosov-Nielsen-Olesen (ANO) flux tubes on the Higgs branch of N=2 QCD with SU(2) gauge group and N f =2 flavors of fundamental matter. In particular, we consider this theory near Argyres-Douglas (AD) point where the mass of monopoles connected by these ANO strings become small. In this regime the effective QED which describes the theory on the Higgs branch becomes strongly coupled. We argue that the appropriate description of the theory is in terms of long and thin flux tubes (strings) with small tension. We interpret this as another example of duality between field theory in strong coupling and string theory in weak coupling. Then we consider the non-critical string theory for these flux tubes which includes fifth (Liouville) dimension. We identify CFT at the AD point as UV fix point corresponding to AdS metric on the 5d 'gravity' side. The perturbation associated with the monopole mass term creates a kink separating UV and IR behavior. We estimate the renormalized string tension and show that it is determined by the small monopole mass. In particular, it goes to zero at the AD point

  5. Flexible SiO2 cantilevers for torsional self-aligning micro scale four-point probes

    DEFF Research Database (Denmark)

    Kjær, Daniel; Gammelgaard, Lauge; Bøggild, Peter

    2007-01-01

    In order to successfully measure the conductivity of a sample with a four- point probe, good alignment of the electrodes to the sample is important to establish even contact pressure and contact areas of the electrodes. By incorporating a hinge in a microfabricated SiO2 mono- cantilever the ability...

  6. Characterizing fixed points

    Directory of Open Access Journals (Sweden)

    Sanjo Zlobec

    2017-04-01

    Full Text Available A set of sufficient conditions which guarantee the existence of a point x⋆ such that f(x⋆ = x⋆ is called a "fixed point theorem". Many such theorems are named after well-known mathematicians and economists. Fixed point theorems are among most useful ones in applied mathematics, especially in economics and game theory. Particularly important theorem in these areas is Kakutani's fixed point theorem which ensures existence of fixed point for point-to-set mappings, e.g., [2, 3, 4]. John Nash developed and applied Kakutani's ideas to prove the existence of (what became known as "Nash equilibrium" for finite games with mixed strategies for any number of players. This work earned him a Nobel Prize in Economics that he shared with two mathematicians. Nash's life was dramatized in the movie "Beautiful Mind" in 2001. In this paper, we approach the system f(x = x differently. Instead of studying existence of its solutions our objective is to determine conditions which are both necessary and sufficient that an arbitrary point x⋆ is a fixed point, i.e., that it satisfies f(x⋆ = x⋆. The existence of solutions for continuous function f of the single variable is easy to establish using the Intermediate Value Theorem of Calculus. However, characterizing fixed points x⋆, i.e., providing answers to the question of finding both necessary and sufficient conditions for an arbitrary given x⋆ to satisfy f(x⋆ = x⋆, is not simple even for functions of the single variable. It is possible that constructive answers do not exist. Our objective is to find them. Our work may require some less familiar tools. One of these might be the "quadratic envelope characterization of zero-derivative point" recalled in the next section. The results are taken from the author's current research project "Studying the Essence of Fixed Points". They are believed to be original. The author has received several feedbacks on the preliminary report and on parts of the project

  7. IceCube-Gen2 sensitivity improvement for steady neutrino point sources

    Energy Technology Data Exchange (ETDEWEB)

    Coenders, Stefan; Resconi, Elisa [TU Muenchen, Physik-Department, Excellence Cluster Universe, Boltzmannstr. 2, 85748 Garching (Germany); Collaboration: IceCube-Collaboration

    2015-07-01

    The observation of an astrophysical neutrino flux by high-energy events starting in IceCube strengthens the search for sources of astrophysical neutrinos. Identification of these sources requires good pointing at high statistics, mainly using muons created by charged-current muon neutrino interactions going through the IceCube detector. We report about preliminary studies of a possible high-energy extension IceCube-Gen2. Using a 6 times bigger detection volume, effective area as well as reconstruction accuracy will improve with respect to IceCube. Moreover, using (in-ice) active veto techniques will significantly improve the performance for Southern hemisphere events, where possible local candidate neutrino sources are located.

  8. Error Mitigation of Point-to-Point Communication for Fault-Tolerant Computing

    Science.gov (United States)

    Akamine, Robert L.; Hodson, Robert F.; LaMeres, Brock J.; Ray, Robert E.

    2011-01-01

    Fault tolerant systems require the ability to detect and recover from physical damage caused by the hardware s environment, faulty connectors, and system degradation over time. This ability applies to military, space, and industrial computing applications. The integrity of Point-to-Point (P2P) communication, between two microcontrollers for example, is an essential part of fault tolerant computing systems. In this paper, different methods of fault detection and recovery are presented and analyzed.

  9. The German energetic turning point: year n+2

    International Nuclear Information System (INIS)

    Cruciani, Michel

    2013-07-01

    This publication proposes an analysis of the evolution of the German energy sector, two years after the adoption of a new energy policy. It notably aims at identifying the consequences of this important turning point which was characterised by the decision to phase out nuclear while keeping on reducing energy consumption and greenhouse gas emissions, and developing renewable energies. In a first part, the author comments the objectives associated with the present evolution in terms of reducing the primary energy consumption, reducing raw electric power consumption, energy consumption in transports, CO_2 emissions, of increasing the share of renewable energies and power production from renewable sources, and of complying with European objectives. The second part discusses technical aspects of the development of power generation from renewable sources by addressing the following issues: prospective, grid extension and strengthening, intermittency management, industrial orientation. The third part addresses economic aspects of this development: promotion of electricity production from renewable sources, relationship between power generation from renewable sources and electricity price, public debate on electricity price, employment and economic benefits, financing the energy transition, and the European dimension. In conclusion, the author discusses whether the German energy shift is a model or a counter-example

  10. ACS Zero Point Verification

    Science.gov (United States)

    Dolphin, Andrew

    2005-07-01

    The uncertainties in the photometric zero points create a fundamental limit to the accuracy of photometry. The current state of the ACS calibration is surprisingly poor, with zero point uncertainties of 0.03 magnitudes. The reason for this is that the ACS calibrations are based primarily on semi-emprical synthetic zero points and observations of fields too crowded for accurate ground-based photometry. I propose to remedy this problem by obtaining ACS images of the omega Cen standard field with all nine broadband ACS/WFC filters. This will permit the direct determination of the ACS zero points by comparison with excellent ground-based photometry, and should reduce their uncertainties to less than 0.01 magnitudes. A second benefit is that it will facilitate the comparison of the WFPC2 and ACS photometric systems, which will be important as WFPC2 is phased out and ACS becomes HST's primary imager. Finally, three of the filters will be repeated from my Cycle 12 observations, allowing for a measurement of any change in sensitivity.

  11. Industrial point source CO2 emission strength estimation with aircraft measurements and dispersion modelling.

    Science.gov (United States)

    Carotenuto, Federico; Gualtieri, Giovanni; Miglietta, Franco; Riccio, Angelo; Toscano, Piero; Wohlfahrt, Georg; Gioli, Beniamino

    2018-02-22

    CO 2 remains the greenhouse gas that contributes most to anthropogenic global warming, and the evaluation of its emissions is of major interest to both research and regulatory purposes. Emission inventories generally provide quite reliable estimates of CO 2 emissions. However, because of intrinsic uncertainties associated with these estimates, it is of great importance to validate emission inventories against independent estimates. This paper describes an integrated approach combining aircraft measurements and a puff dispersion modelling framework by considering a CO 2 industrial point source, located in Biganos, France. CO 2 density measurements were obtained by applying the mass balance method, while CO 2 emission estimates were derived by implementing the CALMET/CALPUFF model chain. For the latter, three meteorological initializations were used: (i) WRF-modelled outputs initialized by ECMWF reanalyses; (ii) WRF-modelled outputs initialized by CFSR reanalyses and (iii) local in situ observations. Governmental inventorial data were used as reference for all applications. The strengths and weaknesses of the different approaches and how they affect emission estimation uncertainty were investigated. The mass balance based on aircraft measurements was quite succesful in capturing the point source emission strength (at worst with a 16% bias), while the accuracy of the dispersion modelling, markedly when using ECMWF initialization through the WRF model, was only slightly lower (estimation with an 18% bias). The analysis will help in highlighting some methodological best practices that can be used as guidelines for future experiments.

  12. Vaginal dose point reporting in cervical cancer patients treated with combined 2D/3D external beam radiotherapy and 2D/3D brachytherapy

    International Nuclear Information System (INIS)

    Westerveld, Henrike; Pötter, Richard; Berger, Daniel; Dankulchai, Pittaya; Dörr, Wolfgang; Sora, Mircea-Constantin; Pötter-Lang, Sarah; Kirisits, Christian

    2013-01-01

    Background and purpose: Traditionally, vaginal dose points have been defined at the vaginal source level, thus not providing dose information for the entire vagina. Since reliable vaginal dose volume/surface histograms are unavailable, a strategy for comprehensive vaginal dose reporting for combined EBRT and BT was established and investigated. Material and methods: An anatomical vaginal reference point was defined at the level of the Posterior–Inferior Border of Symphysis (PIBS), plus two points ±2 cm (mid/introitus vagina). For BT extra points were selected for the upper vagina at 12/3/6/9 o’clock, at the vaginal surface and 5 mm depth. A vaginal reference length (VRL) was defined from ring centre to PIBS. Fifty-nine patients treated for cervical cancer were included in this retrospective feasibility study. Results: The method was applicable to all patients. Total EQD2 doses at PIBS and ±2 cm were 36.7 Gy (3.1–68.2), 49.6 Gy (32.1–89.6) and 4.3 Gy (1.0–46.6). At the vaginal surface at ring level doses were respectively 266.1 Gy (67.6–814.5)/225.9 Gy (61.5–610.5) at 3/9 o’clock, and 85.1 Gy (55.4–140.3)/72.0 Gy (49.1–108.9) at 12/6 o’clock. Mean VRL on MRI was 5.6 cm (2.0–9.4). Conclusions: With this novel system, a comprehensive reporting of vaginal doses is feasible. The present study has demonstrated large dose variations between patients observed in all parts of the vagina, resulting from different contributions from EBRT and BT

  13. EDGAR CO2 purity. Type and quantities of impurities related to CO2 point source and capture technology. A Literature study

    Energy Technology Data Exchange (ETDEWEB)

    Walspurger, S.; Van Dijk, H.A.J. [ECN Biomass and Energy Efficiency, Petten (Netherlands)

    2012-08-15

    Carbon capture and storage (CCS) is an important tool that will contribute significantly to CO2 emissions abatement both in power and industrial sectors. Capture technologies as well as transport and distribution infrastructure development need to be carried out to ensure efficient CO2 separation and safe transport to storage sites. This study aimed at identifying, and when possible quantifying, the impurities present in CO2 streams resulting from various CO2 capture plants, such that challenges in development of appropriate materials and cleaning technologies for future CCS infrastructure may be anticipated. In its first part, the study provides a description of the characteristics of the different CO2 capture technologies with respect to their response to different type and quantity of impurities, striving for describing realistic combinations of point sources and capture technologies. Composition of CO2 gaseous streams was found to be highly dependent upon the type of CO2 point source and the removal technology selected. In most of the capture processes, most impurities concentration may be minimised by fine tuning of process operation. However plant economics eventually govern the impurity level in the CO2 stream. For mature technologies such as absorption by chemical or physical solvents lower impurity levels were found to be theoretically quite low, but when energy spent for regeneration is lowered, or when second generation capture with lower energy requirement are considered, the impurity level in CO2 stream increases. Accordingly, the report also addresses the conditioning technologies that are available or need to be developed for removal of traces elements such as mercury, volatile compounds and other condensable and points at technologies to be developed, especially in the sulphur compounds removal from CO2. In its final part the report addresses the quantification of future specification and concludes based on literature study that pipeline

  14. Farey Statistics in Time n^{2/3} and Counting Primitive Lattice Points in Polygons

    OpenAIRE

    Patrascu, Mihai

    2007-01-01

    We present algorithms for computing ranks and order statistics in the Farey sequence, taking time O (n^{2/3}). This improves on the recent algorithms of Pawlewicz [European Symp. Alg. 2007], running in time O (n^{3/4}). We also initiate the study of a more general algorithmic problem: counting primitive lattice points in planar shapes.

  15. The change points of HbA(1C) for detection of retinopathy in Chinese type 2 diabetic patients.

    Science.gov (United States)

    Hou, Jia-Ning; Bi, Yu-Fang; Xu, Min; Huang, Yun; Li, Xiao-Ying; Wang, Wei-Qing; Chen, Yu-Hong; Ning, Guang

    2011-03-01

    To investigate the change points of HbA(1C) for detection of retinopathy in Chinese type 2 diabetic patients. This cross-sectional investigation included 992 diagnosed type 2 diabetic patients, who received non-mydriatic digital fundus photography examination. Joinpoint regression software was adopted to identify the change points of HbA(1C) in association with retinopathy prevalence. The mean age of all patients was 59.1 ± 8.4 years and the duration of diabetes was 5.5 (95% CI: 5.2-5.9) years. The prevalence of retinopathy was 10.3% in total, and 4.1%, 7.4% and 19.6% in patients with different diabetes duration of ≤ 5 years, 5-10 years and >10 years, respectively. The change point of HbA(1C) was 6.5% (95%CI 5.8-7.5%), at which retinopathy prevalence began to rise sharply. Furthermore, in subjects with diabetes duration ≤ 5 years, 5-10 years and >10 years, the change points of HbA(1C) were 8.1% (95%CI 7.9-8.3%), 6.1% (95%CI 5.7-6.8%), 5.6% (95%CI 5.1-8.1%) for detection of retinopathy, respectively. The steepest increase in retinopathy prevalence occurred when HbA(1C) reached 6.5%. However, the duration of diabetes should be taken into concern, when using the change points of HbA(1C) for detection of retinopathy in diabetic patients. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  16. Alfvén wave dynamics at the neighborhood of a 2.5D magnetic null-point

    Science.gov (United States)

    Sabri, S.; Vasheghani Farahani, S.; Ebadi, H.; Hosseinpour, M.; Fazel, Z.

    2018-05-01

    The aim of the present study is to highlight the energy transfer via the interaction of magnetohydrodynamic waves with a 2.5D magnetic null-point in a finite plasma-β regime of the solar corona. An initially symmetric Alfvén pulse at a specific distance from a magnetic null-point is kicked towards the isothermal null-point. A shock-capturing Godunov-type PLUTO code is used to solve the ideal magnetohydrodynamic set equations in the context of wave-plasma energy transfer. As the Alfvén wave propagates towards the magnetic null-point it experiences speed lowering which ends up in releasing energy along the separatrices. In this line owing to the Alfvén wave, a series of events take place that contribute towards coronal heating. Nonlinear induced waves are by products of the torsional Alfvén interaction with magnetic null-points. The energy of these induced waves which are fast magnetoacoustic (transverse) and slow magnetoacoustic (longitudinal) waves are supplied by the Alfvén wave. The nonlinearly induced density perturbations are proportional to the Alfvén wave energy loss. This supplies energy for the propagation of fast and slow magnetoacoustic waves, where in contrast to the fast wave the slow wave experiences a continuous energy increase. As such, the slow wave may transfer its energy to the medium at later times, maintaining a continuous heating mechanism at the neighborhood of a magnetic null-point.

  17. Evidence of multiband superconductivity in the quaternary borocarbide superconductor YNi2B2C using directional point-contact spectroscopy

    International Nuclear Information System (INIS)

    Raychaudhuri, Pratap; Sheet, Goutam; Mukhopadhyay, Sourin; Takeya, H.

    2007-01-01

    In this paper, we review our recent investigations on the gap anisotropy of the quaternary borocarbide superconductor YNi 2 B 2 C using directional point-contact spectroscopy. Through a detailed study of the temperature and magnetic field dependence of the superconducting energy gaps we show that the gap anisotropy in this material originates from electrons on different Fermi sheets having very different Fermi velocities. The gap anisotropy in this material is therefore well explained through a multiband scenario where electrons in different k-directions have very different electron-phonon coupling strength

  18. Logarithmic two-point correlation functions from a z=2 Lifshitz model

    International Nuclear Information System (INIS)

    Zingg, T.

    2014-01-01

    The Einstein-Proca action is known to have asymptotically locally Lifshitz spacetimes as classical solutions. For dynamical exponent z=2, two-point correlation functions for fluctuations around such a geometry are derived analytically. It is found that the retarded correlators are stable in the sense that all quasinormal modes are situated in the lower half-plane of complex frequencies. Correlators in the longitudinal channel exhibit features that are reminiscent of a structure usually obtained in field theories that are logarithmic, i.e. contain an indecomposable but non-diagonalizable highest weight representation. This provides further evidence for conjecturing the model at hand as a candidate for a gravity dual of a logarithmic field theory with anisotropic scaling symmetry

  19. ACS Photometric Zero Point Verification

    Science.gov (United States)

    Dolphin, Andrew

    2003-07-01

    The uncertainties in the photometric zero points create a fundamental limit to the accuracy of photometry. The current state of the ACS calibration is surprisingly poor, with zero point uncertainties of 0.03 magnitudes in the Johnson filters. The reason for this is that ACS observations of excellent ground-based standard fields, such as the omega Cen field used for WFPC2 calibrations, have not been obtained. Instead, the ACS photometric calibrations are based primarily on semi-emprical synthetic zero points and observations of fields too crowded for accurate ground-based photometry. I propose to remedy this problem by obtaining ACS broadband images of the omega Cen standard field with both the WFC and HRC. This will permit the direct determination of the ACS transformations, and is expected to double the accuracy to which the ACS zero points are known. A second benefit is that it will facilitate the comparison of the WFPC2 and ACS photometric systems, which will be important as WFPC2 is phased out and ACS becomes HST's primary imager.

  20. Zero-point energy conservation in classical trajectory simulations: Application to H2CO

    Science.gov (United States)

    Lee, Kin Long Kelvin; Quinn, Mitchell S.; Kolmann, Stephen J.; Kable, Scott H.; Jordan, Meredith J. T.

    2018-05-01

    A new approach for preventing zero-point energy (ZPE) violation in quasi-classical trajectory (QCT) simulations is presented and applied to H2CO "roaming" reactions. Zero-point energy may be problematic in roaming reactions because they occur at or near bond dissociation thresholds and these channels may be incorrectly open or closed depending on if, or how, ZPE has been treated. Here we run QCT simulations on a "ZPE-corrected" potential energy surface defined as the sum of the molecular potential energy surface (PES) and the global harmonic ZPE surface. Five different harmonic ZPE estimates are examined with four, on average, giving values within 4 kJ/mol—chemical accuracy—for H2CO. The local harmonic ZPE, at arbitrary molecular configurations, is subsequently defined in terms of "projected" Cartesian coordinates and a global ZPE "surface" is constructed using Shepard interpolation. This, combined with a second-order modified Shepard interpolated PES, V, allows us to construct a proof-of-concept ZPE-corrected PES for H2CO, Veff, at no additional computational cost to the PES itself. Both V and Veff are used to model product state distributions from the H + HCO → H2 + CO abstraction reaction, which are shown to reproduce the literature roaming product state distributions. Our ZPE-corrected PES allows all trajectories to be analysed, whereas, in previous simulations, a significant proportion was discarded because of ZPE violation. We find ZPE has little effect on product rotational distributions, validating previous QCT simulations. Running trajectories on V, however, shifts the product kinetic energy release to higher energy than on Veff and classical simulations of kinetic energy release should therefore be viewed with caution.

  1. A MARKED POINT PROCESS MODEL FOR VEHICLE DETECTION IN AERIAL LIDAR POINT CLOUDS

    Directory of Open Access Journals (Sweden)

    A. Börcs

    2012-07-01

    Full Text Available In this paper we present an automated method for vehicle detection in LiDAR point clouds of crowded urban areas collected from an aerial platform. We assume that the input cloud is unordered, but it contains additional intensity and return number information which are jointly exploited by the proposed solution. Firstly, the 3-D point set is segmented into ground, vehicle, building roof, vegetation and clutter classes. Then the points with the corresponding class labels and intensity values are projected to the ground plane, where the optimal vehicle configuration is described by a Marked Point Process (MPP model of 2-D rectangles. Finally, the Multiple Birth and Death algorithm is utilized to find the configuration with the highest confidence.

  2. Two gap superconductivity in Ba0.55K0.45Fe2As2 single crystals studied by the directional point-contact Andreev reflection spectroscopy

    International Nuclear Information System (INIS)

    Szabo, P.; Pribulova, Z.; Pristas, G.; Bud'ko, S.L.; Canfield, P.C.; Samuely, P.

    2009-01-01

    First directional point-contact Andreev reflection spectroscopy on the Ba 0.55 K 0.45 Fe 2 As 2 single crystals is presented. The spectra show significant differences when measured in the ab plane in comparison with those measured in the c direction. In the latter case no traces of superconducting energy gap could be found, just a reduced point-contact conductance persisting up to about 100 K and indicating reduced density of states. On the other hand within the ab plane two nodeless superconducting energy gaps Δ S ∼2-5 meV and Δ L ∼9-11 meV are detected.

  3. Orthopaedic nurses' knowledge and interrater reliability of neurovascular assessments with 2-point discrimination test.

    Science.gov (United States)

    Turney, Jennifer; Raley Noble, Deana; Kim, Son Chae

    2013-01-01

    : This study was conducted to evaluate the effects of education on knowledge and interrater reliability of neurovascular assessments with 2-point discrimination (2-PD) test among pediatric orthopaedic nurses. : A pre- and posttest study was done among 60 nurses attending 2-hour educational sessions. Neurovascular assessments with 2-PD test were performed on 64 casted pediatric patients by the nurses and 5 nurse experts before and after the educational sessions. : The mean neurovascular assessment knowledge score was improved at posteducation compared with the preeducation (p < .001). The 2-PD test interrater reliability also improved from Cohen's kappa value of 0.24-0.48 at posteducation. : The 2-hour educational session may be effective in improving nurses' knowledge and the interrater reliability of neurovascular assessment with 2-PD test.

  4. On the Nature of the Microwave Background at the Lagrange 2 Point. Part II

    Directory of Open Access Journals (Sweden)

    Borissova L.

    2007-10-01

    Full Text Available In this work the mathematical methods of General Relativity are used to answer the following questions: if a microwave background originates from the Earth, what would be its density and associated dipole measured at the altitude of a U2 aeroplane (25 km, the COBE satellite (900 km, and the 2nd Lagrange point (1.5 million km, the position of the WMAP and PLANCK satellites? The first problem is solved via Einstein’s equations for the electromagnetic field of the Earth. The second problem is solved using the geodesic equations for light-like particles (photons which are mediators for electromagnetic radiation. We have determined that a microwave background that originates at the Earth (the Earth microwave background decreases with altitude so that the density of the energy of such a background at the altitude of the COBE orbit (900 km is 0.68 times less than that at the altitude of a U2 aeroplane. The density of the energy of the background at the L2 point is only ~1E-7 of the value detected by a U2 aeroplane or at the COBE orbit. The dipole anisotropy of the Earth microwave background, due to the rapid motion of the Earth relative to the source of another field which isn’t connected to the Earth but is located in depths of the cosmos, doesn’t depend on altitute from the surface of the Earth. Such a dipole will be the same irrespective of the position at which measurements are taken.

  5. Statistical mechanics of the $N$-point vortex system with random intensities on $R^2$

    Directory of Open Access Journals (Sweden)

    Cassio Neri

    2005-01-01

    Full Text Available The system of N -point vortices on $mathbb{R}^2$ is considered under the hypothesis that vortex intensities are independent and identically distributed random variables with respect to a law $P$ supported on $(0,1]$. It is shown that, in the limit as $N$ approaches $infty$, the 1-vortex distribution is a minimizer of the free energy functional and is associated to (some solutions of the following non-linear Poisson Equation:$$ -Delta u(x = C^{-1}int_{(0,1]} rhbox{e}^{-eta ru(x- gamma r|x|^2}P(hbox{d}r, quadforall xin mathbb{R}^2, $$where $displaystyle C = int_{(0,1]}int_{mathbb{R}^2}hbox{e}^{-eta ru(y - gamma r|y|^2}hbox{d} yP(hbox{d}r$

  6. Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation.

    Science.gov (United States)

    Karaer, Kadri; Lissewski, Christina; Zenker, Martin

    2015-02-01

    Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals. © 2014 Wiley Periodicals, Inc.

  7. Longitudinal 2-point dixon muscle magnetic resonance imaging in becker muscular dystrophy.

    Science.gov (United States)

    Bonati, Ulrike; Schmid, Maurice; Hafner, Patricia; Haas, Tanja; Bieri, Oliver; Gloor, Monika; Fischmann, Arne; Fischer, Dirk

    2015-06-01

    Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1-year follow-up using a 2-point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow-up. The severity of muscle involvement varied between various muscle groups. As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. © 2015 Wiley Periodicals, Inc.

  8. The Infrared Fixed Points of 3d $\\mathcal{N}=4$ $USp(2N)$ SQCD Theories arXiv

    CERN Document Server

    Assel, Benjamin

    We derive the algebraic description of the Coulomb branch of 3d $\\mathcal{N}=4$ $USp(2N)$ SQCD theories with $N_f$ fundamental hypermultiplets and determine their low energy physics in any vacuum from the local geometry of the moduli space, identifying the interacting SCFTs which arise at singularities and possible extra free sectors. The SCFT with the largest moduli space arises at the most singular locus on the Coulomb branch. For $N_f>2N$ (good theories) it sits at the origin of the conical variety as expected. For $N_f =2N$ we find two separate most singular points, from which the two isomorphic components of the Higgs branch of the UV theory emanate. The SCFTs sitting at any of these two vacua have only odd dimensional Coulomb branch generators, which transform under an accidental $SU(2)$ global symmetry. We provide a direct derivation of their moduli spaces of vacua, and propose a Lagrangian mirror theory for these fixed points. For $2 \\le N_f < 2N$ the most singular locus has one or two extended com...

  9. Gaussian-2 theory: Use of higher level correlation methods, quadratic configuration interaction geometries, and second-order Moller--Plesset zero-point energies

    International Nuclear Information System (INIS)

    Curtiss, L.A.; Raghavachari, K.; Pople, J.A.

    1995-01-01

    The performance of Gaussian-2 theory is investigated when higher level theoretical methods are included for correlation effects, geometries, and zero-point energies. A higher level of correlation treatment is examined using Brueckner doubles [BD(T)] and coupled cluster [CCSD(T)] methods rather than quadratic configuration interaction [QCISD(T)]. The use of geometries optimized at the QCISD level rather than the second-order Moller--Plesset level (MP2) and the use of scaled MP2 zero-point energies rather than scaled Hartree--Fock (HF) zero-point energies have also been examined. The set of 125 energies used for validation of G2 theory [J. Chem. Phys. 94, 7221 (1991)] is used to test out these variations of G2 theory. Inclusion of higher levels of correlation treatment has little effect except in the cases of multiply-bonded systems. In these cases better agreement is obtained in some cases and poorer agreement in others so that there is no improvement in overall performance. The use of QCISD geometries yields significantly better agreement with experiment for several cases including the ionization potentials of CS and O 2 , electron affinity of CN, and dissociation energies of N 2 , O 2 , CN, and SO 2 . This leads to a slightly better agreement with experiment overall. The MP2 zero-point energies gives no overall improvement. These methods may be useful for specific systems

  10. Acoustic resonator providing fixed points of temperature between 0.1 and 2 K

    International Nuclear Information System (INIS)

    Salmela, Anssi; Tuoriniemi, Juha; Pentti, Elias; Sebedash, Alexander; Rysti, Juho

    2009-01-01

    Below 2 K the speed of second sound in mixtures of liquid 3 He and 4 He first increases to a maximum of 30-40 m/s at about 1 K and then decreases again at lower temperatures to values below 15 m/s. The exact values depend on the concentration and pressure of the mixture. This can be exploited to provide fixed points in temperature by utilizing a resonator with appropriate dimensions and frequency to excite standing waves in the resonator cavity filled with helium mixture. We demonstrate that commercially mass produced quartz tuning forks can be used for this purpose. They are meant for frequency standards operating at 32 kHz. Their dimensions are typically of order 1 mm matching the wavelength of the second sound in helium mixtures at certain values of temperature. Due to the complicated geometry, we observe some 20 sharp acoustic resonances in the range 0.1l 2 K having temperature resolution of order 1 μK. The quartz resonators are cheap, compact, simple to implement, easy to measure with great accuracy, and, above all, they are not sensitive to magnetic field, which is a great advantage compared to fixed point devices based on superconductivity transitions. The reproducibility of the resonance pattern upon thermal cycling remains to be verified.

  11. Effects of temperature at constant air dew point on leaf carboxylation efficiency and CO2 compensation point of different leaf types.

    Science.gov (United States)

    Weber, J A; Tenhunen, J D; Lange, O L

    1985-09-01

    The effect of temperature on photosynthesis at constant water-vapor pressure in the air was investigated using two sclerophyll species, Arbutus unedo and Quercus suber, and one mesophytic species, Spinacia oleracea. Photosynthesis and transpiration were measured over a range of temperatures, 20-39° C. The external concentration of CO2 was varied from 340 μbar to near CO2 compensation. The initial slope (carboxylation efficiency, CE) of the photosynthetic response to intercellular CO2 concentration, the CO2 compensation point (Γ), and the extrapolated rate of CO2 released into CO2-free air (R i) were calculated. At an external CO2 concentration of 320-340 μbar CO2, photosynthesis decreased with temperature in all species. The effect of temperature on Γ was similar in all species. While CE in S. oleracea changed little with temperature, CE decreased by 50% in Q. suber as temperature increased from 25 to 34° C. Arbutus unedo also exhibited a decrease in CE at higher temperatures but not as marked as Q. suber. The absolut value of R i increased with temperature in S. oleracea, while changing little or decreasing in the sclerophylls. Variations in Γ and R i of the sclerophyll species are not consistent with greater increase of respiration with temperature in the light in these species compared with S. oleracea.

  12. Runaway Train: A Leaky Radiosensitive SCID with Skin Lesions and Multiple Lymphomas

    Directory of Open Access Journals (Sweden)

    Børre Fevang

    2018-01-01

    Full Text Available The nuclease Artemis is essential for the development of T-cell and B-cell receptors and repair of DNA double-strand breaks, and a loss of expression or function will lead to a radiosensitive severe combined immunodeficiency with no functional T-cells or B-cells (T-B-SCID. Hypomorphic mutations in the Artemis gene can lead to a functional, but reduced, T-cell and B-cell repertoire with a more indolent clinical course called “leaky” SCID. Here, we present the case of a young man who had increasingly aggressive lymphoproliferative skin lesions from 2 years of age which developed into multiple EBV+ B-cell lymphomas, where a hypomorphic mutation in the Artemis gene was found in a diagnostic race against time using whole exome sequencing. The patient was given a haploidentical stem cell transplant while in remission for his lymphomas and although the initial course was successful, he succumbed to a serious Pneumocystis jirovecii pneumonia 5 months after the transplant. The case underscores the importance of next-generation sequencing in the diagnosis of patients with suspected severe immunodeficiency.

  13. Abnormalities of thymic stroma may contribute to immune dysregulation in murine models of leaky severe combined immunodeficiency

    Directory of Open Access Journals (Sweden)

    Francesca eRucci

    2011-05-01

    Full Text Available Lymphostromal cross-talk in the thymus is essential to allow generation of a diversified repertoire of T lymphocytes and to prevent autoimmunity by self-reactive T cells. Hypomorphic mutations in genes that control T cell development have been associated with immunodeficiency and immune dysregulation both in humans and in mice. We have studied T cell development and thymic stroma architecture and maturation in two mouse models of leaky SCID, carrying hypomorphic mutations in Rag1 and Lig4 genes. Defective T cell development was associated with abnormalities of thymic architecture that predominantly affect the thymic medulla, with reduction of the pool of mature medullary thymic epithelial cells (mTECs. While the ability of mTECs to express Aire is preserved in mutant mice, the frequency of mature mTECs expressing Aire and tissue-specific antigens (TSAs is severely reduced. Similarly, the ability of CD4+ T cells to differentiate into Foxp3+ natural regulatory T cells is preserved in Rag1 and Lig4 mutant mice, but their number is greatly reduced. These data indicate that hypomorphic defects in T cell development may cause defective lymphostromal cross-talk and impinge on thymic stromal cells maturation, and thus favor immune dysregulation.

  14. Dissociation energies of six NO2 isotopologues by laser induced fluorescence spectroscopy and zero point energy of some triatomic molecules.

    Science.gov (United States)

    Michalski, G; Jost, R; Sugny, D; Joyeux, M; Thiemens, M

    2004-10-15

    We have measured the rotationless photodissociation threshold of six isotopologues of NO2 containing 14N, 15N, 16O, and 18O isotopes using laser induced fluorescence detection and jet cooled NO2 (to avoid rotational congestion). For each isotopologue, the spectrum is very dense below the dissociation energy while fluorescence disappears abruptly above it. The six dissociation energies ranged from 25 128.56 cm(-1) for 14N16O2 to 25 171.80 cm(-1) for 15N18O2. The zero point energy for the NO2 isotopologues was determined from experimental vibrational energies, application of the Dunham expansion, and from canonical perturbation theory using several potential energy surfaces. Using the experimentally determined dissociation energies and the calculated zero point energies of the parent NO2 isotopologue and of the NO product(s) we determined that there is a common De = 26 051.17+/-0.70 cm(-1) using the Born-Oppenheimer approximation. The canonical perturbation theory was then used to calculate the zero point energy of all stable isotopologues of SO2, CO2, and O3, which are compared with previous determinations.

  15. A flat Chern-Simons gauge theory for (2+1)-dimensional gravity coupled to point particles

    International Nuclear Information System (INIS)

    Grignani, G.; Nardelli, G.

    1991-01-01

    We present a classical ISO (2,1) Chern-Simons gauge theory for planar gravity coupled to point-like sources. The theory is defined in terms of flat coordinates whose relation with the space-time coordinates is established. Though flat, the theory is equivalent to Einstein's as we show explicitly in two examples. (orig.)

  16. Alternative methods for CYP2D6 phenotyping: comparison of dextromethorphan metabolic ratios from AUC, single point plasma, and urine.

    Science.gov (United States)

    Chen, Rui; Wang, Haotian; Shi, Jun; Hu, Pei

    2016-05-01

    CYP2D6 is a high polymorphic enzyme. Determining its phenotype before CYP2D6 substrate treatment can avoid dose-dependent adverse events or therapeutic failures. Alternative phenotyping methods of CYP2D6 were compared to aluate the appropriate and precise time points for phenotyping after single-dose and ultiple-dose of 30-mg controlled-release (CR) dextromethorphan (DM) and to explore the antimodes for potential sampling methods. This was an open-label, single and multiple-dose study. 21 subjects were assigned to receive a single dose of CR DM 30 mg orally, followed by a 3-day washout period prior to oral administration of CR DM 30 mg every 12 hours for 6 days. Metabolic ratios (MRs) from AUC∞ after single dosing and from AUC0-12h at steady state were taken as the gold standard. The correlations of metabolic ratios of DM to dextrorphan (MRDM/DX) values based on different phenotyping methods were assessed. Linear regression formulas were derived to calculate the antimodes for potential sample methods. In the single-dose part of the study statistically significant correlations were found between MRDM/DX from AUC∞ and from serial plasma points from 1 to 30 hours or from urine (all p-values < 0.001). In the multiple-dose part, statistically significant correlations were found between MRDM/DX from AUC0-12h on day 6 and MRDM/DX from serial plasma points from 0 to 36 hours after the last dosing (all p-values < 0.001). Based on reported urinary antimode and linear regression analysis, the antimodes of AUC and plasma points were derived to profile the trend of antimodes as the drug concentrations changed. MRDM/DX from plasma points had good correlations with MRDM/DX from AUC. Plasma points from 1 to 30 hours after single dose of 30-mg CR DM and any plasma point at steady state after multiple doses of CR DM could potentially be used for phenotyping of CYP2D6.

  17. Inhibition effect of calcium hydroxide point and chlorhexidine point on root canal bacteria of necrosis teeth

    Directory of Open Access Journals (Sweden)

    Andry Leonard Je

    2006-03-01

    Full Text Available Calcium Hydroxide point and Chlorhexidine point are new drugs for eliminating bacteria in the root canal. The points slowly and controly realease Calcium Hydroxide and Chlorhexidine into root canal. The purpose of the study was to determined the effectivity of Calcium hydroxide point (Calcium hydroxide plus point and Chlorhexidine point in eleminating the root canal bacteria of nescrosis teeth. In this study 14 subjects were divided into 2 groups. The first group was treated with Calcium hydroxide point and the second was treated with Chlorhexidine poin. The bacteriological sampling were measured with spectrofotometry. The Paired T Test analysis (before and after showed significant difference between the first and second group. The Independent T Test which analysed the effectivity of both groups had not showed significant difference. Although there was no significant difference in statistical test, the result of second group eliminate more bacteria than the first group. The present finding indicated that the use of Chlorhexidine point was better than Calcium hydroxide point in seven days period. The conclusion is Chlorhexidine point and Calcium hydroxide point as root canal medicament effectively eliminate root canal bacteria of necrosis teeth.

  18. Degree of a isolated real point or a singular complex point on a plane curve defined over Q

    DEFF Research Database (Denmark)

    Hansen, Johan Peder

    2010-01-01

    Let $X$ be a curve in the affine plane defined by a reduced polynomial of degree $d$ with rational coefficients. Assume that $P$ is an isolated real point or a singular complex point on the curve $X$. The coordinates of $P$ are algebraic numbers over the rationals of degree at most $d^2$. The res......Let $X$ be a curve in the affine plane defined by a reduced polynomial of degree $d$ with rational coefficients. Assume that $P$ is an isolated real point or a singular complex point on the curve $X$. The coordinates of $P$ are algebraic numbers over the rationals of degree at most $d^2...

  19. The end point of the first-order phase transition of the SU(2) gauge-Higgs model on a four-dimensional isotropic lattice

    International Nuclear Information System (INIS)

    Aoki, Y.; Csikor, F.; Fodor, Z.; Ukawa, A.

    1999-01-01

    We report results of a study of the end point of the electroweak phase transition of the SU(2) gauge-Higgs model defined on a four-dimensional isotropic lattice with N t = 2. Finite-size scaling study of Lee-Yang zeros yields λ c = 0.00116(16) for the end point. Combined with a zero-temperature measurement of Higgs and W boson masses, this leads to M H,c = 68.2 ± 6.6 GeV for the critical Higgs boson mass. An independent analysis of Binder cumulant gives a consistent value λ c = 0.00102(3) for the end point

  20. Scalable cross-point resistive switching memory and mechanism through an understanding of H2O2/glucose sensing using an IrOx/Al2O3/W structure.

    Science.gov (United States)

    Chakrabarti, Somsubhra; Maikap, Siddheswar; Samanta, Subhranu; Jana, Surajit; Roy, Anisha; Qiu, Jian-Tai

    2017-10-04

    The resistive switching characteristics of a scalable IrO x /Al 2 O 3 /W cross-point structure and its mechanism for pH/H 2 O 2 sensing along with glucose detection have been investigated for the first time. Porous IrO x and Ir 3+ /Ir 4+ oxidation states are observed via high-resolution transmission electron microscope, field-emission scanning electron spectroscopy, and X-ray photo-electron spectroscopy. The 20 nm-thick IrO x devices in sidewall contact show consecutive long dc cycles at a low current compliance (CC) of 10 μA, multi-level operation with CC varying from 10 μA to 100 μA, and long program/erase endurance of >10 9 cycles with 100 ns pulse width. IrO x with a thickness of 2 nm in the IrO x /Al 2 O 3 /SiO 2 /p-Si structure has shown super-Nernstian pH sensitivity of 115 mV per pH, and detection of H 2 O 2 over the range of 1-100 nM is also achieved owing to the porous and reduction-oxidation (redox) characteristics of the IrO x membrane, whereas a pure Al 2 O 3 /SiO 2 membrane does not show H 2 O 2 sensing. A simulation based on Schottky, hopping, and Fowler-Nordheim tunneling conduction, and a redox reaction, is proposed. The experimental I-V curve matches very well with simulation. The resistive switching mechanism is owing to O 2- ion migration, and the redox reaction of Ir 3+ /Ir 4+ at the IrO x /Al 2 O 3 interface through H 2 O 2 sensing as well as Schottky barrier height modulation is responsible. Glucose at a low concentration of 10 pM is detected using a completely new process in the IrO x /Al 2 O 3 /W cross-point structure. Therefore, this cross-point memory shows a method for low cost, scalable, memory with low current, multi-level operation, which will be useful for future highly dense three-dimensional (3D) memory and as a bio-sensor for the future diagnosis of human diseases.

  1. Unconventional Quantum Critical Points

    OpenAIRE

    Xu, Cenke

    2012-01-01

    In this paper we review the theory of unconventional quantum critical points that are beyond the Landau's paradigm. Three types of unconventional quantum critical points will be discussed: (1). The transition between topological order and semiclassical spin ordered phase; (2). The transition between topological order and valence bond solid phase; (3). The direct second order transition between different competing orders. We focus on the field theory and universality class of these unconventio...

  2. Implementing floating-point DSP

    Czech Academy of Sciences Publication Activity Database

    Kadlec, Jiří; Chappel, S.

    2006-01-01

    Roč. 2, č. 3 (2006), s. 12-14 R&D Projects: GA AV ČR 1ET400750406; GA MŠk 1M0567 EU Projects: European Commission(XE) 027611 - AETHER Program:FP6 Institutional research plan: CEZ:AV0Z10750506 Keywords : PicoBlaze * floating point * FPGA Subject RIV: JC - Computer Hardware ; Software http://www.xilinx.com/publications/ magazines /emb_03/xc_pdf/p12-14_3emb-point.pdf

  3. MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways

    Science.gov (United States)

    Paciorkowski, Alex R.; Traylor, Ryan N.; Rosenfeld, Jill A.; Hoover, Jacqueline M.; Harris, Catharine J.; Winter, Susan; Lacassie, Yves; Bialer, Martin; Lamb, Allen N.; Schultz, Roger A.; Berry-Kravis, Elizabeth; Porter, Brenda E.; Falk, Marni; Venkat, Anu; Vanzo, Rena J.; Cohen, Julie S.; Fatemi, Ali; Dobyns, William B.; Shaffer, Lisa G.; Ballif, Blake C.; Marsh, Eric D.

    2013-01-01

    MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types. PMID:23389741

  4. Usefulness of K-Point Injection for the Nonspecific Neck Pain in So-Called K-Point Syndrome.

    Science.gov (United States)

    Moon, Jeong Jae; Ahn, Myun Whan; Ahn, Hyo Sae; Lee, Sung Jun; Lee, Dong Yeol

    2016-12-01

    Shoichi Kokubun introduced his successful experience with local anesthetic injection at the occipital insertion of the sternocleidomastoid muscle in K-point syndrome. The purpose of this study was to evaluate the short-term and long-term effectiveness of K-point injection and investigate factors affecting treatment results. K-point injection was performed in 58 patients with K-point syndrome at Yeungnam University Medical Center. The syndrome was associated with cervical whiplash injury in 10 patients and was of nonspecific origin in the rest. One milliliter of 2% lidocaine mixed with 1 milliliter of dexamethasone was injected in 50 patients and 2 milliliters of 1% lidocaine alone in the rest. Initially, the severity of local tenderness at the K-point and other tender points was examined and the degree of immediate pain relief effect was assessed within 1 hour after injection. Early effect within 1 month after the injection and current effect were evaluated in 27 patients using a modified Kim's questionnaire with regard to the duration of improvement, degree of improvement in pain and daily living activities, and satisfaction. Of the total 58 patients, 44 (75.8%) apparently had immediate pain relief after K-point injection. The only factor associated with successful immediate pain relief was the whiplash injury associated with traffic accident (TA). The early pain control effect was associated with the immediate effect. The current effect was associated with the early effect alone. Satisfaction with the K-point injection was related to early successful pain relief. K-point injection would be useful for early pain relief in nonspecific neck pain syndrome so called K-point syndrome, but not for current pain relief. Especially, it was very effective for early pain control in the whiplash injury associated with TA.

  5. Peculiar thermal points during B2O3 transition from liquid to glass-like state

    International Nuclear Information System (INIS)

    Bartenev, G.M.; Lomovskoj, V.A.

    1992-01-01

    Relaxation transitions in glass-like B 2 O 3 were studied by dynamic methods in vacuum in the temperature range of 70-1070 K and frequency range of 10 -4 -1.2·10 6 Hz. The standard temperature of glass formation is T g =493 K and it corresponds to the standard frequency 5.3·10 -4 Hz. Above T g two special temperature points - T K and T F , position of which does not depend on the frequency, are observed

  6. The 1.4-2.7 micron spectrum of the point source at the galactic center

    Science.gov (United States)

    Treffers, R. R.; Fink, U.; Larson, H. P.; Gautier, T. N., III

    1976-01-01

    The spectrum of the 2-micron point source at the galactic center is presented over the range from 1.4 to 2.7 microns. The two-level-transition CO band heads are seen near 2.3 microns, confirming that the radiation from this source is due to a cool supergiant star. The heliocentric radial velocity is found to be - 173 (+ or -90) km/s and is consistent with the star being in orbit about a dense galactic nucleus. No evidence is found for Brackett-gamma emission, and no interstellar absorption features are seen. Upper limits for the column densities of interstellar H2, CH4, CO, and NH3 are derived.

  7. SHAPE FROM TEXTURE USING LOCALLY SCALED POINT PROCESSES

    Directory of Open Access Journals (Sweden)

    Eva-Maria Didden

    2015-09-01

    Full Text Available Shape from texture refers to the extraction of 3D information from 2D images with irregular texture. This paper introduces a statistical framework to learn shape from texture where convex texture elements in a 2D image are represented through a point process. In a first step, the 2D image is preprocessed to generate a probability map corresponding to an estimate of the unnormalized intensity of the latent point process underlying the texture elements. The latent point process is subsequently inferred from the probability map in a non-parametric, model free manner. Finally, the 3D information is extracted from the point pattern by applying a locally scaled point process model where the local scaling function represents the deformation caused by the projection of a 3D surface onto a 2D image.

  8. Change point in VCO2 during incremental exercise test: a new method for assessment of human exercise tolerance.

    Science.gov (United States)

    Zoladz, J A; Szkutnik, Z; Majerczak, J; Duda, K

    1999-09-01

    The main purpose of this study was to present a new method to determine the level of power output (PO) at which VCO2 during incremental exercise test (IT) begins to rise non-linearly in relation to power output (PO) - the change point in VCO2 (CP-VCO2). Twenty-two healthy non-smoking men (mean +/- SD: age 22.0 +/- 0.9 years; body mass 74.5 +/- 7.5 kg; height 181 +/- 7 cm; VO2max 3.753 +/- 0.335 l min-1) performed an IT on a cycloergometer. The IT started at a PO of 30 W, followed by gradual increases of 30 W every 3 min. Antecubital venous blood samples were taken at the end of each step and analysed for plasma lactate concentration [La]pl, blood PO2, PCO2 [HCO3-]b and [H+]b. In the detection of the change-point VCO2 (CP-VCO2), a two-phase model was assumed for the 'third-minute-data' of each step of the test. In the first phase, a linear relationship between VCO2 and PO was assumed, whereas in the second, an additional increase in VCO2 was allowed, above the values expected from the linear model. The PO at which the first phase ends is called the change point in VCO2. The identification of the model consists of two steps: testing for the existence of the change point, and estimating its location. Both procedures are based on suitably normalized recursive residuals (see Zoladz et al. 1998a. Eur J Appl Physiol 78, 369-377). In the case of each of our subjects it was possible to detect the CP-VCO2 and the CP-VO2 as described in our model. The PO at the CP-VCO2 amounted to 134 +/- 42 W. The CP- VO2 was detected at 136 +/- 32 W, whereas the PO at the LT amounted to 128 +/- 30 W and corresponded to 49 +/- 11, 49 +/- 8 and 47 +/- 8.6% VO2max, respectively, for the CP-VCO2, CP-VO2 and the LT. The [La]pl at the CP-VCO2 (2.65 +/- 0.76 mmol L-1), at the CP-VO2 (2.53 +/- 0. 56 mmol L-1) and at the LT (2.25 +/- 0.49 mmol L-1) were already significantly higher (P < 0.01, Students t-test) than the value reached at rest (1.86 +/- 0.43 mmol L-1). Our study illustrates that the CP

  9. Accuracy of a dose-area product compared to an absorbed dose to water at a point in a 2 cm diameter field

    Energy Technology Data Exchange (ETDEWEB)

    Dufreneix, S.; Ostrowsky, A.; Rapp, B.; Daures, J.; Bordy, J. M., E-mail: jean-marc.bordy@cea.fr [CEA, LIST, Laboratoire National Henri Becquerel (LNE-LNHB), Gif-sur-Yvette F-91191 (France)

    2016-07-15

    Purpose: Graphite calorimeters with a core diameter larger than the beam can be used to establish dosimetric references in small fields. The dose-area product (DAP) measured can theoretically be linked to an absorbed dose at a point by the determination of a profile correction. This study aims at comparing the DAP-based protocol to the usual absorbed dose at a point protocol in a 2 cm diameter field for which both references exist. Methods: Two calorimeters were used, respectively, with a sensitive volume of 0.6 cm (for the absorbed dose at a point measurement) and 3 cm diameter (for the DAP measurement). Profile correction was calculated from a 2D dose mapping using three detectors: a PinPoint chamber, a synthetic diamond, and EBT3 films. A specific protocol to read EBT3 films was implemented and the dose-rate and energy dependences were studied to assure a precise measurement, especially in the penumbra and out-of-field regions. Results: EBT3 films were found independent on dose rates over the range studied but showed a strong under-response (18%) at low energies. Depending on the dosimeter used for calculating the profile correction, a deviation of 0.8% (PinPoint chamber), 0.9% (diamond), or 1.9% (EBT3 films) was observed between the calibration coefficient derived from DAP measurements and the one directly established in terms of absorbed dose to water at a point. Conclusions: The DAP method can currently be linked to the classical dosimetric reference system based in an absorbed dose at a point only with a confidence interval of 95% (k = 2). None of the detectors studied can be used to determine an absorbed dose to water at a point from a DAP measurement with an uncertainty smaller than 1.2%.

  10. Temperature evolution of subharmonic gap structures in MgB{sub 2}/Nb point-contacts

    Energy Technology Data Exchange (ETDEWEB)

    Giubileo, F. [CNR-INFM Laboratorio Regionale SUPERMAT e Dipartimento di Fisica ' E.R. Caianiello' , Universita degli Studi di Salerno, via Salvador Allende, 84081 Baronissi (Italy)], E-mail: giubileo@sa.infn.it; Bobba, F.; Scarfato, A.; Piano, S. [CNR-INFM Laboratorio Regionale SUPERMAT e Dipartimento di Fisica ' E.R. Caianiello' , Universita degli Studi di Salerno, via Salvador Allende, 84081 Baronissi (Italy); Aprili, M. [Laboratoire de Spectroscopie en Lumiere Polarisee, ESPCI, 10 rue Vauquelin, 75005 Paris (France); CSNSM-CNRS, Bat. 108 Universite Paris-Sud, 91405 Orsay (France); Cucolo, A.M. [CNR-INFM Laboratorio Regionale SUPERMAT e Dipartimento di Fisica ' E.R. Caianiello' , Universita degli Studi di Salerno, via Salvador Allende, 84081 Baronissi (Italy)

    2007-09-01

    We have performed point-contact spectroscopy experiments on superconducting micro-constrictions between Nb tips and high quality MgB{sub 2} pellets. We measured the temperature evolution (between 4.2 K and 300 K) of the current-voltage (I-V) and of the dynamical conductance (dI/dV-V) characteristics. Above the Nb critical temperature T{sub C}{sup Nb}, the conductance of the constrictions behaves as predicted by the BTK model for S/N contacts being Nb in its normal state below T{sub C}{sup Nb}, the contacts show Josephson current and subharmonic gap structures, due to multiple Andreev reflections. These observations clearly indicate the coupling of the MgB{sub 2} 3D {pi}-band with the Nb superconducting order parameter. We found {delta}{sub {pi}} = 2.4 {+-} 0.2 meV for the three-dimensional gap of MgB{sub 2}.

  11. Light trapping and circularly polarization at a Dirac point in 2D plasma photonic crystals

    Science.gov (United States)

    Li, Qian; Hu, Lei; Mao, Qiuping; Jiang, Haiming; Hu, Zhijia; Xie, Kang; Wei, Zhang

    2018-03-01

    Light trapping at the Dirac point in 2D plasma photonic crystal has been obtained. The new localized mode, Dirac mode, is attributable to neither photonic bandgap nor total internal reflection. It exhibits a unique algebraic profile and possesses a high-Q factor resonator of about 105. The Dirac point could be modulated by tuning the filling factor, plasma frequency and plasma cyclotron frequency, respectively. When a magnetic field parallel to the wave vector is applied, Dirac modes for right circularly polarized and left circularly polarized waves could be obtained at different frequencies, and the Q factor could be tuned. This property will add more controllability and flexibility to the design and modulation of novel photonic devices. It is also valuable for the possibilities of Dirac modes in photonic crystal containing other kinds of metamaterials.

  12. In-flight calibration of the Hitomi Soft X-ray Spectrometer. (2) Point spread function

    Science.gov (United States)

    Maeda, Yoshitomo; Sato, Toshiki; Hayashi, Takayuki; Iizuka, Ryo; Angelini, Lorella; Asai, Ryota; Furuzawa, Akihiro; Kelley, Richard; Koyama, Shu; Kurashima, Sho; Ishida, Manabu; Mori, Hideyuki; Nakaniwa, Nozomi; Okajima, Takashi; Serlemitsos, Peter J.; Tsujimoto, Masahiro; Yaqoob, Tahir

    2018-03-01

    We present results of inflight calibration of the point spread function of the Soft X-ray Telescope that focuses X-rays onto the pixel array of the Soft X-ray Spectrometer system. We make a full array image of a point-like source by extracting a pulsed component of the Crab nebula emission. Within the limited statistics afforded by an exposure time of only 6.9 ks and limited knowledge of the systematic uncertainties, we find that the raytracing model of 1 {^'.} 2 half-power-diameter is consistent with an image of the observed event distributions across pixels. The ratio between the Crab pulsar image and the raytracing shows scatter from pixel to pixel that is 40% or less in all except one pixel. The pixel-to-pixel ratio has a spread of 20%, on average, for the 15 edge pixels, with an averaged statistical error of 17% (1 σ). In the central 16 pixels, the corresponding ratio is 15% with an error of 6%.

  13. Melting point of yttria

    International Nuclear Information System (INIS)

    Skaggs, S.R.

    1977-06-01

    Fourteen samples of 99.999 percent Y 2 O 3 were melted near the focus of a 250-W CO 2 laser. The average value of the observed melting point along the solid-liquid interface was 2462 +- 19 0 C. Several of these same samples were then melted in ultrahigh-purity oxygen, nitrogen, helium, or argon and in water vapor. No change in the observed temperature was detected, with the exception of a 20 0 C increase in temperature from air to helium gas. Post test examination of the sample characteristics, clarity, sphericity, and density is presented, along with composition. It is suggested that yttria is superior to alumina as a secondary melting-point standard

  14. Optimization of a Nucleic Acids united-RESidue 2-Point model (NARES-2P) with a maximum-likelihood approach

    International Nuclear Information System (INIS)

    He, Yi; Scheraga, Harold A.; Liwo, Adam

    2015-01-01

    Coarse-grained models are useful tools to investigate the structural and thermodynamic properties of biomolecules. They are obtained by merging several atoms into one interaction site. Such simplified models try to capture as much as possible information of the original biomolecular system in all-atom representation but the resulting parameters of these coarse-grained force fields still need further optimization. In this paper, a force field optimization method, which is based on maximum-likelihood fitting of the simulated to the experimental conformational ensembles and least-squares fitting of the simulated to the experimental heat-capacity curves, is applied to optimize the Nucleic Acid united-RESidue 2-point (NARES-2P) model for coarse-grained simulations of nucleic acids recently developed in our laboratory. The optimized NARES-2P force field reproduces the structural and thermodynamic data of small DNA molecules much better than the original force field

  15. Prediction of high-temperature point defect formation in TiO2 from combined ab initio and thermodynamic calculations

    International Nuclear Information System (INIS)

    He, J.; Behera, R.K.; Finnis, M.W.; Li, X.; Dickey, E.C.; Phillpot, S.R.; Sinnott, S.B.

    2007-01-01

    A computational approach that integrates ab initio electronic structure and thermodynamic calculations is used to determine point defect stability in rutile TiO 2 over a range of temperatures, oxygen partial pressures and stoichiometries. Both donors (titanium interstitials and oxygen vacancies) and acceptors (titanium vacancies) are predicted to have shallow defect transition levels in the electronic-structure calculations. The resulting defect formation energies for all possible charge states are then used in thermodynamic calculations to predict the influence of temperature and oxygen partial pressure on the relative stabilities of the point defects. Their ordering is found to be the same as temperature increases and oxygen partial pressure decreases: titanium vacancy → oxygen vacancy → titanium interstitial. The charges on these defects, however, are quite sensitive to the Fermi level. Finally, the combined formation energies of point defect complexes, including Schottky, Frenkel and anti-Frenkel defects, are predicted to limit the further formation of point defects

  16. Defect production due to quenching through a multicritical point

    International Nuclear Information System (INIS)

    Divakaran, Uma; Mukherjee, Victor; Dutta, Amit; Sen, Diptiman

    2009-01-01

    We study the generation of defects when a quantum spin system is quenched through a multicritical point by changing a parameter of the Hamiltonian as t/τ, where τ is the characteristic timescale of quenching. We argue that when a quantum system is quenched across a multicritical point, the density of defects (n) in the final state is not necessarily given by the Kibble–Zurek scaling form n∼1/τ dν/(zν+1) , where d is the spatial dimension, and ν and z are respectively the correlation length and dynamical exponent associated with the quantum critical point. We propose a generalized scaling form of the defect density given by n∼1/τ d/(2z 2 ) , where the exponent z 2 determines the behavior of the off-diagonal term of the 2 × 2 Landau–Zener matrix at the multicritical point. This scaling is valid not only at a multicritical point but also at an ordinary critical point

  17. Evidence that yeast SGS1, DNA2, SRS2, and FOB1 interact to maintain rDNA stability

    International Nuclear Information System (INIS)

    Tao Weitao; Budd, Martin; Campbell, Judith L.

    2003-01-01

    We and others have proposed that faulty processing of arrested replication forks leads to increases in recombination and chromosome instability in Saccharomyces cerevisiae. Now we use the ribosomal DNA locus, which is a good model for all stages of DNA replication, to test this hypothesis. We showed previously that DNA replication pausing at the ribosomal DNA replication fork barrier (RFB) is accompanied by the occurrence of double-strand breaks near the RFB. Both pausing and breakage are elevated in the hypomorphic dna2-2 helicase mutant. Deletion of FOB1 suppresses the elevated pausing and DSB formation. Our current work shows that mutation inactivating Sgs1, the yeast RecQ helicase ortholog, also causes accumulation of stalled replication forks and DSBs at the rDNA RFB. Either deletion of FOB1, which suppresses fork blocking and certain types of rDNA recombination, or an increase in SIR2 gene dosage, which suppresses rDNA recombination, reduces the number of forks persisting at the RFB. Although dna2-2 sgs1Δ double mutants are conditionally lethal, they do not show enhanced rDNA defects compared to sgs1Δ alone. However, surprisingly, the dna2-2 sgs1Δ lethality is suppressed by deletion of FOB1. On the other hand, the dna2-2 sgs1Δ lethality is only partially suppressed by deletion of rad51Δ. We propose that the replication-associated defects that we document in the rDNA are characteristic of similar events occurring either stochastically throughout the genome or at other regions where replication forks move slowly or stall, such as telomeres, centromeres, or replication slow zones

  18. Evidence that yeast SGS1, DNA2, SRS2, and FOB1 interact to maintain rDNA stability

    Energy Technology Data Exchange (ETDEWEB)

    Tao Weitao; Budd, Martin; Campbell, Judith L

    2003-11-27

    We and others have proposed that faulty processing of arrested replication forks leads to increases in recombination and chromosome instability in Saccharomyces cerevisiae. Now we use the ribosomal DNA locus, which is a good model for all stages of DNA replication, to test this hypothesis. We showed previously that DNA replication pausing at the ribosomal DNA replication fork barrier (RFB) is accompanied by the occurrence of double-strand breaks near the RFB. Both pausing and breakage are elevated in the hypomorphic dna2-2 helicase mutant. Deletion of FOB1 suppresses the elevated pausing and DSB formation. Our current work shows that mutation inactivating Sgs1, the yeast RecQ helicase ortholog, also causes accumulation of stalled replication forks and DSBs at the rDNA RFB. Either deletion of FOB1, which suppresses fork blocking and certain types of rDNA recombination, or an increase in SIR2 gene dosage, which suppresses rDNA recombination, reduces the number of forks persisting at the RFB. Although dna2-2 sgs1{delta} double mutants are conditionally lethal, they do not show enhanced rDNA defects compared to sgs1{delta} alone. However, surprisingly, the dna2-2 sgs1{delta} lethality is suppressed by deletion of FOB1. On the other hand, the dna2-2 sgs1{delta} lethality is only partially suppressed by deletion of rad51{delta}. We propose that the replication-associated defects that we document in the rDNA are characteristic of similar events occurring either stochastically throughout the genome or at other regions where replication forks move slowly or stall, such as telomeres, centromeres, or replication slow zones.

  19. A periodic point-based method for the analysis of Nash equilibria in 2 x 2 symmetric quantum games

    International Nuclear Information System (INIS)

    Schneider, David

    2011-01-01

    We present a novel method of looking at Nash equilibria in 2 x 2 quantum games. Our method is based on a mathematical connection between the problem of identifying Nash equilibria in game theory, and the topological problem of the periodic points in nonlinear maps. To adapt our method to the original protocol designed by Eisert et al (1999 Phys. Rev. Lett. 83 3077-80) to study quantum games, we are forced to extend the space of strategies from the initial proposal. We apply our method to the extended strategy space version of the quantum Prisoner's dilemma and find that a new set of Nash equilibria emerge in a natural way. Nash equilibria in this set are optimal as Eisert's solution of the quantum Prisoner's dilemma and include this solution as a limit case.

  20. The central subgroup of the nonabelian tensor square of Bieberbach group of dimension three with point group C2 × C2

    Science.gov (United States)

    Ladi, Nor Fadzilah Abdul; Masri, Rohaidah; Idrus, Nor'ashiqin Mohd; Ting, Tan Yee

    2017-05-01

    Bieberbach groups are crystallographic groups. By computing the central subgroup of the nonabelian tensor square of a group, the properties of the group can be determined. In this paper, the central subgroup of the nonabelian tensor square of one Bieberbach group of dimension three with point group C2 × C2 is computed. In order to compute the ∇ (S3 (3)), the derived subgroup and the abelianization of the group are first constructed.

  1. The Type-2 Fuzzy Logic Controller-Based Maximum Power Point Tracking Algorithm and the Quadratic Boost Converter for Pv System

    Science.gov (United States)

    Altin, Necmi

    2018-05-01

    An interval type-2 fuzzy logic controller-based maximum power point tracking algorithm and direct current-direct current (DC-DC) converter topology are proposed for photovoltaic (PV) systems. The proposed maximum power point tracking algorithm is designed based on an interval type-2 fuzzy logic controller that has an ability to handle uncertainties. The change in PV power and the change in PV voltage are determined as inputs of the proposed controller, while the change in duty cycle is determined as the output of the controller. Seven interval type-2 fuzzy sets are determined and used as membership functions for input and output variables. The quadratic boost converter provides high voltage step-up ability without any reduction in performance and stability of the system. The performance of the proposed system is validated through MATLAB/Simulink simulations. It is seen that the proposed system provides high maximum power point tracking speed and accuracy even for fast changing atmospheric conditions and high voltage step-up requirements.

  2. Some remarks on farthest points

    Czech Academy of Sciences Publication Activity Database

    Montesinos, V.; Zizler, P.; Zizler, Václav

    2011-01-01

    Roč. 105, č. 1 (2011), s. 119-131 ISSN 1578-7303 R&D Projects: GA AV ČR IAA100190901 Institutional research plan: CEZ:AV0Z10190503 Keywords : farthest points * strongly exposed points * generic differentiability * convex functions Subject RIV: BA - General Mathematics Impact factor: 0.340, year: 2011 http://link.springer.com/article/10.1007%2Fs13398-011-0012-z

  3. APOGEE-2: The Second Phase of the Apache Point Observatory Galactic Evolution Experiment in SDSS-IV

    Science.gov (United States)

    Sobeck, Jennifer; Majewski, S.; Hearty, F.; Schiavon, R. P.; Holtzman, J. A.; Johnson, J.; Frinchaboy, P. M.; Skrutskie, M. F.; Munoz, R.; Pinsonneault, M. H.; Nidever, D. L.; Zasowski, G.; Garcia Perez, A.; Fabbian, D.; Meza Cofre, A.; Cunha, K. M.; Smith, V. V.; Chiappini, C.; Beers, T. C.; Steinmetz, M.; Anders, F.; Bizyaev, D.; Roman, A.; Fleming, S. W.; Crane, J. D.; SDSS-IV/APOGEE-2 Collaboration

    2014-01-01

    The second phase of the Apache Point Observatory Galactic Evolution Experiment (APOGEE-2), a part of the Sloan Digital Sky Survey IV (SDSS-IV), will commence operations in 2014. APOGEE-2 represents a significant expansion over APOGEE-1, not only in the size of the stellar sample, but also in the coverage of the sky through observations in both the Northern and Southern Hemispheres. Observations on the 2.5m Sloan Foundation Telescope of the Apache Point Observatory (APOGEE-2N) will continue immediately after the conclusion of APOGEE-1, to be followed by observations with the 2.5m du Pont Telescope of the Las Campanas Observatory (APOGEE-2S) within three years. Over the six-year lifetime of the project, high resolution (R˜22,500), high signal-to-noise (≥100) spectroscopic data in the H-band wavelength regime (1.51-1.69 μm) will be obtained for several hundred thousand stars, more than tripling the total APOGEE-1 sample. Accurate radial velocities and detailed chemical compositions will be generated for target stars in the main Galactic components (bulge, disk, and halo), open/globular clusters, and satellite dwarf galaxies. The spectroscopic follow-up program of Kepler targets with the APOGEE-2N instrument will be continued and expanded. APOGEE-2 will significantly extend and enhance the APOGEE-1 legacy of scientific contributions to understanding the origin and evolution of the elements, the assembly and formation history of galaxies like the Milky Way, and fundamental stellar astrophysics.

  4. Beginning SharePoint 2010 Administration Windows SharePoint Foundation 2010 and Microsoft SharePoint Server 2010

    CERN Document Server

    Husman, Göran

    2010-01-01

    Complete coverage on the latest advances in SharePoint 2010 administration. SharePoint 2010 comprises an abundance of new features, and this book shows you how to take advantage of all SharePoint 2010's many improvements. Written by a four-time SharePoint MVP, Beginning SharePoint 2010 Administration begins with a comparison of SharePoint 2010 compared to the previous version and then examines the differences between WSS 4.0 and MSS 2010. Packed with step-by-step instructions, tips and tricks, and real-world examples, this book dives into the basics of how to install, manage, and administrate

  5. Isolated Deep Venous Thrombosis: Implications for 2-Point Compression Ultrasonography of the Lower Extremity.

    Science.gov (United States)

    Adhikari, Srikar; Zeger, Wes; Thom, Christopher; Fields, J Matthew

    2015-09-01

    Two-point compression ultrasonography focuses on the evaluation of common femoral and popliteal veins for complete compressibility. The presence of isolated thrombi in proximal veins other than the common femoral and popliteal veins should prompt modification of 2-point compression technique. The objective of this study is to determine the prevalence and distribution of deep venous thrombi isolated to lower-extremity veins other than the common femoral and popliteal veins in emergency department (ED) patients with clinically suspected deep venous thrombosis. This was a retrospective study of all adult ED patients who received a lower-extremity venous duplex ultrasonographic examination for evaluation of deep venous thrombosis during a 6-year period. The ultrasonographic protocol included B-mode, color-flow, and spectral Doppler scanning of the common femoral, femoral, deep femoral, popliteal, and calf veins. Deep venous thrombosis was detected in 362 of 2,451 patients (14.7%; 95% confidence interval [CI] 13.3% to 16.1%). Thrombus confined to the common femoral vein alone was found in 5 of 362 cases (1.4%; 95% CI 0.2% to 2.6%). Isolated femoral vein thrombus was identified in 20 of 362 patients (5.5%; 95% CI 3.2% to 7.9%). Isolated deep femoral vein thrombus was found in 3 of 362 cases (0.8%; 95% CI -0.1% to 1.8%). Thrombus in the popliteal vein alone was identified in 53 of 362 cases (14.6%; 95% CI 11% to 18.2%). In our study, 6.3% of ED patients with suspected deep venous thrombosis had isolated thrombi in proximal veins other than common femoral and popliteal veins. Our study results support the addition of femoral and deep femoral vein evaluation to standard compression ultrasonography of the common femoral and popliteal vein, assuming that this does not have a deleterious effect on specificity. Copyright © 2014 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

  6. Safety Evaluation Report related to the operation of Nine Mile Point Nuclear Station, Unit No. 2 (Docket No. 50-410)

    International Nuclear Information System (INIS)

    1987-07-01

    This report supplements the Safety Evaluation Report (NUREG-1047, February 1985) for the application filed by Niagara Mohawk Power Corporation, as applicant and co-owner, for the license to operate Nine Mile Point Nuclear Station, Unit 2 (Docket No. 50-410). It has been prepared by the Office of Nuclear Reactor Regulation of the US Nuclear Regulatory Commission. The facility is located near Oswego, New York. This report supports the issuance of the full-power license for Nine Mile Point Nuclear Station, Unit No. 2

  7. 77 FR 41454 - Entergy Nuclear Indian Point Unit 2, LLC, Entergy Nuclear Indian Point Unit 3, LLC, Entergy...

    Science.gov (United States)

    2012-07-13

    ... at the Indian Point site. Such effects may include human health, biological, cultural, economic, or..., process, recycle, and dispose of gaseous, liquid, and solid wastes that contain radioactive material in a... within NRC regulatory limits and, therefore, would not be significant. Accident Doses to Members of the...

  8. May 2002 Lidar Point Data of Southern California Coastline: Dana Point to Point La Jolla

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data set contains lidar point data from a strip of Southern California coastline (including water, beach, cliffs, and top of cliffs) from Dana Point to Point La...

  9. September 2002 Lidar Point Data of Southern California Coastline: Dana Point to Point La Jolla

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data set contains lidar point data from a strip of Southern California coastline (including water, beach, cliffs, and top of cliffs) from Dana Point to Point La...

  10. Validating the Rett Syndrome Gross Motor Scale.

    Science.gov (United States)

    Downs, Jenny; Stahlhut, Michelle; Wong, Kingsley; Syhler, Birgit; Bisgaard, Anne-Marie; Jacoby, Peter; Leonard, Helen

    2016-01-01

    Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale was developed to measure gross motor abilities in this population. The current study investigated the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age and genotype were investigated. Clinical assessment scores for 38 girls and women with Rett syndrome who attended the Danish Center for Rett Syndrome were used to assess consistency of measurement. Principal components analysis enabled the calculation of three factor scores: Sitting, Standing and Walking, and Challenge. Motor scores were poorer with increasing age and those with the p.Arg133Cys, p.Arg294* or p.Arg306Cys mutation achieved higher scores than those with a large deletion. The repeatability of clinical assessment was excellent (intraclass correlation coefficient for total score 0.99, 95% CI 0.93-0.98). The standard error of measurement for the total score was 2 points and we would be 95% confident that a change 4 points in the 45-point scale would be greater than within-subject measurement error. The Rett Syndrome Gross Motor Scale could be an appropriate measure of gross motor skills in clinical practice and clinical trials.

  11. Wolf Point Substation, Roosevelt County, Montana

    International Nuclear Information System (INIS)

    1991-05-01

    The Western Area Power Administration (Western), an agency of the United States Department of Energy, is proposing to construct the 115-kV Wolf Point Substation near Wolf Point in Roosevelt County, Montana (Figure 1). As part of the construction project, Western's existing Wolf Point Substation would be taken out of service. The existing 115-kV Wolf Point Substation is located approximately 3 miles west of Wolf Point, Montana (Figure 2). The substation was constructed in 1949. The existing Wolf Point Substation serves as a ''Switching Station'' for the 115-kV transmission in the region. The need for substation improvements is based on operational and reliability issues. For this environmental assessment (EA), the environmental review of the proposed project took into account the removal of the old Wolf Point Substation, rerouting of the five Western lines and four lines from the Cooperatives and Montana-Dakota Utilities Company, and the new road into the proposed substation. Reference to the new proposed Wolf Point Substation in the EA includes these facilities as well as the old substation site. The environmental review looked at the impacts to all resource areas in the Wolf Point area. 7 refs., 6 figs

  12. A periodic point-based method for the analysis of Nash equilibria in 2 x 2 symmetric quantum games

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, David, E-mail: schneide@tandar.cnea.gov.ar [Departamento de Fisica, Comision Nacional de EnergIa Atomica. Av. del Libertador 8250, 1429 Buenos Aires (Argentina)

    2011-03-04

    We present a novel method of looking at Nash equilibria in 2 x 2 quantum games. Our method is based on a mathematical connection between the problem of identifying Nash equilibria in game theory, and the topological problem of the periodic points in nonlinear maps. To adapt our method to the original protocol designed by Eisert et al (1999 Phys. Rev. Lett. 83 3077-80) to study quantum games, we are forced to extend the space of strategies from the initial proposal. We apply our method to the extended strategy space version of the quantum Prisoner's dilemma and find that a new set of Nash equilibria emerge in a natural way. Nash equilibria in this set are optimal as Eisert's solution of the quantum Prisoner's dilemma and include this solution as a limit case.

  13. Fixed-point signal processing

    CERN Document Server

    Padgett, Wayne T

    2009-01-01

    This book is intended to fill the gap between the ""ideal precision"" digital signal processing (DSP) that is widely taught, and the limited precision implementation skills that are commonly required in fixed-point processors and field programmable gate arrays (FPGAs). These skills are often neglected at the university level, particularly for undergraduates. We have attempted to create a resource both for a DSP elective course and for the practicing engineer with a need to understand fixed-point implementation. Although we assume a background in DSP, Chapter 2 contains a review of basic theory

  14. Applying inversion to construct planar, rational spirals that satisfy two-point G(2) Hermite data

    CERN Document Server

    Kurnosenko, A

    2010-01-01

    A method of two-point G(2) Hermite interpolation with spirals is proposed. To construct a sought for curve, the inversion is applied to an arc of some other spiral. To illustrate the method, inversions of parabola are considered in detail. The resulting curve is 4th degree rational. The method allows the matching of a wide range of boundary conditions, including those which require an inflection. Although not all G(2) Hermite data can be matched with a spiral generated from a parabolic arc, introducing one intermediate G(2) data solves the problem. Expanding the method by involving other spirals arcs is also discussed. (C) 2009 Elsevier B.V. All rights reserved.

  15. Structure and thermal expansion of Lu2O3 and Yb2O3 up to the melting points

    Science.gov (United States)

    Pavlik, Alfred; Ushakov, Sergey V.; Navrotsky, Alexandra; Benmore, Chris J.; Weber, Richard J. K.

    2017-11-01

    Knowledge of thermal expansion and high temperature phase transformations is essential for prediction and interpretation of materials behavior under the extreme conditions of high temperature and intense radiation encountered in nuclear reactors. Structure and thermal expansion of Lu2O3 and Yb2O3 were studied in oxygen and argon atmospheres up to their melting temperatures using synchrotron X-ray diffraction on laser heated levitated samples. Both oxides retained the cubic bixbyite C-type structure in oxygen and argon to melting. In contrast to fluorite-type structures, the increase in the unit cell parameter of Yb2O3 and Lu2O3 with temperature is linear within experimental error from room temperature to the melting point, with mean thermal expansion coefficients (8.5 ± 0.6) · 10-6 K-1 and (7.7 ± 0.6) · 10-6 K-1, respectively. There is no indication of a superionic (Bredig) transition in the C-type structure or of a previously suggested Yb2O3 phase transformation to hexagonal phase prior to melting.

  16. Address Points - COUNTY_ADDRESS_POINTS_IDHS_IN: Address Points Maintained by County Agencies in Indiana (Indiana Department of Homeland Security, Point feature class)

    Data.gov (United States)

    NSGIC State | GIS Inventory — COUNTY_ADDRESS_POINTS_IDHS_IN is an ESRI Geodatabase point feature class that contains address points maintained by county agencies in Indiana, provided by personnel...

  17. Beginning SharePoint 2010 Building Business Solutions with SharePoint

    CERN Document Server

    Perran, Amanda; Mason, Jennifer; Rogers, Laura

    2010-01-01

    Two SharePoint MVPs provide the ultimate introduction to SharePoint 2010Beginning SharePoint 2010: Building Team Solutions with SharePoint provides information workers and site managers with extensive knowledge and expert advice, empowering them to become SharePoint champions within their organizations.Provides expansive coverage of SharePoint topics, as well as specialty areas such as forms, excel services, records management, and web content managementDetails realistic usage scenarios, and includes practice examples that highlight best practices for configuration and customizationIncludes de

  18. Optimal 25-Point Finite-Difference Subgridding Techniques for the 2D Helmholtz Equation

    Directory of Open Access Journals (Sweden)

    Tingting Wu

    2016-01-01

    Full Text Available We present an optimal 25-point finite-difference subgridding scheme for solving the 2D Helmholtz equation with perfectly matched layer (PML. This scheme is second order in accuracy and pointwise consistent with the equation. Subgrids are used to discretize the computational domain, including the interior domain and the PML. For the transitional node in the interior domain, the finite difference equation is formulated with ghost nodes, and its weight parameters are chosen by a refined choice strategy based on minimizing the numerical dispersion. Numerical experiments are given to illustrate that the newly proposed schemes can produce highly accurate seismic modeling results with enhanced efficiency.

  19. Effect of point defects on the thermal conductivity of UO2: molecular dynamics simulations

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xiang-Yang [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Stanek, Christopher Richard [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Andersson, Anders David Ragnar [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-07-21

    The thermal conductivity of uranium dioxide (UO2) fuel is an important materials property that affects fuel performance since it is a key parameter determining the temperature distribution in the fuel, thus governing, e.g., dimensional changes due to thermal expansion, fission gas release rates, etc. [1] The thermal conductivity of UO2 nuclear fuel is also affected by fission gas, fission products, defects, and microstructural features such as grain boundaries. Here, molecular dynamics (MD) simulations are carried out to determine quantitatively, the effect of irradiation induced point defects on the thermal conductivity of UO2, as a function of defect concentrations, for a range of temperatures, 300 – 1500 K. The results will be used to develop enhanced continuum thermal conductivity models for MARMOT and BISON by INL. These models express the thermal conductivity as a function of microstructure state-variables, thus enabling thermal conductivity models with closer connection to the physical state of the fuel [2].

  20. Minimum Propellant Low-Thrust Maneuvers near the Libration Points

    Science.gov (United States)

    Marinescu, A.; Dumitrache, M.

    The impulse technique certainly can bring the vehicle on orbits around the libration points or close to them. The question that aries is, by what means can the vehicle arrive in such cases at the libration points? A first investigation carried out in this paper can give an answer: the use of the technique of low-thrust, which, in addition, can bring the vehicle from the libration points near to or into orbits around these points. This aspect is considered in this present paper where for the applications we have considered the transfer for orbits of the equidistant point L4 and of the collinear point L2, from Earth-moon system. This transfer maneuver can be used to insertion one satellite on libration points orbits. In Earth- moon system the points L 4 and L 5 because an vehicle in on of the equidistant points in quite stable and remains in its vicinity of perturbed, have potential interest for the establishment of transporder satellite for interplanetary tracking. In contrast an vehicle in one of the collinear points is quite instable and it will oscillate along the Earth-moon-axis at increasing amplitude and gradually escape from the libration point. Let use assume that a space vehicle equipped with a low-thrust propulsion is near a libration point L. We consider the planar motion in the restricted frame of the three bodies in the rotating system L, where the Earth-moon distance D=l. The unit of time T is period of the moon's orbit divided by 2 and multiplied by the square root of the quantity one plus the moon/Earth mass ratio, and the unit of mass is the Earth's mass. With these predictions the motion equatios of the vehicle equiped with a low-thrust propulsion installation in the linear approximation near the libration point, have been established. The parameters of the motion at the beginning and the end of these maneuvers are known, the variational problem has been formulated as a Lagrange type problem with fixed extremities. On established the differential

  1. ELEVATION ON BOINLING POINT OF COFFE EXTRACT

    Directory of Open Access Journals (Sweden)

    Telis-Romero J.

    2002-01-01

    Full Text Available The rise in boiling point of coffee extract was experimentally measured at soluble solids concentrations in the range of 9.2 to 52.4ºBrix and pressures between 5.8 × 10³ and 9.4 × 10(4 Pa (abs.. Different approaches to representing experimental data, including the Dühring's rule, the Antoine equation and empirical models proposed in the literature were tested. In the range of 9.2 to 16.2ºBrix, the rise in boiling point was nearly independent of pressure, varying only with extract concentration. Considerable deviations of this behavior began to occur at concentrations higher than 16.2ºBrix. Experimental data could best be predicted by adjusting an empirical model which consists of a single equation that takes into account the dependence of rise in boiling point on pressure and concentration.

  2. Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation.

    Science.gov (United States)

    Cortelazzo, Alessio; de Felice, Claudio; Leoncini, Silvia; Signorini, Cinzia; Guerranti, Roberto; Leoncini, Roberto; Armini, Alessandro; Bini, Luca; Ciccoli, Lucia; Hayek, Joussef

    2017-03-01

    Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT. Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated. CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status. For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.

  3. IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

    Directory of Open Access Journals (Sweden)

    Giorgio Pini

    2012-01-01

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2. Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1, are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3 IGF1, cross the blood brain barrier, and (1–3 IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy. This study shows that there are no risks associated with IGF1 administration.

  4. Persuasive Effects of Point of View, Protagonist Competence, and Similarity in a Health Narrative About Type 2 Diabetes.

    Science.gov (United States)

    Chen, Meng; Bell, Robert A; Taylor, Laramie D

    2017-08-01

    We examined the persuasive effects of three narrative features in a message about type 2 diabetes: narrative point of view (first- vs. third-person perspective), protagonist competence (positive role model who prevents diabetes vs. negative role model who develops diabetes), and protagonist-reader similarity (demographically similar vs. dissimilar). We posited that a first-person point of view would elevate people's identification levels more than a third-person point of view, especially when the protagonist was depicted as a positive role model. We also expected a similar protagonist to foster greater levels of identification than a dissimilar one. In addition, the positive effect of a competent role model on identification was expected to be enhanced under the condition of reader-protagonist similarity. Finally, we hypothesized that the effects of identification on persuasion would be mediated by self-referencing. Participants 30 years of age or younger (N = 489) were randomly assigned to read a story about a person with a family history of type 2 diabetes that was altered with regard to the experimental factors. Thereafter they completed a questionnaire incorporating measures of study variables. Greater levels of identification were found to foster self-referencing, leading to persuasion. Identification was strongest with a first-person point of view and when the narrator was a positive role model. The effect of identification on persuasion was mediated by self-referencing. Contrary to expectations, protagonist-reader demographic similarity did not affect identification or self-referencing. There was no support for the two moderation hypotheses.

  5. Fermion-induced quantum critical points.

    Science.gov (United States)

    Li, Zi-Xiang; Jiang, Yi-Fan; Jian, Shao-Kai; Yao, Hong

    2017-08-22

    A unified theory of quantum critical points beyond the conventional Landau-Ginzburg-Wilson paradigm remains unknown. According to Landau cubic criterion, phase transitions should be first-order when cubic terms of order parameters are allowed by symmetry in the Landau-Ginzburg free energy. Here, from renormalization group analysis, we show that second-order quantum phase transitions can occur at such putatively first-order transitions in interacting two-dimensional Dirac semimetals. As such type of Landau-forbidden quantum critical points are induced by gapless fermions, we call them fermion-induced quantum critical points. We further introduce a microscopic model of SU(N) fermions on the honeycomb lattice featuring a transition between Dirac semimetals and Kekule valence bond solids. Remarkably, our large-scale sign-problem-free Majorana quantum Monte Carlo simulations show convincing evidences of a fermion-induced quantum critical points for N = 2, 3, 4, 5 and 6, consistent with the renormalization group analysis. We finally discuss possible experimental realizations of the fermion-induced quantum critical points in graphene and graphene-like materials.Quantum phase transitions are governed by Landau-Ginzburg theory and the exceptions are rare. Here, Li et al. propose a type of Landau-forbidden quantum critical points induced by gapless fermions in two-dimensional Dirac semimetals.

  6. Tipping Point

    Medline Plus

    Full Text Available ... en español Blog About OnSafety CPSC Stands for Safety The Tipping Point Home > 60 Seconds of Safety (Videos) > The Tipping Point The Tipping Point by ... danger death electrical fall furniture head injury product safety television tipover tv Watch the video in Adobe ...

  7. NIM Realization of the Gallium Triple Point

    Science.gov (United States)

    Xiaoke, Yan; Ping, Qiu; Yuning, Duan; Yongmei, Qu

    2003-09-01

    In the last three years (1999 to 2001), the gallium triple-point cell has been successfully developed, and much corresponding research has been carried out at the National Institute of Metrology (NIM), Beijing, China. This paper presents the cell design, apparatus and procedure for realizing the gallium triple point, and presents studies on the different freezing methods. The reproducibility is 0.03 mK, and the expanded uncertainty of realization of the gallium triple point is evaluated to be 0.17 mK (p=0.99, k=2.9). Also, the reproducibility of the gallium triple point was compared with that of the triple point of water.

  8. An approximate factorization procedure for solving nine-point elliptic difference equations. Application for a fast 2-D relativistic Fokker-Planck solver

    Energy Technology Data Exchange (ETDEWEB)

    Peysson, Y. [Association Euratom-CEA, CEA Grenoble, 38 (France). Dept. de Recherches sur la Fusion Controlee; Choucri, M. [Centre Canadien de Fusion Magnetique, Varennes, PQ (Canada)

    1997-09-01

    A full implicit numerical procedure based on the use of a nine-point difference operator is presented to solve the two dimensional (2{sub D}) relativistic Fokker-Planck equation for the current drive problem and synergetic effects between the lower hybrid and the electron cyclotron waves in tokamaks. As compared to the standard approach based on the use of a five-point difference operator [M. Shoucri, I. Shkarofsky, Comput. Phys. Comm. 82 (1994) 287], the convergence rate towards the steady state solution may be significantly enhanced with no loss of accuracy on the distribution function. Moreover, it is shown that the numerical stability may be strongly improved without a large degradation of the CPU time consumption as in the five-point scheme, making this approach very attractive for a fast solution of the 2-D Fokker-Planck equation on a fine grid in conjunction with other numerical codes for realistic plasma simulations. This new algorithm, based on an approximate matrix factorization technique, may be applied to all numerical problems with large sets of equations which involve nine-point difference operators. (author) 21 refs.

  9. An approximate factorization procedure for solving nine-point elliptic difference equations. Application for a fast 2-D relativistic Fokker-Planck solver

    International Nuclear Information System (INIS)

    Peysson, Y.

    1997-09-01

    A full implicit numerical procedure based on the use of a nine-point difference operator is presented to solve the two dimensional (2 D ) relativistic Fokker-Planck equation for the current drive problem and synergetic effects between the lower hybrid and the electron cyclotron waves in tokamaks. As compared to the standard approach based on the use of a five-point difference operator [M. Shoucri, I. Shkarofsky, Comput. Phys. Comm. 82 (1994) 287], the convergence rate towards the steady state solution may be significantly enhanced with no loss of accuracy on the distribution function. Moreover, it is shown that the numerical stability may be strongly improved without a large degradation of the CPU time consumption as in the five-point scheme, making this approach very attractive for a fast solution of the 2-D Fokker-Planck equation on a fine grid in conjunction with other numerical codes for realistic plasma simulations. This new algorithm, based on an approximate matrix factorization technique, may be applied to all numerical problems with large sets of equations which involve nine-point difference operators. (author)

  10. The Development and Application of Spatiotemporal Metrics for the Characterization of Point Source FFCO2 Emissions and Dispersion

    Science.gov (United States)

    Roten, D.; Hogue, S.; Spell, P.; Marland, E.; Marland, G.

    2017-12-01

    There is an increasing role for high resolution, CO2 emissions inventories across multiple arenas. The breadth of the applicability of high-resolution data is apparent from their use in atmospheric CO2 modeling, their potential for validation of space-based atmospheric CO2 remote-sensing, and the development of climate change policy. This work focuses on increasing our understanding of the uncertainty in these inventories and the implications on their downstream use. The industrial point sources of emissions (power generating stations, cement manufacturing plants, paper mills, etc.) used in the creation of these inventories often have robust emissions characteristics, beyond just their geographic location. Physical parameters of the emission sources such as number of exhaust stacks, stack heights, stack diameters, exhaust temperatures, and exhaust velocities, as well as temporal variability and climatic influences can be important in characterizing emissions. Emissions from large point sources can behave much differently than emissions from areal sources such as automobiles. For many applications geographic location is not an adequate characterization of emissions. This work demonstrates the sensitivities of atmospheric models to the physical parameters of large point sources and provides a methodology for quantifying parameter impacts at multiple locations across the United States. The sensitivities highlight the importance of location and timing and help to highlight potential aspects that can guide efforts to reduce uncertainty in emissions inventories and increase the utility of the models.

  11. Acid dew point measurements in combustion gases using the dew point measuring system AH 85100

    Energy Technology Data Exchange (ETDEWEB)

    Fehler, D.

    1984-01-01

    Measuring system for continuous monitoring of the SO/sub 2//SO/sub 3/ dew point in the flue gas, characterized by a low failure rate, applicability inside the flue gas duct, maintenance-free continuous operation, and self-cleaning. The measuring principle is the cooling of the sensor element down to the 'onset condensation' message. Sensor surface temperatures are listed and evaluated as flue gas dew point temperatures. The measuring system is described. (DOMA).

  12. Determinants of College Grade Point Averages

    Science.gov (United States)

    Bailey, Paul Dean

    2012-01-01

    Chapter 2: The Role of Class Difficulty in College Grade Point Averages. Grade Point Averages (GPAs) are widely used as a measure of college students' ability. Low GPAs can remove a students from eligibility for scholarships, and even continued enrollment at a university. However, GPAs are determined not only by student ability but also by the…

  13. POINT 2011: ENDF/B-VII.1 Beta2 Temperature Dependent Cross Section Library

    Energy Technology Data Exchange (ETDEWEB)

    Cullen, D E

    2011-04-07

    This report is one in the series of 'POINT' reports that over the years have presented temperature dependent cross sections for the then current version of ENDF/B. In each case I have used my personal computer at home and publicly available data and codes. I have used these in combination to produce the temperature dependent cross sections used in applications and presented in this report. I should mention that today anyone with a personal computer can produce these results. The latest ENDF/B-VII.1 beta2 data library was recently and is now freely available through the National Nuclear Data Center (NNDC), Brookhaven National Laboratory. This release completely supersedes all preceding releases of ENDF/B. As distributed the ENDF/B-VII.1 data includes cross sections represented in the form of a combination of resonance parameters and/or tabulated energy dependent cross sections, nominally at 0 Kelvin temperature. For use in our applications the ENDF/B-VII.1 library has been processed into cross sections at eight neutron reactor like temperatures, between 0 and 2100 Kelvin, in steps of 300 Kelvin (the exception being 293.6 Kelvin, for exact room temperature at 20 Celsius). It has also been processed to five astrophysics like temperatures, 1, 10, 100 eV, 1 and 10 keV. For reference purposes, 300 Kelvin is approximately 1/40 eV, so that 1 eV is approximately 12,000 Kelvin. At each temperature the cross sections are tabulated and linearly interpolable in energy. All results are in the computer independent ENDF-6 character format [R2], which allows the data to be easily transported between computers. In its processed form the POINT 2011 library is approximately 16 gigabyte in size and is distributed on one compressed DVDs (see, below for the details of the contents of each DVD).

  14. Pulsewidth-modulated 2-source neutral-point-clamped inverter

    DEFF Research Database (Denmark)

    Blaabjerg, Frede; Loh, Poh Chang; Gao, Feng

    2007-01-01

    This paper presents the careful integration of a newly proposed Z-source topological concept to the basic neutral-point-clamped (NPC) inverter topology for designing a three-level inverter with both voltage-buck and voltage-boost capabilities. The designed Z-source NPC inverter uses two unique X......-shaped inductance-capacitance (LC) impedance networks that are connected between two isolated dc input power sources and its inverter circuitry for boosting its AC output voltage. Through the design of an appropriate pulsewidth-modulation (PWM) algorithm, the two impedance networks can be short......-circuited sequentially (without shooting through the inverter full DC link) for implementing the ldquonearest-three-vectorrdquo modulation principle with minimized harmonic distortion and device commutations per half carrier cycle while performing voltage boosting. With only a slight modification to the inverter PWM...

  15. Generalized Attractor Points in Gauged Supergravity

    Energy Technology Data Exchange (ETDEWEB)

    Kachru, Shamit; /Stanford U., Phys. Dept. /SLAC; Kallosh, Renata; /Stanford U., Phys. Dept.; Shmakova, Marina; /KIPAC, Menlo Park /SLAC /Stanford U., Phys. Dept.

    2011-08-15

    The attractor mechanism governs the near-horizon geometry of extremal black holes in ungauged 4D N=2 supergravity theories and in Calabi-Yau compactifications of string theory. In this paper, we study a natural generalization of this mechanism to solutions of arbitrary 4D N=2 gauged supergravities. We define generalized attractor points as solutions of an ansatz which reduces the Einstein, gauge field, and scalar equations of motion to algebraic equations. The simplest generalized attractor geometries are characterized by non-vanishing constant anholonomy coefficients in an orthonormal frame. Basic examples include Lifshitz and Schroedinger solutions, as well as AdS and dS vacua. There is a generalized attractor potential whose critical points are the attractor points, and its extremization explains the algebraic nature of the equations governing both supersymmetric and non-supersymmetric attractors.

  16. Two gap superconductivity in Ba{sub 0.55}K{sub 0.45}Fe{sub 2}As{sub 2} single crystals studied by the directional point-contact Andreev reflection spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Szabo, P.; Pribulova, Z. [Centre of Low Temperature Physics, IEP Slovak Academy of Sciences and P.J.Safarik University, Watsonova 47, SK-04001 Kosice (Slovakia); Pristas, G.; Bud' ko, S.L.; Canfield, P.C. [Ames Laboratory and Iowa State University, Ames, IA 50011 (United States); Samuely, P., E-mail: samuely@saske.s [Centre of Low Temperature Physics, IEP Slovak Academy of Sciences and P.J.Safarik University, Watsonova 47, SK-04001 Kosice (Slovakia)

    2009-10-15

    First directional point-contact Andreev reflection spectroscopy on the Ba{sub 0.55}K{sub 0.45}Fe{sub 2}As{sub 2} single crystals is presented. The spectra show significant differences when measured in the ab plane in comparison with those measured in the c direction. In the latter case no traces of superconducting energy gap could be found, just a reduced point-contact conductance persisting up to about 100 K and indicating reduced density of states. On the other hand within the ab plane two nodeless superconducting energy gaps DELTA{sub S}approx2-5 meV and DELTA{sub L}approx9-11 meV are detected.

  17. The Tipping Points of Technology Development

    Directory of Open Access Journals (Sweden)

    Tauno Kekäle

    2014-07-01

    Full Text Available The tipping point, the decisive point in time in the competition between old and new, is an interesting phenomenon in physics of today. This aspect in technology acceptance is connected to many business decisions such as technology investments, product releases, resource allocation, sales forecasts and, ultimately, affects the profitability and even survival of a company. The tipping point itself is based on many stochastic and dynamic variables, and the process may at least partly be described as path-dependent. This paper analyses the tipping point from three aspects: (1 product performance, (2 features of the market and infrastructure (including related technologies and human network externalities, and (3 actions of the incumbents (including customer lock-in, systems lock-in, and sustaining innovation. The paper is based on the Bass s-curve idea and the technology trajectory concept proposed by Dosi. Three illustrative cases are presented to make the point of the multiple factors affecting technology acceptance and, thus, the tipping point. The paper also suggests outlines for further research in field of computer simulation.

  18. Reference: 774 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available an essential gene, the disruption of which causes embryonic lethality. Plants carrying a hypomorphic smg7 mu...e progression from anaphase to telophase in the second meiotic division in Arabidopsis. Arabidopsis SMG7 is

  19. [MPLW515L point mutation in patients with myeloproliferative disease].

    Science.gov (United States)

    Xia, Jun; Xu, Wei; Zhang, Su-Jiang; Fan, Lei; Qiao, Chun; Li, Jian-Yong

    2008-12-01

    In order to investigate the frequency of MPLW515L and JAK2V617F point mutations of the patients with myeloproliferative disease (MPD) in Nanjing area, MPLW515L and JAK2V617F point mutations were simultaneously detected by alleles specific polymerase chain reaction (AS-PCR) and sequencing in 190 MPD patients. The results showed that MPLW515L point mutation was detected in 1 out of 102 essential thrombocythemia (ET) patients (1.0%) and was not detected in 32 polycythemia vera (PV) patients, 13 idiopathic myelofibrosis (IMF) patients, 43 chronic myelogenous leukemia (CML) patients. JAK2V617F point mutation was detected in 20 out of 32 PV patients (62.5%), 43 out of 102 ET patients (42.2%), 5 out of 13 IMF patients (38.5%), and was not detected in 43 CML patients. It is concluded that MPLW515L point mutation exists in ET patient, but is not found in PV, IMF and CML. JAK2V617F point mutation exists in PV, ET and IMF, but not in CML.

  20. The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability.

    Science.gov (United States)

    Ha, Kyungsoo; Shen, Yiping; Graves, Tyler; Kim, Cheol-Hee; Kim, Hyung-Goo

    2016-01-01

    1q21 microdeletion syndrome is a rare contiguous gene deletion disorder with de novo or autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts. MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family. Here we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassing MECP2 in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister is de novo , but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount of MECP2 mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced. From our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication

  1. The Melting Point of Palladium Using Miniature Fixed Points of Different Ceramic Materials: Part II—Analysis of Melting Curves and Long-Term Investigation

    Science.gov (United States)

    Edler, F.; Huang, K.

    2016-12-01

    Fifteen miniature fixed-point cells made of three different ceramic crucible materials (Al2O3, ZrO2, and Al2O3(86 %)+ZrO2(14 %)) were filled with pure palladium and used to calibrate type B thermocouples (Pt30 %Rh/Pt6 %Rh). A critical point by using miniature fixed points with small amounts of fixed-point material is the analysis of the melting curves, which are characterized by significant slopes during the melting process compared to flat melting plateaus obtainable using conventional fixed-point cells. The method of the extrapolated starting point temperature using straight line approximation of the melting plateau was applied to analyze the melting curves. This method allowed an unambiguous determination of an electromotive force (emf) assignable as melting temperature. The strict consideration of two constraints resulted in a unique, repeatable and objective method to determine the emf at the melting temperature within an uncertainty of about 0.1 μ V. The lifetime and long-term stability of the miniature fixed points was investigated by performing more than 100 melt/freeze cycles for each crucible of the different ceramic materials. No failure of the crucibles occurred indicating an excellent mechanical stability of the investigated miniature cells. The consequent limitation of heating rates to values below {± }3.5 K min^{-1} above 1100° C and the carefully and completely filled crucibles (the liquid palladium occupies the whole volume of the crucible) are the reasons for successfully preventing the crucibles from breaking. The thermal stability of the melting temperature of palladium was excellent when using the crucibles made of Al2O3(86 %)+ZrO2(14 %) and ZrO2. Emf drifts over the total duration of the long-term investigation were below a temperature equivalent of about 0.1 K-0.2 K.

  2. The traveling salesman problem with few inner points

    NARCIS (Netherlands)

    Deineko, V.G.; Hoffmann, M.; Okamoto, Y.; Woeginger, G.J.; Chwa, K.Y.; Munro, J.I.

    2004-01-01

    We study the traveling salesman problem (TSP) in the 2-dimensional Euclidean plane. The problem is NP-hard in general, but trivial if the points are in convex position. In this paper, we investigate the influence of the number of inner points (i.e., points in the interior of the convex hull) on the

  3. Hardware-accelerated Point Generation and Rendering of Point-based Impostors

    DEFF Research Database (Denmark)

    Bærentzen, Jakob Andreas

    2005-01-01

    This paper presents a novel scheme for generating points from triangle models. The method is fast and lends itself well to implementation using graphics hardware. The triangle to point conversion is done by rendering the models, and the rendering may be performed procedurally or by a black box API....... I describe the technique in detail and discuss how the generated point sets can easily be used as impostors for the original triangle models used to create the points. Since the points reside solely in GPU memory, these impostors are fairly efficient. Source code is available online....

  4. Twisted vector bundles on pointed nodal curves

    Indian Academy of Sciences (India)

    R. Narasimhan (Krishtel eMaging) 1461 1996 Oct 15 13:05:22

    by identifying the points p1 and p2. If m ≥ 2, let R1,...,Rm−1 be m − 1 copies of the projective line P1 and let xi,yi be two distinct points in Ri. Let R be the nodal curve which arises from the union. R0 ⊔ R1 ⊔···⊔ Rm−1 ⊔ Rm by identifying p1 ∈ R0 and p2 ∈ Rm with x1 ∈ R1 and ym−1 ∈ Rm−1 respectively and by identifying ...

  5. Entanglement entropy of 2D conformal quantum critical points: hearing the shape of a quantum drum.

    Science.gov (United States)

    Fradkin, Eduardo; Moore, Joel E

    2006-08-04

    The entanglement entropy of a pure quantum state of a bipartite system A union or logical sumB is defined as the von Neumann entropy of the reduced density matrix obtained by tracing over one of the two parts. In one dimension, the entanglement of critical ground states diverges logarithmically in the subsystem size, with a universal coefficient that for conformally invariant critical points is related to the central charge of the conformal field theory. We find that the entanglement entropy of a standard class of z=2 conformal quantum critical points in two spatial dimensions, in addition to a nonuniversal "area law" contribution linear in the size of the AB boundary, generically has a universal logarithmically divergent correction, which is completely determined by the geometry of the partition and by the central charge of the field theory that describes the critical wave function.

  6. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

    OpenAIRE

    Fehr, Stephanie; Wilson, Meredith; Downs, Jenny; Williams, Simon; Murgia, Alessandra; Sartori, Stefano; Vecchi, Marilena; Ho, Gladys; Polli, Roberta; Psoni, Stavroula; Bao, Xinhua; de Klerk, Nick; Leonard, Helen; Christodoulou, John

    2012-01-01

    The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of...

  7. Understanding the role of social media in online health: A global perspective on online social support

    OpenAIRE

    Lee, Roderick Lamar; Kvasny, Lynette M.

    2013-01-01

    Around the globe, people are increasingly using social media for the provision of online social support. Online social support may be especially relevant for parents who have children that are afflicted with rare chronic diseases such as MECP2 Duplication Syndrome. Despite increasing evidence that online social support enhances a person’s psychological well-being, there is little research that seeks to understand how and why various forms of social media facilitate social support. This study ...

  8. ["Point by point" approach to structure-function correlation of glaucoma on the ganglion cell complex in the posterior pole].

    Science.gov (United States)

    Zeitoun, M

    2017-01-01

    To try to establish a "point by point" relationship between the local thickness of the retinal ganglion cell complex and its sensitivity. In total, 104 glaucomatous eyes of 89 patients with a confirmed 24-2 visual field, were measured by superimposing the visual field, using imaging software, with the Wide 40° by 30° measurements of retinal ganglion cell complex obtained from the Topcon © 3D 2000 OCT, after upward adjustment, inversion and scaling. Visual fields were classified into two groups according to the extent of the disease: 58 mild to moderate (MD up to -12dB), and 46 severe (MD beyond -12dB). The 6mm by 6mm central region, equipped with a normative database, was studied, corresponding to 16 points in the visual field. These points were individually matched one by one to the local ganglion cell complex, which was classified into 2 groups depending on whether it was greater or less than 70 microns. The normative database confirmed the pathological nature of the thin areas, with a significance of 95 to 99%. Displacement of central retinal ganglion cells was compensated for. Of 1664 points (16 central points for 104 eyes), 283 points were found to be "borderline" and excluded. Of the 1381 analyzed points, 727 points were classified as "over 70 microns" and 654 points "under 70 microns". (1) For all stages combined, 85.8% of the 727 points which were greater than 70 microns had a deviation between -3 and +3dB: areas above 70 microns had no observable loss of light sensitivity. (2) In total, 92.5% of the 428 points having a gap ranging from -6 to -35dB were located on ganglion cell complex areas below 70 microns: functional visual loss was identified in thin areas, which were less than 70 microns. (3) Areas which were less than 70 microns, that is 654 points, had quite variable sensitivity and can be divided into three groups: the first with preserved sensitivity, another with obliterated sensitivity, and an intermediate group connecting

  9. Defining obesity cut-off points for migrant South Asians.

    Directory of Open Access Journals (Sweden)

    Laura J Gray

    Full Text Available Body mass index (BMI and waist circumference (WC are used to define cardiovascular and type 2 diabetes risk. We aimed to derive appropriate BMI and WC obesity cut-off points in a migrant South Asian population.4688 White Europeans and 1333 South Asians resident in the UK aged 40-75 years inclusive were screened for type 2 diabetes. Principal components analysis was used to derive a glycaemia, lipid, and a blood pressure factor. Regression models for each factor, adjusted for age and stratified by sex, were used to identify BMI and WC cut-off points in South Asians that correspond to those defined for White Europeans.For South Asian males, derived BMI obesity cut-off points equivalent to 30.0 kg/m(2 in White Europeans were 22.6 kg/m(2 (95% Confidence Interval (95% CI 20.7 kg/m(2 to 24.5 kg/m(2 for the glycaemia factor, 26.0 kg/m(2 (95% CI 24.7 kg/m(2 to 27.3 kg/m(2 for the lipid factor, and 28.4 kg/m(2 (95% CI 26.5 kg/m(2 to 30.4 kg/m(2 for the blood pressure factor. For WC, derived cut-off points for South Asian males equivalent to 102 cm in White Europeans were 83.8 cm (95% CI 79.3 cm to 88.2 cm for the glycaemia factor, 91.4 cm (95% CI 86.9 cm to 95.8 cm for the lipid factor, and 99.3 cm (95% CI 93.3 cm to 105.2 cm for the blood pressure factor. Lower ethnicity cut-off points were seen for females for both BMI and WC.Substantially lower obesity cut-off points are needed in South Asians to detect an equivalent level of dysglycemia and dyslipidemia as observed in White Europeans. South Asian ethnicity could be considered as a similar level of risk as obesity (in White Europeans for the development of type 2 diabetes.

  10. Methods for the analysis of SO/sub 2/, SO/sub 3/ and H/sub 2/S in flue gas and the calculation of the acid dew point

    Energy Technology Data Exchange (ETDEWEB)

    Albertyn, C.H.

    1986-02-01

    Methods are given for the analysis of SO/sub 2/, SO/sub 3/, and H/sub 2/S in flue gas. Two methods are described for the determination of SO/sub 2/. The method to be used depends on whether or not H/sub 2/S is present in the gas stream. An equation for the calculation of acid dew point is given as well.

  11. Lambda based control O{sub 2} set point optimisation and evaluation; Lambdabaserad reglering. Boervaerdesoptimering av O{sub 2} och utvaerdering

    Energy Technology Data Exchange (ETDEWEB)

    Svensson, Mikael; Brodin, Peter [Vattenfall Utveckling, Aelvkarleby (Sweden)

    2004-10-01

    During winter and spring 2003, the project 'Lambda based control' was carried out at Vattenfall Utveckling AB in Aelvkarleby, Sweden. The main purpose of the project was to explore if conventional lambda sensors could be used to control the fuel/air-ratio in small boilers. The conclusion was that this is possible. To be able to make use of the result, the question of what the numerical set value for O{sub 2} should be, has to be answered. Several parameters have impact on the oxygen level in combustion gas. The main purpose of this project is to explore if there is a cost efficient way of controlling fuel/air-ratio by using lambda sensors. The scope of the project is achieve the following, by using the experience from project P4-209: find out which parameters that correlate most strongly with lambda; develop a method to decide which and how many parameters to use, in order to optimize cost efficiency; calculate optimal set value for O{sub 2} in one of the boilers used for experiments in the project; and evaluate the method and compare important parameters of operation, such as efficiency and emissions. The method developed in the project uses initial measurements to find out the relation between O{sub 2} and emissions at different power levels. Then a set point curve is calculated where set point for O{sub 2} is expressed as a function of power level in the current boiler. The method has been implemented and evaluated at a 400 kW boiler in Aelvkarleby, Sweden. The results are improvements in efficiency (6 %) and emissions, CO decreased 40 %, NO decreased by 20 %. The conclusion is that lambda based control according to this method could be a profitable investment under the right circumstances, where stability in characteristics is the most important property. What makes the method uncertain is its inability to handle changes in characteristics of a boiler.

  12. Simple point vortex model for the relaxation of 2D superfluid turbulence in a Bose-Einstein condensate

    Science.gov (United States)

    Kim, Joon Hyun; Kwon, Woo Jin; Shin, Yong-Il

    2016-05-01

    In a recent experiment, it was found that the dissipative evolution of a corotating vortex pair in a trapped Bose-Einstein condensate is well described by a point vortex model with longitudinal friction on the vortex motion and the thermal friction coefficient was determined as a function of sample temperature. In this poster, we present a numerical study on the relaxation of 2D superfluid turbulence based on the dissipative point vortex model. We consider a homogeneous system in a cylindrical trap having randomly distributed vortices and implement the vortex-antivortex pair annihilation by removing a pair when its separation becomes smaller than a certain threshold value. We characterize the relaxation of the turbulent vortex states with the decay time required for the vortex number to be reduced to a quarter of initial number. We find the vortex decay time is inversely proportional to the thermal friction coefficient. In particular, we observe the decay times obtained from this work show good quantitative agreement with the experimental results in, indicating that in spite of its simplicity, the point vortex model reasonably captures the physics in the relaxation dynamics of the real system.

  13. Torsades de Pointes

    Directory of Open Access Journals (Sweden)

    Richard J Chen, MD

    2018-04-01

    Full Text Available History of present illness: 70-year-old male with a history ventricular arrhythmia, AICD (automated implantable cardioverter defibrillator, coronary artery disease and cardiac stents presented to the Emergency Department after three AICD discharges with dyspnea but no chest pain. During triage, he was found to have an irregular radial pulse and was placed on a cardiac monitor. Significant findings: The patient was found to be in a polymorphic ventricular tachycardia; he was alert, awake and asymptomatic. A rhythm strip showed a wide complex tachycardia with the QRS complex varying in amplitude around the isoelectric line consistent with Torsades de Pointes. Discussion: Torsades de Pointes (TdP is a specific type of polymorphic ventricular tachycardia. The arrhythmia’s characteristic morphology consists of the QRS complex “twisting” around the isoelectric line with gradual variation of the amplitude, reflecting its literal translation of “twisting of the points.”1 This arrhythmia occurs in the context of prolonged QT. The most common form of acquired QT prolongation is medication induced. Common causes include antiarrhythmics, antipsychotics, antiemetics, and antibiotics.2 Patient specific risk factors include female sex, bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, hypothermia and heart disease.3 In the setting of prolonged QT, the repolarization phase is extended. TdP is initiated when a PVC (premature ventricular contraction occurs during this repolarization, known as an ‘R on T’ phenomenon. TdP is often asymptomatic and self-limited. The danger in TdP is its potential to deteriorate into ventricular fibrillation. A mainstay of management of TdP is prevention of risk factors when possible.4 Unstable patients should be treated with synchronized cardioversion. Magnesium sulfate should be administered in all cases of TdP.1 If a patient is not responsive to magnesium, consider isoproterenol, amiodarone, and overdrive

  14. Three point functions in the large N=4 holography

    International Nuclear Information System (INIS)

    Ahn, Changhyun; Kim, Hyunsu

    2015-01-01

    Sixteen higher spin currents with spins (1,(3/2),(3/2),2), ((3/2),2,2,(5/2)), ((3/2),2,2,(5/2)), and (2,(5/2),(5/2),3) were previously obtained in an extension of the large N=4 ‘nonlinear’ superconformal algebra in two dimensions. By carefully analyzing the zero-mode eigenvalue equations, three-point functions of bosonic (higher spin) currents are obtained with two scalars for any finite N (where SU(N+2) is the group of coset) and k (the level of spin-1 Kac Moody current). Furthermore, these 16 higher spin currents are implicitly obtained in an extension of large N=4 ‘linear’ superconformal algebra for generic N and k. The corresponding three-point functions are also determined. Under the large N ’t Hooft limit, the two corresponding three-point functions in the nonlinear and linear versions coincide even though they are completely different for finite N and k.

  15. Zero-point Energy is Needed in Molecular Dynamics Calculations to Access the Saddle Point for H+HCN→H2CN* and cis/trans-HCNH* on a New Potential Energy Surface.

    Science.gov (United States)

    Wang, Xiaohong; Bowman, Joel M

    2013-02-12

    We calculate the probabilities for the association reactions H+HCN→H2CN* and cis/trans-HCNH*, using quasiclassical trajectory (QCT) and classical trajectory (CT) calculations, on a new global ab initio potential energy surface (PES) for H2CN including the reaction channels. The surface is a linear least-squares fit of roughly 60 000 CCSD(T)-F12b/aug-cc-pVDZ electronic energies, using a permutationally invariant basis with Morse-type variables. The reaction probabilities are obtained at a variety of collision energies and impact parameters. Large differences in the threshold energies in the two types of dynamics calculations are traced to the absence of zero-point energy in the CT calculations. We argue that the QCT threshold energy is the realistic one. In addition, trajectories find a direct pathway to trans-HCNH, even though there is no obvious transition state (TS) for this pathway. Instead the saddle point (SP) for the addition to cis-HCNH is evidently also the TS for direct formation of trans-HCNH.

  16. Phase transitions and multicritical points in the mixed spin-32 and spin-2 Ising system with a single-ion anisotropy

    International Nuclear Information System (INIS)

    Bobak, A.; Dely, J.

    2007-01-01

    The effect of a single-ion anisotropy on the phase diagram of the mixed spin-32 and spin-2 Ising system is investigated by the use of a mean-field theory based on the Bogoliubov inequality for the free energy. Topologically different kinds of phase diagrams are achieved by changing values of the parameter in the model Hamiltonian. Besides second-order transitions, lines of first-order transitions terminating either at a tricritical point or an isolated critical point, are found

  17. Dew-point measurements at high water vapour pressure

    Science.gov (United States)

    Lomperski, S.; Dreier, J.

    1996-05-01

    A dew-point meter capable of measuring humidity at high vapour pressure and high temperature has been constructed and tested. Humidity measurements in pure steam were made over the temperature range 100 - 1500957-0233/7/5/003/img1C and a vapour pressure range of 1 - 4 bar. The dew-point meter performance was assessed by comparing measurements with a pressure transmitter and agreement between the two was within 0957-0233/7/5/003/img2% relative humidity. Humidity measurements in steam - air mixtures were also made and the dew-point meter readings were compared to those of a zirconia oxygen sensor. For these tests the dew-point meter readings were generally within 0957-0233/7/5/003/img2% relative humidity of the oxygen sensor measurements.

  18. Verification of alternative dew point hygrometer for CV-LRT in MONJU. Short- and long-term verification of capacitance-type dew point hygrometer (Translated document)

    International Nuclear Information System (INIS)

    Ichikawa, Shoichi; Chiba, Yusuke; Ono, Fumiyasu; Hatori, Masakazu; Kobayashi, Takanori; Uekura, Ryoichi; Hashiri, Nobuo; Inuzuka, Taisuke; Kitano, Hiroshi; Abe, Hisashi

    2017-03-01

    To reduce the influence of maintenance of dew point hygrometers on the plant schedule at the prototype fast-breeder reactor MONJU, Japan Atomic Energy Agency examined a capacitance-type dew point hygrometer as an alternative to the lithium-chloride dew point hygrometer being used in the containment vessel leak rate test. As verifications, a capacitance-type dew point hygrometer was compared with a lithium-chloride dew point hygrometer under a containment vessel leak rate test condition. And the capacitance-type dew point hygrometer was compared with a high-precision-mirror-surface dew point hygrometer for long-term (2 years) in the containment vessel as an unprecedented try. A comparison of a capacitance-type dew point hygrometer with a lithium-chloride dew point hygrometer in a containment vessel leak rate test (Atmosphere: nitrogen, Testing time: 24 h) revealed no significant difference between the capacitance-type dew point hygrometer and the lithium-chloride dew point hygrometer. A comparison of the capacitance-type dew point hygrometer with the high-precision-mirror-surface dew point hygrometer for long-term verification (Atmosphere: air, Testing time: 24 months) revealed that the capacitance-type dew point hygrometer satisfied the instrumental specification (synthesized precision of detector and converter: ±2.04°C) specified in the Leak Rate Test Regulations for Nuclear Reactor Containment Vessel. It was confirmed that the capacitance-type dew point hygrometer can be used as a long-term alternative to the lithium-chloride dew point hygrometer without affecting the dew point hygrometer maintenance schedule of the MONJU plant. (author)

  19. PointFinder: a novel web tool for WGS-based detection of antimicrobial resistance associated with chromosomal point mutations in bacterial pathogens

    DEFF Research Database (Denmark)

    Zankari, Ea; Allesøe, Rosa Lundbye; Joensen, Katrine Grimstrup

    2017-01-01

    enterica, Escherichia coli and Campylobacter jejuni. The web-server ResFinder-2.1 was used to identify acquired antimicrobial resistance genes and two methods, the novel PointFinder (using BLAST) and an in-house method (mapping of raw WGS reads), were used to identify chromosomal point mutations. Results...... or when mapping the reads. Conclusions PointFinder proved, with high concordance between phenotypic and predicted antimicrobial susceptibility, to be a user-friendly web tool for detection of chromosomal point mutations associated with antimicrobial resistance....

  20. Accurate experimental determination of the isotope effects on the triple point temperature of water. I. Dependence on the "2H abundance

    International Nuclear Information System (INIS)

    Faghihi, V.; Aerts-Bijma, A.T.; Jansen, H.G.; Spriensma, J.J.; Meijer, H.A.J.; Peruzzi, A.; Geel, J. van

    2015-01-01

    Variation in the isotopic composition of water is one of the major contributors to uncertainty in the realization of the triple point of water (TPW). Although the dependence of the TPW on the isotopic composition of the water has been known for years, there is still a lack of a detailed and accurate experimental determination of the values for the correction constants. This paper is the first of two articles (Part I and Part II) that address quantification of isotope abundance effects on the triple point temperature of water. In this paper, we describe our experimental assessment of the "2H isotope effect. We manufactured five triple point cells with prepared water mixtures with a range of "2H isotopic abundances encompassing widely the natural abundance range, while the "1"8O and "1"7O isotopic abundance were kept approximately constant and the "1"8O - "1"7O ratio was close to the Meijer-Li relationship for natural waters. The selected range of "2H isotopic abundances led to cells that realised TPW temperatures between approximately -140 μK to + 2500 μK with respect to the TPW temperature as realized by VSMOW (Vienna Standard Mean Ocean Water). Our experiment led to determination of the value for the δ"2H correction parameter of A_2_H = 673 μK/(per thousand deviation of δ"2H from VSMOW) with a combined uncertainty of 4 μK (k = 1, or 1 s). (authors)

  1. Validating the Rett Syndrome Gross Motor Scale.

    Directory of Open Access Journals (Sweden)

    Jenny Downs

    Full Text Available Rett syndrome is a pervasive neurodevelopmental disorder associated with a pathogenic mutation on the MECP2 gene. Impaired movement is a fundamental component and the Rett Syndrome Gross Motor Scale was developed to measure gross motor abilities in this population. The current study investigated the validity and reliability of the Rett Syndrome Gross Motor Scale. Video data showing gross motor abilities supplemented with parent report data was collected for 255 girls and women registered with the Australian Rett Syndrome Database, and the factor structure and relationships between motor scores, age and genotype were investigated. Clinical assessment scores for 38 girls and women with Rett syndrome who attended the Danish Center for Rett Syndrome were used to assess consistency of measurement. Principal components analysis enabled the calculation of three factor scores: Sitting, Standing and Walking, and Challenge. Motor scores were poorer with increasing age and those with the p.Arg133Cys, p.Arg294* or p.Arg306Cys mutation achieved higher scores than those with a large deletion. The repeatability of clinical assessment was excellent (intraclass correlation coefficient for total score 0.99, 95% CI 0.93-0.98. The standard error of measurement for the total score was 2 points and we would be 95% confident that a change 4 points in the 45-point scale would be greater than within-subject measurement error. The Rett Syndrome Gross Motor Scale could be an appropriate measure of gross motor skills in clinical practice and clinical trials.

  2. Impact Points and Their Effect on Trajectory in Soccer

    Directory of Open Access Journals (Sweden)

    Kaoru Kimachi

    2018-02-01

    Full Text Available The kick skill and its analysis are important in Soccer. To detect impact point by using virtual impact model is aim of this study. The virtual impact model was made as a surface composed of virtual markers. As the result, mean coordinate values of impact point were below; straight (Lateral: −24.0 ± 5.6 mm, Horizontal: 152.7 ± 8.4 mm, Vertical: 52.3 ± 4.0 mm, curve (Lateral: −35.6 ± 4.8 mm, Horizontal: 151.6 ± 13.7 mm, Vertical: 47.5 ± 5.2 mm, knuckle (Lateral: −33.3 ± 9.0 mm, Horizontal: 140.8 ± 10.7 mm, Vertical: 52.1 ± 2.7 mm. According to comparison of coordinate value of each trial, mean point of straight was near the center line of foot on instep, mean point of curve was located on inside of foot, mean point of knuckle was near the foot joint. We revealed difference of impact point and showed trajectory of impact point.

  3. Stability and kinetics of point defects in SiO2 and in SiC

    International Nuclear Information System (INIS)

    Roma, G.

    2012-01-01

    This document is conceived as an overview of Guido Roma's research achievements on defects stability and kinetics in two materials of interest in nuclear science and for many other application domains: silicon dioxide and silicon carbide. An extended summary in french is followed by the main document, in english. Chapter 1 describes the context, introduces the approach and explains the choice of silicon dioxide and silicon carbide. Chapter 2 discusses several approximations and specific issues of the application of Density Functional Theory to point defects in non-metallic materials for the study of defects energetics and diffusion. Chapter 3 is devoted to native defects in silicon dioxide and the understanding of self-diffusion in crystalline and amorphous SiO 2 . Chapter 4 summarises the results on native defects and palladium impurities in silicon carbide. A conclusion, including suggestions for future developments, closes the main part of the document. (author) [fr

  4. Knockdown expression and hepatic deficiency reveal anatheroprotective role for SR-BI in liver and peripheral tissues

    Energy Technology Data Exchange (ETDEWEB)

    Huby, Thierry; Doucet, Chantal; Dachet, Christiane; Ouzilleau,Betty; Ueda, Yukihiko; Afzal, Veena; Rubin, Edward; Chapman, M. John; Lesnik, Philippe

    2006-07-18

    Scavenger receptor SR-BI has been implicated inHDL-dependent atheroprotective mechanisms. We report the generation of anSR-BI conditional knockout mouse model in which SR-BI gene targeting byloxP site insertion produced a hypomorphic allele (hypomSR-BI).Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-foldelevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BIgene inactivation of the hypomorphic SR-BI allele in hepatocytes(hypomSR-BI-KOliver) was associated with high plasma TC concentrations,increased plasma free cholesterol/TC (FC/TC) ratio, and alipoprotein-cholesterol profile typical of SR-BI-/- mice. Plasma TClevels were increased 2-fold in hypomSR-BI and control mice fed anatherogenic diet, whereas hypomSR-BI-KOliver and SR-BI-/- mice developedsevere hypercholesterolemia due to accumulation of FC-rich, VLDL-sizedparticles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold)compared with that in controls, but to a much lower degree than inhypomSR-BI-KOliver (32-fold) and SR-BI-/- (48-fold) mice. The lattermodels did not differ in either plasma lipid levels or in the capacity ofVLDL-sized lipoproteins to induce macrophage cholesterol loading.However, reduced atherosclerosis in hypomSR-BI-KOliver mice wasassociated with decreased lesional macrophage content as compared withthat in SR-BI-/- mice. These data imply that, in addition to its majoratheroprotective role in liver, SR-BI may exert an antiatherogenic rolein extrahepatic tissues.

  5. College-Based Case Studies in Using PowerPoint Effectively

    Science.gov (United States)

    Inoue-Smith, Yukiko

    2016-01-01

    This study reexamined PowerPoint's potential to enhance traditional pedagogical practices in higher education. The study addressed (1) the conditions under which PowerPoint meets students' needs in typical lecture-based classrooms, (2) whether professors consider PowerPoint-based lectures more effective than lectures supported by material on…

  6. EBTR design-point selection

    International Nuclear Information System (INIS)

    Krakowski, R.A.; Bathke, C.G.

    1981-01-01

    The procedure used to select the design point for the ELMO Bumpy Torus Reactor (EBTR) study is described. The models used in each phase of the selection process are described, with an emphasis placed on the parametric design curves produced by each model. The tradeoffs related to burn physics, stability/equilibrium, electron-ring physics, and magnetics design are discussed. The resulting design point indicates a plasma with a 35-m major radius and a 1-m minor radium operating at an average core-plasma beta of 0.17, which at approx. 30 keV produces an average neutron wall loading of 1.4 MW/m 2 while maintaining key magnet (< 10 T) and total power (less than or equal to 4000 MWt) constraints

  7. Point splitting in a curved space-time background

    International Nuclear Information System (INIS)

    Liggatt, P.A.J.; Macfarlane, A.J.

    1979-01-01

    A prescription is given for point splitting in a curved space-time background which is a natural generalization of that familiar in quantum electrodynamics and Yang-Mills theory. It is applied (to establish its validity) to the verification of the gravitational anomaly in the divergence of a fermion axial current. Notable features of the prescription are that it defines a point-split current that can be differentiated straightforwardly, and that it involves a natural way of averaging (four-dimensionally) over the directions of point splitting. The method can extend directly from the spin-1/2 fermion case treated to other cases, e.g., to spin-3/2 Rarita-Schwinger fermions. (author)

  8. Current singularities at finitely compressible three-dimensional magnetic null points

    International Nuclear Information System (INIS)

    Pontin, D.I.; Craig, I.J.D.

    2005-01-01

    The formation of current singularities at line-tied two- and three-dimensional (2D and 3D, respectively) magnetic null points in a nonresistive magnetohydrodynamic environment is explored. It is shown that, despite the different separatrix structures of 2D and 3D null points, current singularities may be initiated in a formally equivalent manner. This is true no matter whether the collapse is triggered by flux imbalance within closed, line-tied null points or driven by externally imposed velocity fields in open, incompressible geometries. A Lagrangian numerical code is used to investigate the finite amplitude perturbations that lead to singular current sheets in collapsing 2D and 3D null points. The form of the singular current distribution is analyzed as a function of the spatial anisotropy of the null point, and the effects of finite gas pressure are quantified. It is pointed out that the pressure force, while never stopping the formation of the singularity, significantly alters the morphology of the current distribution as well as dramatically weakening its strength. The impact of these findings on 2D and 3D magnetic reconnection models is discussed

  9. Coupling of c  =  ‑2 and c =\\frac{1}{2} and c  =  0 conformal field theories: the geometrical point of view

    Science.gov (United States)

    Najafi, M. N.

    2018-04-01

    The coupling of the c  =  ‑2, c=\\frac{1}{2} and c  =  0 conformal field theories are numerically considered in this paper. As the prototypes of the couplings, (c_1=-2)\\oplus (c_2=0) and (c_1=-2)\\oplus (c_2=\\frac{1}{2}) , we consider the Bak–Tang–Weisenfeld (BTW) model on the 2D square critical site-percolation and the BTW model on Ising-correlated percolation lattices respectively. Some geometrical techniques are used to characterize the presumable conformal symmetry of the resultant systems. Based on the numerical analysis of the diffusivity parameter (κ) in the Schramm–Loewner evolution (SLE) theory we propose that the algebra of the central charges of the coupled models is closed. This result is based on the analysis of the conformal loop ensemble (CLE) analysis. The diffusivity parameter in each case is obtained by calculating the fractal dimension of loops (and the corresponding exponent of mean-square root distance), the direct SLE mapping method, the left passage probability and the winding angle analysis. More precisely we numerically show that the coupling (c_1=-2)\\oplus (c_2=\\frac{1}{2}) results to 2D self-avoiding walk (SAW) fixed point corresponding to c  =  0 conformal field theory, whereas the coupling (c_1=-2)\\oplus (c_2=0) results to the 2D critical Ising fixed point corresponding to the c=\\frac{1}{2} conformal field theory.

  10. Controllable resonant tunnelling through single-point potentials: A point triode

    International Nuclear Information System (INIS)

    Zolotaryuk, A.V.; Zolotaryuk, Yaroslav

    2015-01-01

    A zero-thickness limit of three-layer heterostructures under two bias voltages applied externally, where one of which is supposed to be a gate parameter, is studied. As a result, an effect of controllable resonant tunnelling of electrons through single-point potentials is shown to exist. Therefore the limiting structure may be termed a “point triode” and considered in the theory of point interactions as a new object. The simple limiting analytical expressions adequately describe the resonant behaviour in the transistor with realistic parameter values and thus one can conclude that the zero-range limit of multi-layer structures may be used in fabricating nanodevices. The difference between the resonant tunnelling across single-point potentials and the Fabry–Pérot interference effect is also emphasized. - Highlights: • The zero-thickness limit of three-layer heterostructures is described in terms of point interactions. • The effect of resonant tunnelling through these single-point potentials is established. • The resonant tunnelling is shown to be controlled by a gate voltage

  11. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

    International Nuclear Information System (INIS)

    Noda, Saori; Takahashi, Atsushi; Hayashi, Takeru; Tanuma, Sei-ichi; Hatakeyama, Masanori

    2016-01-01

    SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

  12. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Noda, Saori [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Takahashi, Atsushi; Hayashi, Takeru [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Tanuma, Sei-ichi [Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Hatakeyama, Masanori, E-mail: mhata@m.u-tokyo.ac.jp [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

    2016-01-22

    SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

  13. QCD and the chiral critical point

    International Nuclear Information System (INIS)

    Gavin, S.; Gocksch, A.; Pisarski, R.D.

    1994-01-01

    As an extension of QCD, consider a theory with ''2+1'' flavors, where the current quark masses are held in a fixed ratio as the overall scale of the quark masses is varied. At nonzero temperature and baryon density it is expected that in the chiral limit the chiral phase transition is of first order. Increasing the quark mass from zero, the chiral transition becomes more weakly first order, and can end in a chiral critical point. We show that the only massless field at the chiral critical point is a σ meson, with the universality class that of the Ising model. Present day lattice simulations indicate that QCD is (relatively) near to the chiral critical point

  14. Interaction of the deubiquitinating enzyme Ubp2 and the e3 ligase Rsp5 is required for transporter/receptor sorting in the multivesicular body pathway.

    Directory of Open Access Journals (Sweden)

    Mandy H Y Lam

    Full Text Available Protein ubiquitination is essential for many events linked to intracellular protein trafficking. We sought to elucidate the possible involvement of the S. cerevisiae deubiquitinating enzyme Ubp2 in transporter and receptor trafficking after we (this study and others established that affinity purified Ubp2 interacts stably with the E3 ubiquitin ligase Rsp5 and the (ubiquitin associated UBA domain containing protein Rup1. UBP2 interacts genetically with RSP5, while Rup1 facilitates the tethering of Ubp2 to Rsp5 via a PPPSY motif. Using the uracil permease Fur4 as a model reporter system, we establish a role for Ubp2 in membrane protein turnover. Similar to hypomorphic rsp5 alleles, cells deleted for UBP2 exhibited a temporal stabilization of Fur4 at the plasma membrane, indicative of perturbed protein trafficking. This defect was ubiquitin dependent, as a Fur4 N-terminal ubiquitin fusion construct bypassed the block and restored sorting in the mutant. Moreover, the defect was absent in conditions where recycling was absent, implicating Ubp2 in sorting at the multivesicular body. Taken together, our data suggest a previously overlooked role for Ubp2 as a positive regulator of Rsp5-mediated membrane protein trafficking subsequent to endocytosis.

  15. Tipping Point

    Medline Plus

    Full Text Available ... OnSafety CPSC Stands for Safety The Tipping Point Home > 60 Seconds of Safety (Videos) > The Tipping Point ... 24 hours a day. For young children whose home is a playground, it’s the best way to ...

  16. CF2 represses Actin 88F gene expression and maintains filament balance during indirect flight muscle development in Drosophila.

    Directory of Open Access Journals (Sweden)

    Kathleen M Gajewski

    2010-05-01

    Full Text Available The zinc finger protein CF2 is a characterized activator of muscle structural genes in the body wall muscles of the Drosophila larva. To investigate the function of CF2 in the indirect flight muscle (IFM, we examined the phenotypes of flies bearing five homozygous viable mutations. The gross structure of the IFM was not affected, but the stronger hypomorphic alleles caused an increase of up to 1.5X in the diameter of the myofibrils. This size increase did not cause any disruption of the hexameric arrangement of thick and thin filaments. RT-PCR analysis revealed an increase in the transcription of several structural genes. Ectopic overexpression of CF2 in the developing IFM disrupts muscle formation. While our results indicate a role for CF2 as a direct negative regulator of the thin filament protein gene Actin 88F (Act88F, effects on levels of transcripts of myosin heavy chain (mhc appear to be indirect. This role is in direct contrast to that described in the larval muscles, where CF2 activates structural gene expression. The variation in myofibril phenotypes of CF2 mutants suggest the CF2 may have separate functions in fine-tuning expression of structural genes to insure proper filament stoichiometry, and monitoring and/or controlling the final myofibril size.

  17. Interesting Interest Points

    DEFF Research Database (Denmark)

    Aanæs, Henrik; Dahl, Anders Lindbjerg; Pedersen, Kim Steenstrup

    2012-01-01

    on spatial invariance of interest points under changing acquisition parameters by measuring the spatial recall rate. The scope of this paper is to investigate the performance of a number of existing well-established interest point detection methods. Automatic performance evaluation of interest points is hard......Not all interest points are equally interesting. The most valuable interest points lead to optimal performance of the computer vision method in which they are employed. But a measure of this kind will be dependent on the chosen vision application. We propose a more general performance measure based...... position. The LED illumination provides the option for artificially relighting the scene from a range of light directions. This data set has given us the ability to systematically evaluate the performance of a number of interest point detectors. The highlights of the conclusions are that the fixed scale...

  18. 47 CFR 90.419 - Points of communication.

    Science.gov (United States)

    2010-10-01

    ... importance to mobile stations; or (2) Wireline communications facilities between such points are inoperative... transmitted are of immediate importance to mobile stations; or (2) Wireline communications facilities between...

  19. Geometric fit of a point set by generalized circles

    DEFF Research Database (Denmark)

    Körner, Mark-Christopher; Brimberg, Jack; Juel, Henrik

    2010-01-01

    In our paper we approximate a set of given points by a general circle. More precisely, given two norms k 1 and k 2 and a set of points in the plane, we consider the problem of locating and scaling the unit circle of norm k 1 such that the sum of weighted distances between the circumference...... of the circle and the given points is minimized, where the distance is measured by a norm k 2. We present results for the general case. In the case that k 1 and k 2 are both polyhedral norms, we are able to solve the problem by investigating a finite candidate set....

  20. UHE point source survey at Cygnus experiment

    International Nuclear Information System (INIS)

    Lu, X.; Yodh, G.B.; Alexandreas, D.E.; Allen, R.C.; Berley, D.; Biller, S.D.; Burman, R.L.; Cady, R.; Chang, C.Y.; Dingus, B.L.; Dion, G.M.; Ellsworth, R.W.; Gilra, M.K.; Goodman, J.A.; Haines, T.J.; Hoffman, C.M.; Kwok, P.; Lloyd-Evans, J.; Nagle, D.E.; Potter, M.E.; Sandberg, V.D.; Stark, M.J.; Talaga, R.L.; Vishwanath, P.R.; Zhang, W.

    1991-01-01

    A new method of searching for UHE point source has been developed. With a data sample of 150 million events, we have surveyed the sky for point sources over 3314 locations (1.4 degree <δ<70.4 degree). It was found that their distribution is consistent with a random fluctuation. In addition, fifty two known potential sources, including pulsars and binary x-ray sources, were studied. The source with the largest positive excess is the Crab Nebula. An excess of 2.5 sigma above the background is observed in a bin of 2.3 degree by 2.5 degree in declination and right ascension respectively

  1. Characterization of MIPAS elevation pointing

    Directory of Open Access Journals (Sweden)

    M. Kiefer

    2007-01-01

    Full Text Available Sufficient knowledge of the pointing is essential for analyses of limb emission measurements. The scientific retrieval processor for MIPAS on ENVISAT operated at IMK allows the retrieval of pointing information in terms of tangent altitudes along with temperature. The retrieved tangent altitudes are independent of systematic offsets in the engineering Line-Of-Sight (LOS information delivered with the ESA Level 1b product. The difference of pointing retrieved from the reprocessed high resolution MIPAS spectra and the engineering pointing information was examined with respect to spatial/temporal behaviour. Among others the following characteristics of MIPAS pointing could be identified: Generally the engineering tangent altitudes are too high by 0–1.8 km with conspicuous variations in this range over time. Prior to December of 2003 there was a drift of about 50–100 m/h, which was due to a slow change in the satellite attitude. A correction of this attitude is done twice a day, which leads to discontinuities in the order of 1–1.5 km in the tangent altitudes. Occasionally discontinuities up to 2.5 km are found, as already reported from MIPAS and SCIAMACHY observations. After an update of the orbit position software in December 2003 values of drift and jumps are much reduced. There is a systematic difference in the mispointing between the poles which amounts to 1.5–2 km, i.e. there is a conspicuous orbit-periodic feature. The analysis of the correlation between the instrument's viewing angle azimuth and differential mispointing supports the hypotheses that a major part of this latter phenomenon can be attributed to an error in the roll angle of the satellite/instrument system of approximately 42 mdeg. One conclusion is that ESA level 2 data should be compared to other data exclusively on tangent pressure levels. Complementary to IMK data, ESA operational LOS calibration results were used to characterize MIPAS pointing. For this purpose

  2. A new compact fixed-point blackbody furnace

    International Nuclear Information System (INIS)

    Hiraka, K.; Oikawa, H.; Shimizu, T.; Kadoya, S.; Kobayashi, T.; Yamada, Y.; Ishii, J.

    2013-01-01

    More and more NMIs are realizing their primary scale themselves with fixed-point blackbodies as their reference standard. However, commercially available fixed-point blackbody furnaces of sufficient quality are not always easy to obtain. CHINO Corp. and NMIJ, AIST jointly developed a new compact fixed-point blackbody furnace. The new furnace has such features as 1) improved temperature uniformity when compared to previous products, enabling better plateau quality, 2) adoption of the hybrid fixed-point cell structure with internal insulation to improve robustness and thereby to extend lifetime, 3) easily ejectable and replaceable heater unit and fixed-point cell design, leading to reduced maintenance cost, 4) interchangeability among multiple fixed points from In to Cu points. The replaceable cell feature facilitates long term maintenance of the scale through management of a group of fixed-point cells of the same type. The compact furnace is easily transportable and therefore can also function as a traveling standard for disseminating the radiation temperature scale, and for maintaining the scale at the secondary level and industrial calibration laboratories. It is expected that the furnace will play a key role of the traveling standard in the anticipated APMP supplementary comparison of the radiation thermometry scale

  3. Zero-point oscillations, zero-point fluctuations, and fluctuations of zero-point oscillations

    International Nuclear Information System (INIS)

    Khalili, Farit Ya

    2003-01-01

    Several physical effects and methodological issues relating to the ground state of an oscillator are considered. Even in the simplest case of an ideal lossless harmonic oscillator, its ground state exhibits properties that are unusual from the classical point of view. In particular, the mean value of the product of two non-negative observables, kinetic and potential energies, is negative in the ground state. It is shown that semiclassical and rigorous quantum approaches yield substantially different results for the ground state energy fluctuations of an oscillator with finite losses. The dependence of zero-point fluctuations on the boundary conditions is considered. Using this dependence, it is possible to transmit information without emitting electromagnetic quanta. Fluctuations of electromagnetic pressure of zero-point oscillations are analyzed, and the corresponding mechanical friction is considered. This friction can be viewed as the most fundamental mechanism limiting the quality factor of mechanical oscillators. Observation of these effects exceeds the possibilities of contemporary experimental physics but almost undoubtedly will be possible in the near future. (methodological notes)

  4. Tipping Point

    Medline Plus

    Full Text Available ... 60 Seconds of Safety (Videos) > The Tipping Point The Tipping Point by CPSC Blogger September 22, 2009 appliance child Childproofing CPSC danger death electrical fall furniture head injury product safety television tipover tv Watch the video in Adobe Flash ...

  5. Accurate experimental determination of the isotope effects on the triple point temperature of water. I. Dependence on the 2H abundance

    Science.gov (United States)

    Faghihi, V.; Peruzzi, A.; Aerts-Bijma, A. T.; Jansen, H. G.; Spriensma, J. J.; van Geel, J.; Meijer, H. A. J.

    2015-12-01

    Variation in the isotopic composition of water is one of the major contributors to uncertainty in the realization of the triple point of water (TPW). Although the dependence of the TPW on the isotopic composition of the water has been known for years, there is still a lack of a detailed and accurate experimental determination of the values for the correction constants. This paper is the first of two articles (Part I and Part II) that address quantification of isotope abundance effects on the triple point temperature of water. In this paper, we describe our experimental assessment of the 2H isotope effect. We manufactured five triple point cells with prepared water mixtures with a range of 2H isotopic abundances encompassing widely the natural abundance range, while the 18O and 17O isotopic abundance were kept approximately constant and the 18O  -  17O ratio was close to the Meijer-Li relationship for natural waters. The selected range of 2H isotopic abundances led to cells that realised TPW temperatures between approximately  -140 μK to  +2500 μK with respect to the TPW temperature as realized by VSMOW (Vienna Standard Mean Ocean Water). Our experiment led to determination of the value for the δ2H correction parameter of A2H  =  673 μK / (‰ deviation of δ2H from VSMOW) with a combined uncertainty of 4 μK (k  =  1, or 1σ).

  6. Relativity, Symmetry, and the Structure of Quantum Theory, Volume 2; Point form relativistic quantum mechanics

    Science.gov (United States)

    Klink, William H.; Schweiger, Wolfgang

    2018-03-01

    This book covers relativistic quantum theory from the point of view of a particle theory, based on the irreducible representations of the Poincaré group, the group that expresses the symmetry of Einstein relativity. There are several ways of formulating such a theory; this book develops what is called relativistic point form quantum mechanics, which, unlike quantum field theory, deals with a fixed number of particles in a relativistically invariant way. A chapter is devoted to applications of point form quantum mechanics to nuclear physics.

  7. The ATM signaling cascade promotes recombination-dependent pachytene arrest in mouse spermatocytes.

    Directory of Open Access Journals (Sweden)

    Sarai Pacheco

    2015-03-01

    Full Text Available Most mutations that compromise meiotic recombination or synapsis in mouse spermatocytes result in arrest and apoptosis at the pachytene stage of the first meiotic prophase. Two main mechanisms are thought to trigger arrest: one independent of the double-strand breaks (DSBs that initiate meiotic recombination, and another activated by persistent recombination intermediates. Mechanisms underlying the recombination-dependent arrest response are not well understood, so we sought to identify factors involved by examining mutants deficient for TRIP13, a conserved AAA+ ATPase required for the completion of meiotic DSB repair. We find that spermatocytes with a hypomorphic Trip13 mutation (Trip13mod/mod arrest with features characteristic of early pachynema in wild type, namely, fully synapsed chromosomes without incorporation of the histone variant H1t into chromatin. These cells then undergo apoptosis, possibly in response to the arrest or in response to a defect in sex body formation. However, TRIP13-deficient cells that additionally lack the DSB-responsive kinase ATM progress further, reaching an H1t-positive stage (i.e., similar to mid/late pachynema in wild type despite the presence of unrepaired DSBs. TRIP13-deficient spermatocytes also progress to an H1t-positive stage if ATM activity is attenuated by hypomorphic mutations in Mre11 or Nbs1 or by elimination of the ATM-effector kinase CHK2. These mutant backgrounds nonetheless experience an apoptotic block to further spermatogenic progression, most likely caused by failure to form a sex body. DSB numbers are elevated in Mre11 and Nbs1 hypomorphs but not Chk2 mutants, thus delineating genetic requirements for the ATM-dependent negative feedback loop that regulates DSB numbers. The findings demonstrate for the first time that ATM-dependent signaling enforces the normal pachytene response to persistent recombination intermediates. Our work supports the conclusion that recombination defects trigger

  8. Branes, superpotentials and superconformal fixed points

    International Nuclear Information System (INIS)

    Aharony, O.

    1997-01-01

    We analyze various brane configurations corresponding to field theories in three, four and five dimensions. We find brane configurations which correspond to three-dimensional N=2 and four-dimensional N=1 supersymmetric QCD theories with quartic superpotentials, in which what appear to be ''hidden parameters'' play an important role. We discuss the construction of five-dimensional N=1 supersymmetric gauge theories and superconformal fixed points using branes, which leads to new five-dimensional N=1 superconformal field theories. The same five-dimensional theories are also used, in a surprising way, to describe new superconformal fixed points of three-dimensional N=2 supersymmetric theories, which have both ''electric'' and ''magnetic'' Coulomb branches. (orig.)

  9. PCX, Interior-Point Linear Programming Solver

    International Nuclear Information System (INIS)

    Czyzyk, J.

    2004-01-01

    1 - Description of program or function: PCX solves linear programming problems using the Mehrota predictor-corrector interior-point algorithm. PCX can be called as a subroutine or used in stand-alone mode, with data supplied from an MPS file. The software incorporates modules that can be used separately from the linear programming solver, including a pre-solve routine and data structure definitions. 2 - Methods: The Mehrota predictor-corrector method is a primal-dual interior-point method for linear programming. The starting point is determined from a modified least squares heuristic. Linear systems of equations are solved at each interior-point iteration via a sparse Cholesky algorithm native to the code. A pre-solver is incorporated in the code to eliminate inefficiencies in the user's formulation of the problem. 3 - Restriction on the complexity of the problem: There are no size limitations built into the program. The size of problem solved is limited by RAM and swap space on the user's computer

  10. A scalable and multi-purpose point cloud server (PCS) for easier and faster point cloud data management and processing

    Science.gov (United States)

    Cura, Rémi; Perret, Julien; Paparoditis, Nicolas

    2017-05-01

    In addition to more traditional geographical data such as images (rasters) and vectors, point cloud data are becoming increasingly available. Such data are appreciated for their precision and true three-Dimensional (3D) nature. However, managing point clouds can be difficult due to scaling problems and specificities of this data type. Several methods exist but are usually fairly specialised and solve only one aspect of the management problem. In this work, we propose a comprehensive and efficient point cloud management system based on a database server that works on groups of points (patches) rather than individual points. This system is specifically designed to cover the basic needs of point cloud users: fast loading, compressed storage, powerful patch and point filtering, easy data access and exporting, and integrated processing. Moreover, the proposed system fully integrates metadata (like sensor position) and can conjointly use point clouds with other geospatial data, such as images, vectors, topology and other point clouds. Point cloud (parallel) processing can be done in-base with fast prototyping capabilities. Lastly, the system is built on open source technologies; therefore it can be easily extended and customised. We test the proposed system with several billion points obtained from Lidar (aerial and terrestrial) and stereo-vision. We demonstrate loading speeds in the ˜50 million pts/h per process range, transparent-for-user and greater than 2 to 4:1 compression ratio, patch filtering in the 0.1 to 1 s range, and output in the 0.1 million pts/s per process range, along with classical processing methods, such as object detection.

  11. Physiological background of the change point in VO2 and the slow component of oxygen uptake kinetics.

    Science.gov (United States)

    Zoładź, J A; Korzeniewski, B

    2001-06-01

    It is generally believed that oxygen uptake during incremental exercise--until VO2max, increases linearly with power output (see eg. Astrand & Rodahl, 1986). On the other hand, it is well established that the oxygen uptake reaches a steady state only during a low power output exercise, but during a high power output exercise, performed above the lactate threshold (LT), the oxygen uptake shows a continuous increase until the end of the exercise. This effect has been called the slow component of VO2 kinetics (Whipp & Wasserman, 1972). The presence of a slow component in VO2 kinetics implies that during an incremental exercise test, after the LT has been exceeded, the VO2 to power output relationship has to become curvilinear. Indeed, it has recently been shown that during the incremental exercise, the exceeding of the power output, at which blood lactate begins to accumulate (LT), causes a non-proportional increase in VO2 (Zoladz et al. 1995) which indicates a drop in muscle mechanical efficiency. The power output at which VO2 starts to rise non-proportionally to the power output has been called "the change point in VO2" (Zoladz et al. 1998). In this paper, the significance of the factors most likely involved in the physiological mechanism responsible for the change point in oxygen uptake (CP-VO2) and for the slow component of VO2 kinetics, including: increase of activation of additional muscle groups, intensification of the respiratory muscle activity, recruitment of type II muscle fibres, increase of muscle temperature, increase of the basal metabolic rate, lactate and hydrogen ion accumulation, proton leak through the inner mitochondrial membrane, slipping of the ATP synthase and a decrease in the cytosolic phosphorylation potential, are discussed. Finally, an original own model describing the sequence of events leading to the non-proportional increase of oxygen cost of work at a high exercise intensity is presented.

  12. Geometric Spanners for Weighted Point Sets

    DEFF Research Database (Denmark)

    Abam, Mohammad; de Berg, Mark; Farshi, Mohammad

    2009-01-01

    Let (S,d) be a finite metric space, where each element p ∈ S has a non-negative weight w(p). We study spanners for the set S with respect to weighted distance function d w , where d w (p,q) is w(p) + d(p,q) + wq if p ≠ q and 0 otherwise. We present a general method for turning spanners with respect...... to the d-metric into spanners with respect to the d w -metric. For any given ε> 0, we can apply our method to obtain (5 + ε)-spanners with a linear number of edges for three cases: points in Euclidean space ℝ d , points in spaces of bounded doubling dimension, and points on the boundary of a convex body...... in ℝ d where d is the geodesic distance function. We also describe an alternative method that leads to (2 + ε)-spanners for points in ℝ d and for points on the boundary of a convex body in ℝ d . The number of edges in these spanners is O(nlogn). This bound on the stretch factor is nearly optimal...

  13. Metallic and antiferromagnetic fixed points from gravity

    Science.gov (United States)

    Paul, Chandrima

    2018-06-01

    We consider SU(2) × U(1) gauge theory coupled to matter field in adjoints and study RG group flow. We constructed Callan-Symanzik equation and subsequent β functions and study the fixed points. We find there are two fixed points, showing metallic and antiferromagnetic behavior. We have shown that metallic phase develops an instability if certain parametric conditions are satisfied.

  14. Fixed Points

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 5; Issue 5. Fixed Points - From Russia with Love - A Primer of Fixed Point Theory. A K Vijaykumar. Book Review Volume 5 Issue 5 May 2000 pp 101-102. Fulltext. Click here to view fulltext PDF. Permanent link:

  15. On the contribution of intramolecular zero point energy to the equation of state of solid H2

    Science.gov (United States)

    Chandrasekharan, V.; Etters, R. D.

    1978-01-01

    Experimental evidence shows that the internal zero-point energy of the H2 molecule exhibits a relatively strong pressure dependence in the solid as well as changing considerably upon condensation. It is shown that these effects contribute about 6% to the total sublimation energy and to the pressure in the solid state. Methods to modify the ab initio isolated pair potential to account for these environmental effects are discussed.

  16. Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model.

    Science.gov (United States)

    Balestrini, Alessia; Nicolas, Laura; Yang-Lott, Katherine; Guryanova, Olga A; Levine, Ross L; Bassing, Craig H; Chaudhuri, Jayanta; Petrini, John H J

    2016-02-01

    The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATM(flox)) was crossed to hypomorphic NBS1 mutants (Nbs1(ΔB/ΔB) mice). Nbs1(ΔB/ΔB) Atm(-/-) hematopoietic cells derived by crossing to vav(cre) were viable in vivo. Nbs1(ΔB/ΔB) Atm(-/-) (VAV) mice exhibited a pronounced defect in double-strand break repair and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress. A novel mouse model was developed, by combining a vav(cre)-inducible ATM knockout mouse with an NBS1 hypomorphic mutation, to analyze ATM-independent functions of the Mre11 complex in vivo. These data show that the DNA repair, rather than DDR signaling functions of the complex, is acutely required in the context of ATM deficiency to suppress genome instability and lymphomagenesis. ©2015 American Association for Cancer Research.

  17. Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders.

    Science.gov (United States)

    Schaevitz, Laura R; Picker, Jonathan D; Rana, Jasmine; Kolodny, Nancy H; Shane, Barry; Berger-Sweeney, Joanne E; Coyle, Joseph T

    2012-06-01

    Interactions between genetic and environmental risk factors underlie a number of neuropsychiatric disorders, including schizophrenia (SZ) and autism (AD). Due to the complexity and multitude of the genetic and environmental factors attributed to these disorders, recent research strategies focus on elucidating the common molecular pathways through which these multiple risk factors may function. In this study, we examine the combined effects of a haplo-insufficiency of glutamate carboxypeptidase II (GCPII) and dietary folic acid deficiency. In addition to serving as a neuropeptidase, GCPII catalyzes the absorption of folate. GCPII and folate depletion interact within the one-carbon metabolic pathway and/or of modulate the glutamatergic system. Four groups of mice were tested: wild-type, GCPII hypomorphs, and wild-types and GCPII hypomorphs both fed a folate deficient diet. Due to sex differences in the prevalence of SZ and AD, both male and female mice were assessed on a number of behavioral tasks including locomotor activity, rotorod, social interaction, prepulse inhibition, and spatial memory. Wild-type mice of both sexes fed a folic acid deficient diet showed motor coordination impairments and cognitive deficits, while social interactions were decreased only in males. GCPII mutant mice of both sexes also exhibited reduced social propensities. In contrast, all folate-depleted GCPII hypomorphs performed similarly to untreated wild-type mice, suggesting that reduced GCPII expression and folate deficiency are mutually protective. Analyses of folate and neurometabolite levels associated with glutamatergic function suggest several potential mechanisms through which GCPII and folate may be interacting to create this protective effect. Copyright © 2011 Wiley Periodicals, Inc.

  18. Enhanced superconductivity at the interface of W/Sr2RuO4 point contact

    Science.gov (United States)

    Wei, Jian; Wang, He; Lou, Weijian; Luo, Jiawei; Liu, Ying; Ortmann, J. E.; Mao, Z. Q.

    Differential resistance measurements are conducted for point contacts (PCs) between the Sr2RuO4 (SRO) single crystal and the tungsten tip. Since the tungsten tip is hard enough to penetrate through the surface layer, consistent superconducting features are observed. Firstly, with the tip pushed towards the crystal, the zero bias conductance peak (ZBCP) due to Andreev reflection at the normal-superconducting interface increases from 3% to more than 20%, much larger than previously reported, and extends to temperature higher than the bulk transition temperature. Reproducible ZBCP within 0.2 mV may also help determine the gap value of SRO, on which no consensus has been reached. Secondly, the logarithmic background can be fitted with the Altshuler-Aronov theory of electron-electron interaction for tunneling into quasi two dimensional electron system. Feasibility of such fitting confirms that spectroscopic information like density of states is probed, and electronic temperature retrieved from such fitting can be important to analyse the PC spectra. Third, at bias much higher than 0.2 mV there are conductance dips due to the critical current effect and these dips persist up to 6.2 K. For more details see. National Basic Research Program of China (973 Program) through Grant No. 2011CBA00106 and No. 2012CB927400.

  19. Multigap superconductivity and strong electron-boson coupling in Fe-based superconductors: a point-contact Andreev-reflection study of Ba(Fe(1-x)Co(x))2As2 single crystals.

    Science.gov (United States)

    Tortello, M; Daghero, D; Ummarino, G A; Stepanov, V A; Jiang, J; Weiss, J D; Hellstrom, E E; Gonnelli, R S

    2010-12-03

    Directional point-contact Andreev-reflection measurements in Ba(Fe(1-x)Co(x))2As2 single crystals (T(c) = 24.5 K) indicate the presence of two superconducting gaps with no line nodes on the Fermi surface. The point-contact Andreev-reflection spectra also feature additional structures related to the electron-boson interaction, from which the characteristic boson energy Ω(b)(T) is obtained, very similar to the spin-resonance energy observed in neutron scattering experiments. Both the gaps and the additional structures can be reproduced within a three-band s ± Eliashberg model by using an electron-boson spectral function peaked at Ω(0) = 12 meV ≃ Ω(b)(0).

  20. Application of the nudged elastic band method to the point-to-point radio wave ray tracing in IRI modeled ionosphere

    Science.gov (United States)

    Nosikov, I. A.; Klimenko, M. V.; Bessarab, P. F.; Zhbankov, G. A.

    2017-07-01

    Point-to-point ray tracing is an important problem in many fields of science. While direct variational methods where some trajectory is transformed to an optimal one are routinely used in calculations of pathways of seismic waves, chemical reactions, diffusion processes, etc., this approach is not widely known in ionospheric point-to-point ray tracing. We apply the Nudged Elastic Band (NEB) method to a radio wave propagation problem. In the NEB method, a chain of points which gives a discrete representation of the radio wave ray is adjusted iteratively to an optimal configuration satisfying the Fermat's principle, while the endpoints of the trajectory are kept fixed according to the boundary conditions. Transverse displacements define the radio ray trajectory, while springs between the points control their distribution along the ray. The method is applied to a study of point-to-point ionospheric ray tracing, where the propagation medium is obtained with the International Reference Ionosphere model taking into account traveling ionospheric disturbances. A 2-dimensional representation of the optical path functional is developed and used to gain insight into the fundamental difference between high and low rays. We conclude that high and low rays are minima and saddle points of the optical path functional, respectively.

  1. Estimation of boiling point of radon by radiogas chromatography

    International Nuclear Information System (INIS)

    Takahashi, N.; Otozai, K.

    1986-01-01

    The retention volume of radon was measured by means of radiogas chromatography. The boiling point of radon was estimated from the retention volume by the use of the semi-empirical formula relating the boiling point to the retention volume. The obtained boiling point (198+-2)K was lower by 13 K than that measured by Gray and Ramsay. (author)

  2. Zero-point energy, tunnelling, and vibrational adiabaticity in the Mu + H2 reaction

    Science.gov (United States)

    Mielke, Steven L.; Garrett, Bruce C.; Fleming, Donald G.; Truhlar, Donald G.

    2015-01-01

    Isotopic substitution of muonium for hydrogen provides an unparalleled opportunity to deepen our understanding of quantum mass effects on chemical reactions. A recent topical review in this journal of the thermal and vibrationally state-selected reaction of Mu with H2 raises a number of issues that are addressed here. We show that some earlier quantum mechanical calculations of the Mu + H2 reaction, which are highlighted in this review, and which have been used to benchmark approximate methods, are in error by as much as 19% in the low-temperature limit. We demonstrate that an approximate treatment of the Born-Oppenheimer diagonal correction that was used in some recent studies is not valid for treating the vibrationally state-selected reaction. We also discuss why vibrationally adiabatic potentials that neglect bend zero-point energy are not a useful analytical tool for understanding reaction rates, and why vibrationally non-adiabatic transitions cannot be understood by considering tunnelling through vibrationally adiabatic potentials. Finally, we present calculations on a hierarchical family of potential energy surfaces to assess the sensitivity of rate constants to the quality of the potential surface.

  3. Constitutional and thermal point defects in B2 NiAl

    DEFF Research Database (Denmark)

    Korzhavyi, P. A.; Ruban, Andrei; Lozovoi, A. Y.

    2000-01-01

    The formation energies of point defects and the interaction energies of various defect pairs in NiAl are calculated from first principles within an order N, locally self-consistent Green's-function method in conjunction with multipole electrostatic corrections to the atomic sphere approximation...... distance on their sublattice. The dominant thermal defects in Ni-rich and stoichiometric NiAl are calculated to be triple defects. In Al-rich alloys another type of thermal defect dominates, where two Ni vacancies are replaced by one antisite Al atom. As a result, the vacancy concentration decreases...

  4. Controlling superconductivity by tunable quantum critical points.

    Science.gov (United States)

    Seo, S; Park, E; Bauer, E D; Ronning, F; Kim, J N; Shim, J-H; Thompson, J D; Park, Tuson

    2015-03-04

    The heavy fermion compound CeRhIn5 is a rare example where a quantum critical point, hidden by a dome of superconductivity, has been explicitly revealed and found to have a local nature. The lack of additional examples of local types of quantum critical points associated with superconductivity, however, has made it difficult to unravel the role of quantum fluctuations in forming Cooper pairs. Here, we show the precise control of superconductivity by tunable quantum critical points in CeRhIn5. Slight tin-substitution for indium in CeRhIn5 shifts its antiferromagnetic quantum critical point from 2.3 GPa to 1.3 GPa and induces a residual impurity scattering 300 times larger than that of pure CeRhIn5, which should be sufficient to preclude superconductivity. Nevertheless, superconductivity occurs at the quantum critical point of the tin-doped metal. These results underline that fluctuations from the antiferromagnetic quantum criticality promote unconventional superconductivity in CeRhIn5.

  5. Four-point functions in N=4 SYM

    International Nuclear Information System (INIS)

    Heslop, Paul J.; Howe, Paul S.

    2003-01-01

    A new derivation is given of four-point functions of charge Q chiral primary multiplets in N=4 supersymmetric Yang-Mills theory. A compact formula, valid for arbitrary Q, is given which is manifestly superconformal and analytic in the internal bosonic coordinates of analytic superspace. This formula allows one to determine the spacetime four-point function of any four component fields in the multiplets in terms of the four-point function of the leading chiral primary fields. The leading term is expressed in terms of 1/2Q(Q-1) functions of two conformal invariants and a number of single variable functions. Crossing symmetry reduces the number of independent functions, while the OPE implies that the single-variable functions arise from protected operators and should therefore take their free form. This is the partial non-renormalisation property of such four-point functions which can be viewed as a consequence of the OPE and the non-renormalisation of three-point functions of protected operators. (author)

  6. Publication point indicators

    DEFF Research Database (Denmark)

    Elleby, Anita; Ingwersen, Peter

    2010-01-01

    ; the Cumulated Publication Point Indicator (CPPI), which graphically illustrates the cumulated gain of obtained vs. ideal points, both seen as vectors; and the normalized Cumulated Publication Point Index (nCPPI) that represents the cumulated gain of publication success as index values, either graphically......The paper presents comparative analyses of two publication point systems, The Norwegian and the in-house system from the interdisciplinary Danish Institute of International Studies (DIIS), used as case in the study for publications published 2006, and compares central citation-based indicators...... with novel publication point indicators (PPIs) that are formalized and exemplified. Two diachronic citation windows are applied: 2006-07 and 2006-08. Web of Science (WoS) as well as Google Scholar (GS) are applied to observe the cite delay and citedness for the different document types published by DIIS...

  7. X pinch a point x-ray source

    International Nuclear Information System (INIS)

    Garg, A.B.; Rout, R.K.; Shyam, A.; Srinivasan, M.

    1993-01-01

    X ray emission from an X pinch, a point x-ray source has been studied using a pin-hole camera by a 30 kV, 7.2 μ F capacitor bank. The wires of different material like W, Mo, Cu, S.S.(stainless steel) and Ti were used. Molybdenum pinch gives the most intense x-rays and stainless steel gives the minimum intensity x-rays for same bank energy (∼ 3.2 kJ). Point x-ray source of size (≤ 0.5 mm) was observed using pin hole camera. The size of the source is limited by the size of the pin hole camera. The peak current in the load is approximately 150 kA. The point x-ray source could be useful in many fields like micro lithography, medicine and to study the basic physics of high Z plasmas. (author). 4 refs., 3 figs

  8. Point mutations in the post-M2 region of human alpha-ENaC regulate cation selectivity.

    Science.gov (United States)

    Ji, H L; Parker, S; Langloh, A L; Fuller, C M; Benos, D J

    2001-07-01

    We tested the hypothesis that an arginine-rich region immediately following the second transmembrane domain may constitute part of the inner mouth of the epithelial Na+ channel (ENaC) pore and, hence, influence conduction and/or selectivity properties of the channel by expressing double point mutants in Xenopus oocytes. Double point mutations of arginines in this post-M2 region of the human alpha-ENaC (alpha-hENaC) led to a decrease and increase in the macroscopic conductance of alphaR586E,R587Ebetagamma- and alphaR589E,R591Ebetagamma-hENaC, respectively, but had no effect on the single-channel conductance of either double point mutant. However, the apparent equilibrium dissociation constant for Na+ was decreased for both alphaR586E,R587Ebetagamma- and alphaR589E,R591Ebetagamma-hENaC, and the maximum amiloride-sensitive Na+ current was decreased for alphaR586E,R587Ebetagamma-hENaC and increased for alphaR589E,R591Ebetagamma-hENaC. The relative permeabilities of Li+ and K+ vs. Na+ were increased 11.25- to 27.57-fold for alphaR586E,R587Ebetagamma-hENaC compared with wild type. The relative ion permeability of these double mutants and wild-type ENaC was inversely related to the crystal diameter of the permeant ions. Thus the region of positive charge is important for the ion permeation properties of the channel and may form part of the pore itself.

  9. Analysis of points of dew and contents of humidity of gassy mixtures N2-H2 O and CH4 H2 O

    International Nuclear Information System (INIS)

    Bedoya M, D; Muller, C; Oellrich, L R

    1995-01-01

    The actual knowledge of the exact water content in saturated gas mixtures still is incomplete, especially in the high pressure and low temperature region. Hence, dew point measurements with nitrogen - water and methane-water mixtures were performed; at pressures of 3 and 6 MPa and temperatures from 258 K to 288 K. The dew points were determined with the dew point mirror method and the water content by means of the Karl-Fischer-titration. The experimental values were compared to correlations from the literature. The approach by Sharma-Campbell resulted in the best description of the system nitrogen - water. For temperatures below 273 K the assumption of ideal behavior proved to be sufficient for the system methane-water, whereas for temperatures above 273 K calculations with the two-parameter corresponding states principle in combination with a fugacity correction turned out to be the best

  10. Use of libration-point orbits for space observatories

    Science.gov (United States)

    Farquhar, Robert W.; Dunham, David W.

    1990-01-01

    The sun-earth libration points, L1 and L2, are located 1.5 million kilometers from the earth toward and away from the sun. Halo orbits about these points have significant advantages for space observatories in terms of viewing geometry, thermal and radiation environment, and delta-V expediture.

  11. A three-point Taylor algorithm for three-point boundary value problems

    NARCIS (Netherlands)

    J.L. López; E. Pérez Sinusía; N.M. Temme (Nico)

    2011-01-01

    textabstractWe consider second-order linear differential equations $\\varphi(x)y''+f(x)y'+g(x)y=h(x)$ in the interval $(-1,1)$ with Dirichlet, Neumann or mixed Dirichlet-Neumann boundary conditions given at three points of the interval: the two extreme points $x=\\pm 1$ and an interior point

  12. Evaluating lidar point densities for effective estimation of aboveground biomass

    Science.gov (United States)

    Wu, Zhuoting; Dye, Dennis G.; Stoker, Jason M.; Vogel, John M.; Velasco, Miguel G.; Middleton, Barry R.

    2016-01-01

    The U.S. Geological Survey (USGS) 3D Elevation Program (3DEP) was recently established to provide airborne lidar data coverage on a national scale. As part of a broader research effort of the USGS to develop an effective remote sensing-based methodology for the creation of an operational biomass Essential Climate Variable (Biomass ECV) data product, we evaluated the performance of airborne lidar data at various pulse densities against Landsat 8 satellite imagery in estimating above ground biomass for forests and woodlands in a study area in east-central Arizona, U.S. High point density airborne lidar data, were randomly sampled to produce five lidar datasets with reduced densities ranging from 0.5 to 8 point(s)/m2, corresponding to the point density range of 3DEP to provide national lidar coverage over time. Lidar-derived aboveground biomass estimate errors showed an overall decreasing trend as lidar point density increased from 0.5 to 8 points/m2. Landsat 8-based aboveground biomass estimates produced errors larger than the lowest lidar point density of 0.5 point/m2, and therefore Landsat 8 observations alone were ineffective relative to airborne lidar for generating a Biomass ECV product, at least for the forest and woodland vegetation types of the Southwestern U.S. While a national Biomass ECV product with optimal accuracy could potentially be achieved with 3DEP data at 8 points/m2, our results indicate that even lower density lidar data could be sufficient to provide a national Biomass ECV product with accuracies significantly higher than that from Landsat observations alone.

  13. [Management of intractable epistaxis and bleeding points localization].

    Science.gov (United States)

    Yang, Da-Zhang; Cheng, Jing-Ning; Han, Jun; Shu, Ping; Zhang, Hua

    2005-05-01

    To investigate the common nasal bleeding points and the management of intractable epistaxis. The bleeding points and its correlation with age distribution, surgical techniques as well as its effects were studied retrospectively in 92 patients, in whom the bleeding points were not found by routine nasal endoscopy and the hemorrhage was not controlled with standard nasal packing. The bleeding points were found in the following different sites: superior wall of inferior nasal meatus (56.5%, 52/92), olfactory cleft of nasal septum (27.2%, 25/92), posterosuperior wall of middle nasal meatus (8.7%, 8/92) and uncertain (7.6%, 7/92). The results showed that the bleeding points had correlation with age. Epistaxis was well controlled by electrocoagulation in 83 cases, gelfoam packing in 8 cases, and transcatheter maxillary artery embolization in 1 case. There were no complications during a followed-up for 1 - 3 months after management. Among the 92 cases, the numbers of treatment needed to stop bleeding were 82 cases (89.1%) after 1 time of treatment, 9 cases (9.8%) after 2 times and in one case (1.1%) after 4 times. Endoscopy combined with displacement of the middle and inferior turbinate gives good visualization and direct management of the deeply-sited bleeding points, which were difficult in localization. The combined method provides an effective and safe way to control intractable epistaxis.

  14. A novel mouse Fgfr2 mutant, hobbyhorse (hob, exhibits complete XY gonadal sex reversal.

    Directory of Open Access Journals (Sweden)

    Pam Siggers

    Full Text Available The secreted molecule fibroblast growth factor 9 (FGF9 plays a critical role in testis determination in the mouse. In embryonic gonadal somatic cells it is required for maintenance of SOX9 expression, a key determinant of Sertoli cell fate. Conditional gene targeting studies have identified FGFR2 as the main gonadal receptor for FGF9 during sex determination. However, such studies can be complicated by inefficient and variable deletion of floxed alleles, depending on the choice of Cre deleter strain. Here, we report a novel, constitutive allele of Fgfr2, hobbyhorse (hob, which was identified in an ENU-based forward genetic screen for novel testis-determining loci. Fgr2hob is caused by a C to T mutation in the invariant exon 7, resulting in a polypeptide with a mis-sense mutation at position 263 (Pro263Ser in the third extracellular immunoglobulin-like domain of FGFR2. Mutant homozygous embryos show severe limb and lung defects and, when on the sensitised C57BL/6J (B6 genetic background, undergo complete XY gonadal sex reversal associated with failure to maintain expression of Sox9. Genetic crosses employing a null mutant of Fgfr2 suggest that Fgr2hob is a hypomorphic allele, affecting both the FGFR2b and FGFR2c splice isoforms of the receptor. We exploited the consistent phenotype of this constitutive mutant by analysing MAPK signalling at the sex-determining stage of gonad development, but no significant abnormalities in mutant embryos were detected.

  15. [Orthogonal design method to optimize rehabilitation prescription of pulsed electric field at Jiaji (EX-B 2) points for spinal cord injury].

    Science.gov (United States)

    Zhang, Lifeng; Zhang, Hui; Wang, Lin; Liu, Yanyan; Sun, Xianyue; Li, Lingyan; Hou, Jing

    2015-01-01

    By using orthogonal design method to optimnize prescription of pulsed electric field at Jiaji (EX- B 2) points for spinal cord injury (SCI). Fifty six patients of SCI were selected, in which 36 cases were divided into orthogonal design trial and 20 cases were into clinical verification. With 36 patients who received orthogonal design trial, Frankel grading scale was used as observation index to screen optimal prescription of pulsed electric field. Pulse frequency (factor A) included low frequency (factor A(I), 10(2) Hz). moderate frequency (factor A(II), 10(4) Hz) and high frequency (factor A(III), 10(3) Hz); pulse amplitude (factor B) included 0-30 V (factor B ), 0-60 V (factor B(II)) and 0-90 V (factor B(III)); pulse width (factor C) included 0.1 ms (factor C(I)). 0.6 ms (factor C(II)) and 0.9 ms (factor C(III)); acupuncture time (factor D) included one month (DI), three months (D(II)) and five months (D(III)). Twenty patients were used for clinical efficacy observation and the effects of screened optimal pre scription of pulsed electric field at Jiaji (EX-B 2) points combined with regular rehabilitation training on spasm se- verity, score of sensory and motor functions, Barthel index and Frankel score were observed. (1) As results of orthogonal design trial, the optimal prescription was A(III) B(III), C(I), D(III), which were high frequency (10(3) Hz), 0-90 V of pulse amplitude, 0.4 ms of pulse width and 5 months of treatment time. (2) As results of 20 patient clinical verification, Ashworth score, tendon reflex and clonus were all significantly improved (Ppulsed electric field at Jiaji (EX-B 2) points for spinal cord injury is high frequency (10& Hz), 0-90 V of pulse amplitude, 0.4 ms of pulse width and 5 months of treatment time. The optimal prescription of pulsed electric field at Jiaji (EX-B 2) points combined with regular rehabilitation could obviously improve spasm severity, enhance senso- ry and motor functions, and ameliorate activity of daily life and

  16. Bright point study

    International Nuclear Information System (INIS)

    Tang, F.; Harvey, K.; Bruner, M.; Kent, B.; Antonucci, E.

    1982-01-01

    Transition region and coronal observations of bright points by instruments aboard the Solar Maximum Mission and high resolution photospheric magnetograph observations on September 11, 1980 are presented. A total of 31 bipolar ephemeral regions were found in the photosphere from birth in 9.3 hours of combined magnetograph observations from three observatories. Two of the three ephemeral regions present in the field of view of the Ultraviolet Spectrometer-Polarimeter were observed in the C IV 1548 line. The unobserved ephemeral region was determined to be the shortest-lived (2.5 hr) and lowest in magnetic flux density (13G) of the three regions. The Flat Crystal Spectrometer observed only low level signals in the O VIII 18.969 A line, which were not statistically significant to be positively identified with any of the 16 ephemeral regions detected in the photosphere. In addition, the data indicate that at any given time there lacked a one-to-one correspondence between observable bright points and photospheric ephemeral regions, while more ephemeral regions were observed than their counterparts in the transition region and the corona

  17. Georeferenced Point Clouds: A Survey of Features and Point Cloud Management

    Directory of Open Access Journals (Sweden)

    Johannes Otepka

    2013-10-01

    Full Text Available This paper presents a survey of georeferenced point clouds. Concentration is, on the one hand, put on features, which originate in the measurement process themselves, and features derived by processing the point cloud. On the other hand, approaches for the processing of georeferenced point clouds are reviewed. This includes the data structures, but also spatial processing concepts. We suggest a categorization of features into levels that reflect the amount of processing. Point clouds are found across many disciplines, which is reflected in the versatility of the literature suggesting specific features.

  18. THE 31 DEG{sup 2} RELEASE OF THE STRIPE 82 X-RAY SURVEY: THE POINT SOURCE CATALOG

    Energy Technology Data Exchange (ETDEWEB)

    LaMassa, Stephanie M.; Urry, C. Megan; Ananna, Tonima; Civano, Francesca; Marchesi, Stefano; Pecoraro, Robert [Yale Center for Astronomy and Astrophysics, Physics Department, P.O. Box 208120, New Haven, CT 06520 (United States); Cappelluti, Nico; Comastri, Andrea; Brusa, Marcella [INAF-Osservatorio Astronomico di Bologna, via Ranzani 1, I-40127 Bologna (Italy); Böhringer, Hans; Chon, Gayoung [Max-Planck-Institut für extraterrestrische Physik, D-85748 Garching (Germany); Glikman, Eilat [Department of Physics, Middlebury College, Middlebury, VT 05753 (United States); Richards, Gordon [Department of Physics, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104 (United States); Cardamone, Carie [Department of Math and Science, Wheelock College, 200 Riverway, Boston, MA 02215 (United States); Farrah, Duncan [Department of Physics MC 0435, Virginia Polytechnic Institute and State University, 850 West Campus Drive, Blacksburg, VA 24061 (United States); Gilfanov, Marat [Max-Planck Institut für Astrophysik, Karl-Schwarzschild-Str. 1, Postfach 1317, D-85741 Garching (Germany); Green, Paul [Smithsonian Astrophysical Observatory, 60 Garden Street, Cambridge, MA 02138 (United States); Komossa, S. [Max-Planck-Institut für Radioastronomie, Auf dem Hügel 69, D-53121 Bonn (Germany); Lira, Paulina [Departamento de Astronomia, Universidad de Chile, Camino del Observatorio 1515, Santiago (Chile); Makler, Martin [Centro Brasileiro de Pesquisas Fisicas, Rua Dr Xavier Sigaud 150, Rio de Janeiro, RJ 22290-180 (Brazil); and others

    2016-02-01

    We release the next installment of the Stripe 82 X-ray survey point-source catalog, which currently covers 31.3 deg{sup 2} of the Sloan Digital Sky Survey (SDSS) Stripe 82 Legacy field. In total, 6181 unique X-ray sources are significantly detected with XMM-Newton (>5σ) and Chandra (>4.5σ). This catalog release includes data from XMM-Newton cycle AO 13, which approximately doubled the Stripe 82X survey area. The flux limits of the Stripe 82X survey are 8.7 × 10{sup −16} erg s{sup −1} cm{sup −2}, 4.7 × 10{sup −15} erg s{sup −1} cm{sup −2}, and 2.1 × 10{sup −15} erg s{sup −1} cm{sup −2} in the soft (0.5–2 keV), hard (2–10 keV), and full bands (0.5–10 keV), respectively, with approximate half-area survey flux limits of 5.4 × 10{sup −15} erg s{sup −1} cm{sup −2}, 2.9 × 10{sup −14} erg s{sup −1} cm{sup −2}, and 1.7 × 10{sup −14} erg s{sup −1} cm{sup −2}. We matched the X-ray source lists to available multi-wavelength catalogs, including updated matches to the previous release of the Stripe 82X survey; 88% of the sample is matched to a multi-wavelength counterpart. Due to the wide area of Stripe 82X and rich ancillary multi-wavelength data, including coadded SDSS photometry, mid-infrared WISE coverage, near-infrared coverage from UKIDSS and VISTA Hemisphere Survey, ultraviolet coverage from GALEX, radio coverage from FIRST, and far-infrared coverage from Herschel, as well as existing ∼30% optical spectroscopic completeness, we are beginning to uncover rare objects, such as obscured high-luminosity active galactic nuclei at high-redshift. The Stripe 82X point source catalog is a valuable data set for constraining how this population grows and evolves, as well as for studying how they interact with the galaxies in which they live.

  19. International Conference on Fixed Point Theory and Applications (Colloque International Theorie Du Point Fixe et Applications)

    Science.gov (United States)

    1989-06-09

    could be used to establish a conjectured minimax for a search game of Baston and Bostock [2]. An application of Theorem 1 is to the problem of getting...Alpern S., Search for point in interval, with high-low feedback, Math. Proc., Cambridge Phil. Soc. 98, (1985), 569-578. [2] Baston V. J. and Bostock F. A

  20. Engineering Surface Critical Behavior of (2 +1 )-Dimensional O(3) Quantum Critical Points

    Science.gov (United States)

    Ding, Chengxiang; Zhang, Long; Guo, Wenan

    2018-06-01

    Surface critical behavior (SCB) refers to the singularities of physical quantities on the surface at the bulk phase transition. It is closely related to and even richer than the bulk critical behavior. In this work, we show that three types of SCB universality are realized in the dimerized Heisenberg models at the (2 +1 )-dimensional O(3) quantum critical points by engineering the surface configurations. The ordinary transition happens if the surface is gapped in the bulk disordered phase, while the gapless surface state generally leads to the multicritical special transition, even though the latter is precluded in classical phase transitions because the surface is in the lower critical dimension. An extraordinary transition is induced by the ferrimagnetic order on the surface of the staggered Heisenberg model, in which the surface critical exponents violate the results of the scaling theory and thus seriously challenge our current understanding of extraordinary transitions.

  1. The superconducting gaps of C-substituted and Al-substituted MgB2 single crystals by point-contact spectroscopy

    International Nuclear Information System (INIS)

    Daghero, D.; Gonnelli, R.S.; Ummarino, G.A.; Calzolari, A.; Dellarocca, Valeria; Stepanov, V.A.; Zhigadlo, N.; Kazakov, S.M.; Karpinski, J.

    2005-01-01

    We studied the effects of carbon and aluminum substitutions on the gaps of the two-band superconductor MgB 2 by means of point-contact measurements in Mg(B 1-x C x ) 2 and Mg 1-y Al y B 2 single crystals with 0≤x≤0.132 and 0≤y≤0.21. The gap amplitudes, Δ ω and Δ π , were determined by fitting the conductance curves of the point contacts with the standard Blonder-Tinkham-Klapwijk (BTK) model generalized to the two-band case. Whenever possible, their values were confirmed by the independent fit (with a single-band BTK model) of the partial contribution of the two bands to the conductance, separated by means of a suitable magnetic field B*. In C-substituted crystals, the two gaps remain clearly distinct up to x∝0.10, but at x=0.132 we observed for the first time their merging into a single gap Δ≅3 meV with a gap ratio 2Δ=k B T c close to the standard BCS value. In Al-substituted crystals, we found no evidence of this gap merging. Instead, Δ π reaches the value 0.4 meV at y=0.21, where Δ π saturates at about 4 meV. These results are compared with other recent experimental findings in polycrystals and with the predictions of the models for multiband superconductivity. (copyright 2005 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  2. Point charges optimally placed to represent the multipole expansion of charge distributions.

    Directory of Open Access Journals (Sweden)

    Ramu Anandakrishnan

    Full Text Available We propose an approach for approximating electrostatic charge distributions with a small number of point charges to optimally represent the original charge distribution. By construction, the proposed optimal point charge approximation (OPCA retains many of the useful properties of point multipole expansion, including the same far-field asymptotic behavior of the approximate potential. A general framework for numerically computing OPCA, for any given number of approximating charges, is described. We then derive a 2-charge practical point charge approximation, PPCA, which approximates the 2-charge OPCA via closed form analytical expressions, and test the PPCA on a set of charge distributions relevant to biomolecular modeling. We measure the accuracy of the new approximations as the RMS error in the electrostatic potential relative to that produced by the original charge distribution, at a distance 2x the extent of the charge distribution--the mid-field. The error for the 2-charge PPCA is found to be on average 23% smaller than that of optimally placed point dipole approximation, and comparable to that of the point quadrupole approximation. The standard deviation in RMS error for the 2-charge PPCA is 53% lower than that of the optimal point dipole approximation, and comparable to that of the point quadrupole approximation. We also calculate the 3-charge OPCA for representing the gas phase quantum mechanical charge distribution of a water molecule. The electrostatic potential calculated by the 3-charge OPCA for water, in the mid-field (2.8 Å from the oxygen atom, is on average 33.3% more accurate than the potential due to the point multipole expansion up to the octupole order. Compared to a 3 point charge approximation in which the charges are placed on the atom centers, the 3-charge OPCA is seven times more accurate, by RMS error. The maximum error at the oxygen-Na distance (2.23 Å is half that of the point multipole expansion up to the octupole

  3. Influence of the burning point on the dew point in a diesel engine

    Energy Technology Data Exchange (ETDEWEB)

    Teetz, C.

    1982-06-01

    A computation on the influence of the ignition point on the dew point in a cylinder of a diesel engine is presented. The cylinder-pressure diagrams are shown. The results of computation are given. A later ignition point diminishes the area with cylinder wall temperatures below the dew point. The endangering by cylinder wall temperatures below the dew point is illustrated.

  4. Point specificity in acupuncture

    Directory of Open Access Journals (Sweden)

    Choi Emma M

    2012-02-01

    Full Text Available Abstract The existence of point specificity in acupuncture is controversial, because many acupuncture studies using this principle to select control points have found that sham acupoints have similar effects to those of verum acupoints. Furthermore, the results of pain-related studies based on visual analogue scales have not supported the concept of point specificity. In contrast, hemodynamic, functional magnetic resonance imaging and neurophysiological studies evaluating the responses to stimulation of multiple points on the body surface have shown that point-specific actions are present. This review article focuses on clinical and laboratory studies supporting the existence of point specificity in acupuncture and also addresses studies that do not support this concept. Further research is needed to elucidate the point-specific actions of acupuncture.

  5. Point X-ray sources in the SNR G 315.4-2.30 (MSH 14-63, RCW 86)

    Science.gov (United States)

    Gvaramadze, V. V.; Vikhlinin, A. A.

    2003-04-01

    We report the results of a search for a point X-ray source (stellar remnant) in the southwest protrusion of the supernova remnant G 315.4-2.30 (MSH 14-63, RCW 86) using the archival data of the Chandra X-ray Observatory. The search was motivated by a hypothesis that G 315.4-2.30 is the result of an off-centered cavity supernova explosion of a moving massive star, which ended its evolution just near the edge of the main-sequence wind-driven bubble. This hypothesis implies that the southwest protrusion in G 315.4-2.30 is the remainder of a pre-existing bow shock-like structure created by the interaction of the supernova progenitor's wind with the interstellar medium and that the actual location of the supernova blast center is near the center of this hemispherical structure. We have discovered two point X-ray sources in the ``proper" place. One of the sources has an optical counterpart with the photographic magnitude 13.38+/-0.40, while the spectrum of the source can be fitted with an optically thin plasma model. We interpret this source as a foreground active star of late spectral type. The second source has no optical counterpart to a limiting magnitude ~ 21. The spectrum of this source can be fitted almost equally well with several simple models (power law: photon index =1.87; two-temperature blackbody: kT1 =0.11 keV, R1 =2.34 km and kT2 =0.71 keV, R2 =0.06 km; blackbody plus power law: kT =0.07 keV, photon index =2.3). We interpret this source as a candidate stellar remnant (neutron star), while the photon index and non-thermal luminosity of the source (almost the same as those of the Vela pulsar and the recently discovered pulsar PSR J 0205+6449 in the supernova remnant 3C 58) suggest that it can be a young ``ordinary" pulsar.

  6. Non-perturbative measurement of cross-field thermal diffusivity reduction at the O-point of 2/1 neoclassical tearing mode islands in the DIII-D tokamak

    Energy Technology Data Exchange (ETDEWEB)

    Bardóczi, L.; Rhodes, T. L.; Carter, T. A.; Crocker, N. A.; Peebles, W. A. [University of California Los Angeles, Los Angeles, California 90095 (United States); Grierson, B. A. [Princeton Plasma Physics Laboratory, Princeton, New Jersey 08543 (United States)

    2016-05-15

    Neoclassical tearing modes (NTMs) often lead to the decrease of plasma performance and can lead to disruptions, which makes them a major impediment in the development of operating scenarios in present toroidal fusion devices. Recent gyrokinetic simulations predict a decrease of plasma turbulence and cross-field transport at the O-point of the islands, which in turn affects the NTM dynamics. In this paper, a heat transport model of magnetic islands employing spatially non-uniform cross-field thermal diffusivity (χ{sub ⊥}) is presented. This model is used to derive χ{sub ⊥} at the O-point from electron temperature data measured across 2/1 NTM islands in DIII-D. It was found that χ{sub ⊥} at the O-point is 1 to 2 orders of magnitude smaller than the background plasma transport, in qualitative agreement with gyrokinetic predictions. As the anomalously large values of χ{sub ⊥} are often attributed to turbulence driven transport, the reduction of the O-point χ{sub ⊥} is consistent with turbulence reduction found in recent experiments. Finally, the implication of reduced χ{sub ⊥} at the O-point on NTM dynamics was investigated using the modified Rutherford equation that predicts a significant effect of reduced χ{sub ⊥} at the O-point on NTM saturation.

  7. A New Blind Pointing Model Improves Large Reflector Antennas Precision Pointing at Ka-Band (32 GHz)

    Science.gov (United States)

    Rochblatt, David J.

    2009-01-01

    The National Aeronautics and Space Administration (NASA), Jet Propulsion Laboratory (JPL)-Deep Space Network (DSN) subnet of 34-m Beam Waveguide (BWG) Antennas was recently upgraded with Ka-Band (32-GHz) frequency feeds for space research and communication. For normal telemetry tracking a Ka-Band monopulse system is used, which typically yields 1.6-mdeg mean radial error (MRE) pointing accuracy on the 34-m diameter antennas. However, for the monopulse to be able to acquire and lock, for special radio science applications where monopulse cannot be used, or as a back-up for the monopulse, high-precision open-loop blind pointing is required. This paper describes a new 4th order pointing model and calibration technique, which was developed and applied to the DSN 34-m BWG antennas yielding 1.8 to 3.0-mdeg MRE pointing accuracy and amplitude stability of 0.2 dB, at Ka-Band, and successfully used for the CASSINI spacecraft occultation experiment at Saturn and Titan. In addition, the new 4th order pointing model was used during a telemetry experiment at Ka-Band (32 GHz) utilizing the Mars Reconnaissance Orbiter (MRO) spacecraft while at a distance of 0.225 astronomical units (AU) from Earth and communicating with a DSN 34-m BWG antenna at a record high rate of 6-megabits per second (Mb/s).

  8. OFF-Stagnation point testing in plasma facility

    Science.gov (United States)

    Viladegut, A.; Chazot, O.

    2015-06-01

    Reentry space vehicles face extreme conditions of heat flux when interacting with the atmosphere at hypersonic velocities. Stagnation point heat flux is normally used as a reference for Thermal Protection Material (TPS) design; however, many critical phenomena also occur at off-stagnation point. This paper adresses the implementation of an offstagnation point methodology able to duplicate in ground facility the hypersonic boundary layer over a flat plate model. The first analysis using two-dimensional (2D) computational fluid dynamics (CFD) simulations is carried out to understand the limitations of this methodology when applying it in plasma wind tunnel. The results from the testing campaign at VKI Plasmatron are also presented.

  9. Variational estimates of point-kinetics parameters

    International Nuclear Information System (INIS)

    Favorite, J.A.; Stacey, W.M. Jr.

    1995-01-01

    Variational estimates of the effect of flux shifts on the integral reactivity parameter of the point-kinetics equations and on regional power fractions were calculated for a variety of localized perturbations in two light water reactor (LWR) model problems representing a small, tightly coupled core and a large, loosely coupled core. For the small core, the flux shifts resulting from even relatively large localized reactivity changes (∼600 pcm) were small, and the standard point-kinetics approximation estimates of reactivity were in error by only ∼10% or less, while the variational estimates were accurate to within ∼1%. For the larger core, significant (>50%) flux shifts occurred in response to local perturbations, leading to errors of the same magnitude in the standard point-kinetics approximation of the reactivity worth. For positive reactivity, the error in the variational estimate of reactivity was only a few percent in the larger core, and the resulting transient power prediction was 1 to 2 orders of magnitude more accurate than with the standard point-kinetics approximation. For a large, local negative reactivity insertion resulting in a large flux shift, the accuracy of the variational estimate broke down. The variational estimate of the effect of flux shifts on reactivity in point-kinetics calculations of transients in LWR cores was found to generally result in greatly improved accuracy, relative to the standard point-kinetics approximation, the exception being for large negative reactivity insertions with large flux shifts in large, loosely coupled cores

  10. Synergistic cloud point extraction behavior of aluminum(III) with 2-methyl-8-quinolinol and 3,5-dichlorophenol.

    Science.gov (United States)

    Ohashi, Akira; Tsuguchi, Akira; Imura, Hisanori; Ohashi, Kousaburo

    2004-07-01

    The cloud point extraction behavior of aluminum(III) with 8-quinolinol (HQ) or 2-methyl-8-quinolinol (HMQ) and Triton X-100 was investigated in the absence and presence of 3,5-dichlorophenol (Hdcp). Aluminum(III) was almost extracted with HQ and 4(v/v)% Triton X-100 above pH 5.0, but was not extracted with HMQ-Triton X-100. However, in the presence of Hdcp, it was almost quantitatively extracted with HMQ-Triton X-100. The synergistic effect of Hdcp on the extraction of aluminum(III) with HMQ and Triton X-100 may be caused by the formation of a mixed-ligand complex, Al(dcp)(MQ)2.

  11. Nonconvergence to Saddle Boundary Points under Perturbed Reinforcement Learning

    Science.gov (United States)

    2012-12-07

    of the ODE (12). Note that for some games not all stationary points of the ODE (12) are Nash equilibria. For example, if you consider the Typewriter ...B A 4, 4 2, 2 B 2, 2 3, 3 Table 1: The Typewriter Game. On the other hand, any stationary point in the interior of the probability simplex will... Typewriter Game of Table 1. We observe that it is possible for the process to converge to a pure strategy profile which is not a Nash equilibrium when Ri(α

  12. Point Lepreau refurbishment project programmable digital comparator (PDC) replacement for SDS1 and SDS2

    International Nuclear Information System (INIS)

    Ichiyen, N.M.; Chan, D.; Thompson, P.D.

    2003-01-01

    NB Power is tentatively planning to conduct an 18-month maintenance outage of the Point Lepreau Generating Station (PLGS) starting in April 2007. The scope of the outage was determined from the outcome of a two year study (Phase 1) involving a detailed condition assessment of the station which examined issues relating to ageing and obsolescence, along with a detailed review of Safety and Licensing issues associated with extended operation. In order to minimize schedule and regulatory risk for the Refurbishment project, pre-project work was initiated in early 2002. This program is called Phase 2 ESA (Early Start Activities). As part of the Phase 1 assessments it was concluded that replacement of the PDCs (Programmable Digital Comparators) for both shutdown systems was required in order to ensure operation of the plant for a further 25-30 years. Critical tasks were identified related to PDC replacement as part of the Phase 2 ESA program. This paper describes the activities that have taken place in the Phase 2 ESA program as well as the plan for future work for the PDC replacement for SDS 1 (Shutdown System Number One) and SDS2 (Shutdown System Number Two). (author)

  13. Cloud Point Extraction and Determination of Silver Ion in Real Sample using Bis((1H-benzo[d ]imidazol-2ylmethylsulfane

    Directory of Open Access Journals (Sweden)

    Farshid Ahmadi

    2011-01-01

    Full Text Available Bis((1H-benzo[d]imidazol-2ylmethylsulfane (BHIS was used as a complexing agent in cloud point extraction for the first time and applied for selective pre-concentration of trace amounts of silver. The method is based on the extraction of silver at pH 8.0 by using non-ionic surfactant T-X114 and bis((1H-benzo[d]imidazol-2ylmethylsulfane as a chelating agent. The adopted concentrations for BHIS, Triton X-114 and HNO3, bath temperature, centrifuge rate and time were optimized. Detection limits (3SDb/m of 1.7 along with enrichment factor of 39 for silver ion was achieved. The high efficiency of cloud point extraction to carry out the determination of analytes in complex matrices was demonstrated. The proposed method was successfully applied to the ultra-trace determination of silver in real samples.

  14. COMPARISON OF 2D AND 3D APPROACHES FOR THE ALIGNMENT OF UAV AND LIDAR POINT CLOUDS

    Directory of Open Access Journals (Sweden)

    R. A. Persad

    2017-08-01

    Full Text Available The automatic alignment of 3D point clouds acquired or generated from different sensors is a challenging problem. The objective of the alignment is to estimate the 3D similarity transformation parameters, including a global scale factor, 3 rotations and 3 translations. To do so, corresponding anchor features are required in both data sets. There are two main types of alignment: i Coarse alignment and ii Refined Alignment. Coarse alignment issues include lack of any prior knowledge of the respective coordinate systems for a source and target point cloud pair and the difficulty to extract and match corresponding control features (e.g., points, lines or planes co-located on both point cloud pairs to be aligned. With the increasing use of UAVs, there is a need to automatically co-register their generated point cloud-based digital surface models with those from other data acquisition systems such as terrestrial or airborne lidar point clouds. This works presents a comparative study of two independent feature matching techniques for addressing 3D conformal point cloud alignment of UAV and lidar data in different 3D coordinate systems without any prior knowledge of the seven transformation parameters.

  15. Point-to-point microwave power transmission experiment; Maikuroha ni yoru denryoku yuso no kiso kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Shimokura, N.; Kirihara, T. [Kansai Electric Power Co. Inc., Osaka (Japan)

    1997-09-30

    In order to demonstrate the power transmission using microwave and arrange advantages and problems in the wireless power transmission, field tests of point-to-point power transmission were conducted. Microwave frequency of 2.45 GHz was used, which is assigned as the industrial, scientific and medical frequency. The transmission system is composed of generator, director tube, primary radiator, and transmission antenna. The maximum 5 kW of microwave power can be transmitted by combining a 3 m-diameter parabolic antenna and a magnetron. The receiving system is composed of devices called as RECTENNA (rectifying antenna). A large capacity and high efficiency RECTENNA was developed, by which the maximum 2.5 W of input power per single device can be provided. As a result of the experiments, efficiency at the transmission side was over 70%, and RF-DC efficiency at the receiving side was about 51%. At the open-air test site, however, the total efficiency of only 14.8% could be obtained. 8 refs., 12 figs.

  16. Low-melting point heat transfer fluid

    Science.gov (United States)

    Cordaro, Joseph Gabriel; Bradshaw, Robert W.

    2010-11-09

    A low-melting point, heat transfer fluid made of a mixture of five inorganic salts including about 29.1-33.5 mol % LiNO.sub.3, 0-3.9 mol % NaNO.sub.3, 2.4-8.2 mol % KNO.sub.3, 18.6-19.9 mol % NaNO.sub.2, and 40-45.6 mol % KNO.sub.2. These compositions can have liquidus temperatures below 80.degree. C. for some compositions.

  17. Turning points in reactor design

    International Nuclear Information System (INIS)

    Beckjord, E.S.

    1995-01-01

    This article provides some historical aspects on nuclear reactor design, beginning with PWR development for Naval Propulsion and the first commercial application at Yankee Rowe. Five turning points in reactor design and some safety problems associated with them are reviewed: (1) stability of Dresden-1, (2) ECCS, (3) PRA, (4) TMI-2, and (5) advanced passive LWR designs. While the emphasis is on the thermal-hydraulic aspects, the discussion is also about reactor systems

  18. Turning points in reactor design

    Energy Technology Data Exchange (ETDEWEB)

    Beckjord, E.S.

    1995-09-01

    This article provides some historical aspects on nuclear reactor design, beginning with PWR development for Naval Propulsion and the first commercial application at Yankee Rowe. Five turning points in reactor design and some safety problems associated with them are reviewed: (1) stability of Dresden-1, (2) ECCS, (3) PRA, (4) TMI-2, and (5) advanced passive LWR designs. While the emphasis is on the thermal-hydraulic aspects, the discussion is also about reactor systems.

  19. Wrapping interactions and the genus expansion of the 2-point function of composite operators

    International Nuclear Information System (INIS)

    Sieg, Christoph; Torrielli, Alessandro

    2005-01-01

    We perform a systematic analysis of wrapping interactions for a general class of theories with color degrees of freedom, including N=4 SYM. Wrapping interactions arise in the genus expansion of the 2-point function of composite operators as finite size effects that start to appear at a certain order in the coupling constant at which the range of the interaction is equal to the length of the operators. We analyze in detail the relevant genus expansions, and introduce a strategy to single out the wrapping contributions, based on adding spectator fields. We use a toy model to demonstrate our procedure, performing all computations explicitly. Although completely general, our treatment should be particularly useful for applications to the recent problem of wrapping contributions in some checks of the AdS/CFT correspondence

  20. Vernal Point and Anthropocene

    Science.gov (United States)

    Chavez-Campos, Teodosio; Chavez S, Nadia; Chavez-Sumarriva, Israel

    2014-05-01

    The time scale was based on the internationally recognized formal chronostratigraphical /geochronological subdivisions of time: The Phanerozoic Eonathem/Eon; the Cenozoic Erathem/Era; the Quaternary System/Period; the Pleistocene and Holocene Series/Epoch. The Quaternary was divided into: (1) The Pleistocene that was characterized by cycles of glaciations (intervals between 40,000 and 100,000 years). (2) The Holocene that was an interglacial period that began about 12,000 years ago. It was believed that the Milankovitch cycles (eccentricity, axial tilt and the precession of the equinoxes) were responsible for the glacial and interglacial Holocene periods. The magnetostratigraphic units have been widely used for global correlations valid for Quaternary. The gravitational influence of the sun and moon on the equatorial bulges of the mantle of the rotating earth causes the precession of the earth. The retrograde motion of the vernal point through the zodiacal band is 26,000 years. The Vernal point passes through each constellation in an average of 2000 years and this period of time was correlated to Bond events that were North Atlantic climate fluctuations occurring every ≡1,470 ± 500 years throughout the Holocene. The vernal point retrogrades one precessional degree approximately in 72 years (Gleissberg-cycle) and approximately enters into the Aquarius constellation on March 20, 1940. On earth this entry was verify through: a) stability of the magnetic equator in the south central zone of Peru and in the north zone of Bolivia, b) the greater intensity of equatorial electrojet (EEJ) in Peru and Bolivia since 1940. With the completion of the Holocene and the beginning of the Anthropocene (widely popularized by Paul Crutzen) it was proposed the date of March 20, 1940 as the beginning of the Anthropocene. The date proposed was correlated to the work presented in IUGG (Italy 2007) with the title "Cusco base meridian for the study of geophysical data"; Cusco was

  1. Automated Identification of Fiducial Points on 3D Torso Images

    Directory of Open Access Journals (Sweden)

    Manas M. Kawale

    2013-01-01

    Full Text Available Breast reconstruction is an important part of the breast cancer treatment process for many women. Recently, 2D and 3D images have been used by plastic surgeons for evaluating surgical outcomes. Distances between different fiducial points are frequently used as quantitative measures for characterizing breast morphology. Fiducial points can be directly marked on subjects for direct anthropometry, or can be manually marked on images. This paper introduces novel algorithms to automate the identification of fiducial points in 3D images. Automating the process will make measurements of breast morphology more reliable, reducing the inter- and intra-observer bias. Algorithms to identify three fiducial points, the nipples, sternal notch, and umbilicus, are described. The algorithms used for localization of these fiducial points are formulated using a combination of surface curvature and 2D color information. Comparison of the 3D coordinates of automatically detected fiducial points and those identified manually, and geodesic distances between the fiducial points are used to validate algorithm performance. The algorithms reliably identified the location of all three of the fiducial points. We dedicate this article to our late colleague and friend, Dr. Elisabeth K. Beahm. Elisabeth was both a talented plastic surgeon and physician-scientist; we deeply miss her insight and her fellowship.

  2. Quantum Group U_q(sl(2 Symmetry and Explicit Evaluation of the One-Point Functions of the Integrable Spin-1 XXZ Chain

    Directory of Open Access Journals (Sweden)

    Tetsuo Deguchi

    2011-06-01

    Full Text Available We show some symmetry relations among the correlation functions of the integrable higher-spin XXX and XXZ spin chains, where we explicitly evaluate the multiple integrals representing the one-point functions in the spin-1 case. We review the multiple-integral representations of correlation functions for the integrable higher-spin XXZ chains derived in a region of the massless regime including the anti-ferromagnetic point. Here we make use of the gauge transformations between the symmetric and asymmetric R-matrices, which correspond to the principal and homogeneous gradings, respectively, and we send the inhomogeneous parameters to the set of complete 2s-strings. We also give a numerical support for the analytical expression of the one-point functions in the spin-1 case.

  3. The registration of non-cooperative moving targets laser point cloud in different view point

    Science.gov (United States)

    Wang, Shuai; Sun, Huayan; Guo, Huichao

    2018-01-01

    Non-cooperative moving target multi-view cloud registration is the key technology of 3D reconstruction of laser threedimension imaging. The main problem is that the density changes greatly and noise exists under different acquisition conditions of point cloud. In this paper, firstly, the feature descriptor is used to find the most similar point cloud, and then based on the registration algorithm of region segmentation, the geometric structure of the point is extracted by the geometric similarity between point and point, The point cloud is divided into regions based on spectral clustering, feature descriptors are created for each region, searching to find the most similar regions in the most similar point of view cloud, and then aligning the pair of point clouds by aligning their minimum bounding boxes. Repeat the above steps again until registration of all point clouds is completed. Experiments show that this method is insensitive to the density of point clouds and performs well on the noise of laser three-dimension imaging.

  4. Preconditioners for regularized saddle point matrices

    Czech Academy of Sciences Publication Activity Database

    Axelsson, Owe

    2011-01-01

    Roč. 19, č. 2 (2011), s. 91-112 ISSN 1570-2820 Institutional research plan: CEZ:AV0Z30860518 Keywords : saddle point matrices * preconditioning * regularization * eigenvalue clustering Subject RIV: BA - General Mathematics Impact factor: 0.533, year: 2011 http://www.degruyter.com/view/j/jnma.2011.19.issue-2/jnum.2011.005/jnum.2011.005. xml

  5. Highly precise (liquid + liquid) equilibrium and heat capacity measurements near the critical point for [Bmim][BF4] + 1H, 1H, 2H, 2H perfluoroctanol

    International Nuclear Information System (INIS)

    Pérez-Sánchez, G.; Troncoso, J.; Losada-Pérez, P.; Méndez-Castro, P.; Romaní, L.

    2013-01-01

    Highlights: • Highly precise liquid–liquid curves for [Bmim][BF 4 ] + perfluoroctanol are reported. • Critical behavior of heat capacity for the same system was also characterized. • In contrast to previous results, no coulombic/solvophobic crossover for coexistence curve diameter was found. • The system criticality shows characteristics both solvophobic and coulombic. -- Abstract: Liquid + liquid equilibrium of the system [Bmim][BF 4 ] + 1H, 1H, 2H, 2H perfluoroctanol using a highly precise methodology based on refractive index measurements was experimentally determined. In addition, isobaric heat capacity near the critical point was obtained. The performance of the new refractive index set-up was successfully checked against the coexistence curve of the system dimethyl carbonate + decane, since highly accurate data are available in the literature. The choice of [Bmim][BF 4 ] + 1H, 1H, 2H, 2H perfluoroctanol was motivated by a previous experimental work, whose results suggest that this system could present characteristics of both solvophobic and coulombic behavior, which are the two categories to which an ionic system can belong. Although this was previously observed for other ionic systems, this mixture presented a very striking feature: the diameter of the coexistence curve seemed to change its criticality in the studied temperature range, from solvophobic far away to coulombic close to the critical point. The results of this work reveal that, in fact, [Bmim][BF 4 ] + 1H, 1H, 2H, 2H perfluoroctanol presents characteristics of both solvophobic and coulombic criticality, but no evidence of the observed crossover over the experimental temperature range has been found

  6. Blue-noise remeshing with farthest point optimization

    KAUST Repository

    Yan, Dongming

    2014-08-01

    In this paper, we present a novel method for surface sampling and remeshing with good blue-noise properties. Our approach is based on the farthest point optimization (FPO), a relaxation technique that generates high quality blue-noise point sets in 2D. We propose two important generalizations of the original FPO framework: adaptive sampling and sampling on surfaces. A simple and efficient algorithm for accelerating the FPO framework is also proposed. Experimental results show that the generalized FPO generates point sets with excellent blue-noise properties for adaptive and surface sampling. Furthermore, we demonstrate that our remeshing quality is superior to the current state-of-the art approaches. © 2014 The Eurographics Association and John Wiley & Sons Ltd.

  7. Blue-noise remeshing with farthest point optimization

    KAUST Repository

    Yan, Dongming; Guo, Jianwei; Jia, Xiaohong; Zhang, Xiaopeng; Wonka, Peter

    2014-01-01

    In this paper, we present a novel method for surface sampling and remeshing with good blue-noise properties. Our approach is based on the farthest point optimization (FPO), a relaxation technique that generates high quality blue-noise point sets in 2D. We propose two important generalizations of the original FPO framework: adaptive sampling and sampling on surfaces. A simple and efficient algorithm for accelerating the FPO framework is also proposed. Experimental results show that the generalized FPO generates point sets with excellent blue-noise properties for adaptive and surface sampling. Furthermore, we demonstrate that our remeshing quality is superior to the current state-of-the art approaches. © 2014 The Eurographics Association and John Wiley & Sons Ltd.

  8. A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.

    Science.gov (United States)

    Sprovieri, T; Conforti, F L; Fiumara, A; Mazzei, R; Ungaro, C; Citrigno, L; Muglia, M; Arena, A; Quattrone, A

    2009-02-15

    Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.

  9. Visual impairment in FOXG1-mutated individuals and mice.

    Science.gov (United States)

    Boggio, E M; Pancrazi, L; Gennaro, M; Lo Rizzo, C; Mari, F; Meloni, I; Ariani, F; Panighini, A; Novelli, E; Biagioni, M; Strettoi, E; Hayek, J; Rufa, A; Pizzorusso, T; Renieri, A; Costa, M

    2016-06-02

    The Forkead Box G1 (FOXG1 in humans, Foxg1 in mice) gene encodes for a DNA-binding transcription factor, essential for the development of the telencephalon in mammalian forebrain. Mutations in FOXG1 have been reported to be involved in the onset of Rett Syndrome, for which sequence alterations of MECP2 and CDKL5 are known. While visual alterations are not classical hallmarks of Rett syndrome, an increasing body of evidence shows visual impairment in patients and in MeCP2 and CDKL5 animal models. Herein we focused on the functional role of FOXG1 in the visual system of animal models (Foxg1(+/Cre) mice) and of a cohort of subjects carrying FOXG1 mutations or deletions. Visual physiology of Foxg1(+/Cre) mice was assessed by visually evoked potentials, which revealed a significant reduction in response amplitude and visual acuity with respect to wild-type littermates. Morphological investigation showed abnormalities in the organization of excitatory/inhibitory circuits in the visual cortex. No alterations were observed in retinal structure. By examining a cohort of FOXG1-mutated individuals with a panel of neuro-ophthalmological assessments, we found that all of them exhibited visual alterations compatible with high-level visual dysfunctions. In conclusion our data show that Foxg1 haploinsufficiency results in an impairment of mouse and human visual cortical function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons

    Science.gov (United States)

    Griesi-Oliveira, Karina; Acab, Allan; Gupta, Abha R.; Sunaga, Daniele Yumi; Chailangkarn, Thanathom; Nicol, Xavier; Nunez, Yanelli; Walker, Michael F.; Murdoch, John D.; Sanders, Stephan J.; Fernandez, Thomas V.; Ji, Weizhen; Lifton, Richard P.; Vadasz, Estevão; Dietrich, Alexander; Pradhan, Dennis; Song, Hongjun; Ming, Guo-li; Guoe, Xiang; Haddad, Gabriel; Marchetto, Maria C. N.; Spitzer, Nicholas; Passos-Bueno, Maria Rita; State, Matthew W.; Muotri, Alysson R.

    2014-01-01

    An increasing number of genetic variants have been implicated in autism spectrum disorders (ASD), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, iPSC-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology, and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with IGF1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway might benefit from these drugs. We also demonstrate that MeCP2 levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells. PMID:25385366

  11. [Dancing with Pointe Shoes: Characteristics and Assessment Criteria for Pointe Readiness].

    Science.gov (United States)

    Wanke, Eileen M; Exner-Grave, Elisabeth

    2017-12-01

    Training with pointe shoes is an integral part of professional dance education and ambitious hobby dancing. Pointe shoes - developed more than hundred years ago and almost unaltered since then - are highly specific and strike a balance between aesthetics, function, protection, and health care. Therefore, pointe readiness should be tested prior to all dance training or career training. Medical specialists are often confronted with this issue. Specific anatomical dance technique-orientated general conditional and coordinative preconditions as well as dance-technical prerequisites must be met by pointe readiness tests in order to keep traumatic injuries or long-term damage at a minimum. In addition to a (training) history, medical counselling sessions have come to include various tests that enable a reliable decision for or against pointe work. This article suggests adequate testing procedures (STT TEST), taking account of professional dancing as well as hobby dancing. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Appropriate neck circumference cut-off points for metabolic syndrome in Turkish patients with type 2 diabetes.

    Science.gov (United States)

    Ozkaya, Ismail; Yardimci, Bulent; Tunckale, Aydin

    2017-12-01

    To investigate the association between neck circumference (NC), overweight, and metabolic syndrome (MS) in Turkish patients with type 2 diabetes. A total of 264 diabetic patients (mean age: 52.9±8.1 years) were recruited from two centers in Istanbul to perform anthropometric measurements, including waist and hip circumference, NC, and body mass index. Blood pressure, fasting glucose, and lipid profile (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels) were determined. NC correlated with waist circumference, systolic blood pressure, and triglycerides in men, whereas NC only correlated with waist circumference in women. Additionally, NC was shown to negatively correlate with high-density lipoprotein cholesterol in both men and women. Receiver operating characteristic analysis showed that the area under the curve for NC and overweight was 0.95 for both men and women (P<0.001). Moreover, a NC of 38cm for men and 37cm for women was the best cut-off point for determining overweight. The area under the curve for NC and MS was 0.87 for men and 0.83 for women (P<0.001). A NC of 39cm for men and 37cm for women was the best cut-off point to determine participants with MS. Our findings suggest a positive correlation of NC with MetS in Turkish patients with type 2 diabetes, and could be a useful and accurate tool to identify MS. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. Reprogramming to pluripotency can conceal somatic cell chromosomal instability.

    Directory of Open Access Journals (Sweden)

    Masakazu Hamada

    Full Text Available The discovery that somatic cells are reprogrammable to pluripotency by ectopic expression of a small subset of transcription factors has created great potential for the development of broadly applicable stem-cell-based therapies. One of the concerns regarding the safe use of induced pluripotent stem cells (iPSCs in therapeutic applications is loss of genomic integrity, a hallmark of various human conditions and diseases, including cancer. Structural chromosome defects such as short telomeres and double-strand breaks are known to limit reprogramming of somatic cells into iPSCs, but whether defects that cause whole-chromosome instability (W-CIN preclude reprogramming is unknown. Here we demonstrate, using aneuploidy-prone mouse embryonic fibroblasts (MEFs in which chromosome missegregation is driven by BubR1 or RanBP2 insufficiency, that W-CIN is not a barrier to reprogramming. Unexpectedly, the two W-CIN defects had contrasting effects on iPSC genomic integrity, with BubR1 hypomorphic MEFs almost exclusively yielding aneuploid iPSC clones and RanBP2 hypomorphic MEFs karyotypically normal iPSC clones. Moreover, BubR1-insufficient iPSC clones were karyotypically unstable, whereas RanBP2-insufficient iPSC clones were rather stable. These findings suggest that aneuploid cells can be selected for or against during reprogramming depending on the W-CIN gene defect and present the novel concept that somatic cell W-CIN can be concealed in the pluripotent state. Thus, karyotypic analysis of somatic cells of origin in addition to iPSC lines is necessary for safe application of reprogramming technology.

  14. Penggunaan Media Presentase Microsoft Power Point Untuk Meningkatkan Hasil Belajar IPS Terpadu Pada Siswa Kelas VIII a SMP Negeri 2 Tanantovea

    OpenAIRE

    Hitler, Ahmad

    2014-01-01

    Permasalahan yang diangkat dalam penelitian adalah apakah dengan penggunaan media Presentase Microsoft Power Point pada mata pembelajaran IPS Terpadu dapat meningkatkan hasil belajar siswa kelas VIII A di SMP Negeri 2 Tanantovea. Penelitian ini bertujuan untuk meningkatkan hasil belajar siswa pada pokok bahasan Kolonialisme dan Imperialisme Barat di kelas VIII A SMP Negeri 2 Tanantovea. Penelitian ini dilakukan dalam 2 siklus, setiap siklus terdiri dari perencanaan, pelaksanaan tindakan, obs...

  15. Modeling for analysis of the effect of Young's modulus on soft active hydrogels subject to pH stimulus

    International Nuclear Information System (INIS)

    Li Hua; Ng, Teng Yong; Yew, Yong Kin

    2009-01-01

    Modeling is conducted in this paper for analysis of the influence of Young's modulus on the response of soft active hydrogels to environmental solution pH changes. A chemo–electro–mechanical formulation termed the multi-effect-coupling pH-stimulus (MECpH) model, which was developed previously according to linear elastic theory for small deformation description, is improved in this paper through incorporation of the finite deformation formulation into the mechanical equilibrium equation. The model is expressed by coupled nonlinear partial differential equations and solved via the meshless Hermite-cloud method with the modified Newton iteration technique. The improved MECpH model is examined by comparison between the computational and published experimental results. Numerical studies are then done on the influence of Young's modulus on the distributive variations of the diffusive ion concentrations and electric potential, and on the deformation variations of the pH-stimulus-responsive hydrogels within different buffered solutions

  16. On the regularization of extremal three-point functions involving giant gravitons

    Directory of Open Access Journals (Sweden)

    Charlotte Kristjansen

    2015-11-01

    Full Text Available In the AdS5/CFT4 set-up, extremal three-point functions involving two giant 1/2 BPS gravitons and one point-like 1/2 BPS graviton, when calculated using semi-classical string theory methods, match the corresponding three-point functions obtained in the tree-level gauge theory. The string theory computation relies on a certain regularization procedure whose justification is based on the match between gauge and string theory. We revisit the regularization procedure and reformulate it in a way which allows a generalization to the ABJM set-up where three-point functions of 1/2 BPS operators are not protected and where a match between tree-level gauge theory and semi-classical string theory is hence not expected.

  17. Comparison of Dose When Prescribed to Point A and Point H for Brachytherapy in Cervical Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gang, Ji Hyeong; Gim, Il Hwan; Hwang, Seon Boong; Kim, Woong; Im, Hyeong Seo; Gang, Jin Mook; Gim, Gi Hwan; Lee, Ah Ram [Dept. of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seou (Korea, Republic of)

    2012-09-15

    The purpose of this study is to compare plans prescribed to point A with these prescribed to point H recommended by ABS (American Brachytherapy Society) in high dose rate intracavitary brachytherapy for cervical carcinoma. This study selected 103 patients who received HDR (High Dose Rate) brachytherapy using tandem and ovoids from March 2010 to January 2012. Point A, bladder point, and rectal point conform with Manchester System. Point H conforms with ABS recommendation. Also Sigmoid colon point, and vagina point were established arbitrarily. We examined distance between point A and point H. The percent dose at point A was calculated when 100% dose was prescribed to point H. Additionally, the percent dose at each reference points when dose is prescribed to point H and point A were calculated. The relative dose at point A was lower when point H was located inferior to point A. The relative doses at bladder, rectal, sigmoid colon, and vagina points were higher when point H was located superior to point A, and lower when point H was located inferior to point A. This study found out that as point H got located much superior to point A, the absorbed dose of surrounding normal organs became higher, and as point H got located much inferior to point A, the absorbed dose of surrounding normal organs became lower. This differences dose not seem to affect the treatment. However, we suggest this new point is worth being considered for the treatment of HDR if dose distribution and absorbed dose at normal organs have large differences between prescribed to point A and H.

  18. Performances improvement of maximum power point tracking perturb and observe method

    Energy Technology Data Exchange (ETDEWEB)

    Egiziano, L.; Femia, N.; Granozio, D.; Petrone, G.; Spagnuolo, G. [Salermo Univ., Salermo (Italy); Vitelli, M. [Seconda Univ. di Napoli, Napoli (Italy)

    2006-07-01

    Perturb and observe best operation conditions were investigated in order to identify edge efficiency performance capabilities of a maximum power point (MPP) tracking technique for photovoltaic (PV) applications. The strategy was developed to ensure a 3-points behavior across the MPP under a fixed irradiation level with a central point blocked on the MPP and 2 operating points operating at voltage values that guaranteed the same power levels. The system was also devised to quickly detect the MPP movement in the presence of varying atmospheric conditions by increasing the perturbation so that the MPP was guaranteed within a few sampling periods. A perturbation equation was selected where amplitude was represented as a function of the actual power drawn from the PV field together with the adoption of a parabolic interpolation of the sequence of the final 3 acquired voltage power couples corresponding to as many operating points. The technique was developed to ensure that the power difference between 2 consecutive operating points was higher than the power quantization error. Simulations were conducted to demonstrate that the proposed technique arranged operating points symmetrically around the MPP. The average power of the 3-points set was achieved by means of the parabolic prediction. Experiments conducted to validate the simulation showed a reduced power oscillation below the MPP and a real power gain. 2 refs., 8 figs.

  19. Robust tie points selection for InSAR image coregistration

    Science.gov (United States)

    Skanderi, Takieddine; Chabira, Boulerbah; Afifa, Belkacem; Belhadj Aissa, Aichouche

    2013-10-01

    Image coregistration is an important step in SAR interferometry which is a well known method for DEM generation and surface displacement monitoring. A practical and widely used automatic coregistration algorithm is based on selecting a number of tie points in the master image and looking for the correspondence of each point in the slave image using correlation technique. The characteristics of these points, their number and their distribution have a great impact on the reliability of the estimated transformation. In this work, we present a method for automatic selection of suitable tie points that are well distributed over the common area without decreasing the desired tie points' number. First we select candidate points using Harris operator. Then from these points we select tie points depending on their cornerness measure (the highest first). Once a tie point is selected, its correspondence is searched for in the slave image, if the similarity measure maximum is less than a given threshold or it is at the border of the search window, this point is discarded and we proceed to the next Harris point, else, the cornerness of the remaining candidates Harris points are multiplied by a spatially radially increasing function centered at the selected point to disadvantage the points in a neighborhood of a radius determined from the size of the common area and the desired number of points. This is repeated until the desired number of points is selected. Results of an ERS1/2 tandem pair are presented and discussed.

  20. Naïve Point Estimation

    Science.gov (United States)

    Lindskog, Marcus; Winman, Anders; Juslin, Peter

    2013-01-01

    The capacity of short-term memory is a key constraint when people make online judgments requiring them to rely on samples retrieved from memory (e.g., Dougherty & Hunter, 2003). In this article, the authors compare 2 accounts of how people use knowledge of statistical distributions to make point estimates: either by retrieving precomputed…