WorldWideScience

Sample records for large fmr1 premutation

  1. Phenobarbital use and neurological problems in FMR1 premutation carriers

    Science.gov (United States)

    Saldarriaga, Wilmar; Lein, Pamela; Teshima, Laura Yuriko González; Isaza, Carolina; Rosa, Lina; Polyak, Andrew; Hagerman, Randi; Girirajan, Santhosh; Silva, Marisol; Tassone, Flora

    2016-01-01

    Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a CGG expansion in the FMR1 gene located at Xq27.3. Patients with the premutation in FMR1 present specific clinical problems associated with the number of CGG repeats (55–200 CGG repeats). Premutation carriers have elevated FMR1 mRNA expression levels, which have been associated with neurotoxicity potentially causing neurodevelopmental problems or neurological problems associated with aging. However, cognitive impairments or neurological problems may also be related to increased vulnerability of premutation carriers to neurotoxicants, including phenobarbital. Here we present a study of three sisters with the premutation who were exposed differentially to phenobarbital therapy throughout their lives, allowing us to compare the neurological effects of this drug in these patients. PMID:26802682

  2. Phenobarbital use and neurological problems in FMR1 premutation carriers.

    Science.gov (United States)

    Saldarriaga, Wilmar; Lein, Pamela; González Teshima, Laura Yuriko; Isaza, Carolina; Rosa, Lina; Polyak, Andrew; Hagerman, Randi; Girirajan, Santhosh; Silva, Marisol; Tassone, Flora

    2016-03-01

    Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a CGG expansion in the FMR1 gene located at Xq27.3. Patients with the premutation in FMR1 present specific clinical problems associated with the number of CGG repeats (55-200 CGG repeats). Premutation carriers have elevated FMR1 mRNA expression levels, which have been associated with neurotoxicity potentially causing neurodevelopmental problems or neurological problems associated with aging. However, cognitive impairments or neurological problems may also be related to increased vulnerability of premutation carriers to neurotoxicants, including phenobarbital. Here we present a study of three sisters with the premutation who were exposed differentially to phenobarbital therapy throughout their lives, allowing us to compare the neurological effects of this drug in these patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. PSP-CBS with Dopamine Deficiency in a Female with a FMR1 Premutation.

    Science.gov (United States)

    Paucar, Martin; Beniaminov, Stanislav; Paslawski, Wojciech; Svenningsson, Per

    2016-10-01

    Premutations in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (POI). Female FMR1 premutation carriers rarely develop motor features. Dual pathology is an emerging phenomenon among FMR1 premutation carriers. Here, we describe a family affected by FMR1-related disorders in which the female index case has developed a rapidly progressive and disabling syndrome of atypical parkinsonism. This syndrome consists of early onset postural instability, echolalia, dystonia, and varying types of apraxia like early onset orobuccal apraxia and oculomotor apraxia. She has also developed supranuclear gaze palsy, increased latency of saccade initiation, and slow saccades. These features are compatible with progressive supranuclear palsy (PSP) of a corticobasal syndrome (CBS) variant. Imaging displays a marked reduction of presynaptic dopaminergic uptake and cerebrospinal fluid analysis showed reduced dopamine metabolism; however, the patient is unresponsive to levodopa. Midbrain atrophy ("hummingbird sign") and mild cerebellar atrophy were found on brain MRI. Her father was affected by a typical FXTAS presentation but also displayed dopamine deficiency along with the hummingbird sign. The mechanisms by which FMR1 premutations predispose to atypical parkinsonism and dopamine deficiency await further elucidation.

  4. High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene.

    Science.gov (United States)

    Kenna, Heather A; Tartter, Molly; Hall, Scott S; Lightbody, Amy A; Nguyen, Quynh; de los Angeles, C Paula; Reiss, Allan L; Rasgon, Natalie L

    2013-12-01

    Phenotypic variations are emerging from investigations of carriers of the fragile X mental retardation 1 (FMR1) premutation gene (55 to 200 CGG repeats). Initial studies suggest elevated psychiatric and reproductive system dysfunction, but have largely used self-reports for assessment of psychiatric history. The present study used diagnostic psychiatric interviews and assessed reproductive and menstrual history in women with FMR1 premutation. History of psychiatric diagnoses and data on reproductive functioning were collected in 46 women with FMR1 premutation who were mothers of at least one child with the fragile X full mutation. Results showed a significantly earlier age of menopause (mean age = 45.6 years) relative to the national average age of menopause (mean age = 51 years) and a high rate (76%) of lifetime depressive or anxiety history, with 43% of the overall sample reporting a comorbid history of both diagnoses. Compared to those free of psychiatric history, significantly longer premutation length was observed among women with psychiatric history after adjusting for age, with comorbid women having the highest number of CGG repeats (mean = 95.8) compared to women free of psychiatric history (mean = 79.9). Psychiatric history did not appear significantly related to reproductive system dysfunction, though results may have been obscured by the high rates of psychiatric dysfunction in the sample. These data add to the growing evidence base that women with the FMR1 premutation have an increased risk of psychiatric illness and risk for early menopause. Future investigations may benefit from inclusion of biochemical reproductive markers and longitudinal assessment of psychiatric and reproductive functioning.

  5. Ovarian dysfunction and FMR1 alleles in a large Italian family with POF and FRAXA disorders: case report

    Directory of Open Access Journals (Sweden)

    D'Urso Michele

    2007-04-01

    Full Text Available Abstract Background The association between premature ovarian failure (POF and the FMR1 repeat number (41> CGGnFMR1 alleles. Case presentation We describe the coexistence in a large Italian kindred of Fragile X syndrome and familial POF in females with ovarian dysfunctions who carried normal or expanded FMR1 alleles. Genetic analysis of the FMR1 gene in over three generations of females revealed that six carried pre-mutated alleles (61–200, of which two were also affected by POF. However a young woman, who presented a severe ovarian failure with early onset, carried normal FMR1 alleles ( Conclusion Our case study represents a helpful observation and will provide familial cases with heterogeneous etiology that could be further studied when candidate genes in addition to the FMR1 premutation will be available.

  6. The effects of optimism, religion, and hope on mood and anxiety disorders in women with the FMR1 premutation.

    Science.gov (United States)

    Lowell, E P; Tonnsen, B L; Bailey, D B; Roberts, J E

    2017-10-01

    The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort. Eighty-three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM-IV-TR Disorders at two-time points, 3 years apart. Participants also completed measures of optimism, religion, personal faith, hope, and child and family characteristics. We used logistic regression to examine correlates of major depressive disorder (MDD) and anxiety disorders at the initial assessment, as well as predictors of the diagnostic course over time. Lower optimism and higher religious participation relevant to fragile X syndrome at the initial assessment were associated with a lifetime history of MDD. Lower optimism also predicted the occurrence and reoccurrence of an anxiety disorder 3 years later. In women with the FMR1 premutation, elevated optimism may reduce the occurrence or severity of MDD and anxiety disorders. These findings underscore the importance of supporting mental health across the FMR1 spectrum of involvement. © 2017 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

  7. Pragmatic Language Features of Mothers with the "FMR1" Premutation Are Associated with the Language Outcomes of Adolescents and Young Adults with Fragile X Syndrome

    Science.gov (United States)

    Klusek, Jessica; McGrath, Sara E.; Abbeduto, Leonard; Roberts, Jane E.

    2016-01-01

    Purpose: Pragmatic language difficulties have been documented as part of the FMR1 premutation phenotype, yet the interplay between these features in mothers and the language outcomes of their children with fragile X syndrome is unknown. This study aimed to determine whether pragmatic language difficulties in mothers with the "FMR1"…

  8. Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Battistella, Giovanni; Niederhauser, Julien; Fornari, Eleonora; Hippolyte, Loyse; Gronchi Perrin, Aline; Lesca, Gaetan; Forzano, Francesca; Hagmann, Patric; Vingerhoets, Francois J G; Draganski, Bogdan; Maeder, Philippe; Jacquemont, Sébastien

    2013-06-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.

  9. Mapping Self-Reports of Working Memory Deficits to Executive Dysfunction in Fragile X Mental Retardation 1 ("FMR1") Gene Premutation Carriers Asymptomatic for FXTAS

    Science.gov (United States)

    Kogan, Cary S.; Cornish, Kim M.

    2010-01-01

    Fragile X Syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation 1 ("FMR1") gene. In recent years, the premutation ("carrier") status has received considerable attention and there is now an emerging consensus that despite intellectual functioning being within…

  10. Pragmatic Language Features of Mothers With the FMR1 Premutation Are Associated With the Language Outcomes of Adolescents and Young Adults With Fragile X Syndrome

    Science.gov (United States)

    McGrath, Sara E.; Abbeduto, Leonard; Roberts, Jane E.

    2016-01-01

    Purpose Pragmatic language difficulties have been documented as part of the FMR1 premutation phenotype, yet the interplay between these features in mothers and the language outcomes of their children with fragile X syndrome is unknown. This study aimed to determine whether pragmatic language difficulties in mothers with the FMR1 premutation are related to the language development of their children. Method Twenty-seven mothers with the FMR1 premutation and their adolescent/young adult sons with fragile X syndrome participated. Maternal pragmatic language violations were rated from conversational samples using the Pragmatic Rating Scale (Landa et al., 1992). Children completed standardized assessments of vocabulary, syntax, and reading. Results Maternal pragmatic language difficulties were significantly associated with poorer child receptive vocabulary and expressive syntax skills, with medium effect sizes. Conclusions This work contributes to knowledge of the FMR1 premutation phenotype and its consequences at the family level, with the goal of identifying modifiable aspects of the child's language-learning environment that may promote the selection of treatments targeting the specific needs of families affected by fragile X. Findings contribute to our understanding of the multifaceted environment in which children with fragile X syndrome learn language and highlight the importance of family-centered intervention practices for this group. PMID:26895548

  11. Mapping Self-Reports of Working Memory Deficits to Executive Dysfunction in Fragile X Mental Retardation 1 ("FMR1") Gene Premutation Carriers Asymptomatic for FXTAS

    Science.gov (United States)

    Kogan, Cary S.; Cornish, Kim M.

    2010-01-01

    Fragile X Syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation 1 ("FMR1") gene. In recent years, the premutation ("carrier") status has received considerable attention and there is now an emerging consensus that despite intellectual functioning being within…

  12. Health and reproductive experiences of women with an FMR1 premutation with and without fragile X premature ovarian insufficiency

    Directory of Open Access Journals (Sweden)

    Anne Caroline Wheeler

    2014-09-01

    Full Text Available Recently, research has indicated an increased risk for greater medical and emotional comorbidity and physical health symptoms among women with an FMR1 expansion. However, these studies have generally been limited in their ability to model multiple risk factors associated with these symptoms by small numbers (n = 112 to 146 of participants. This study used survey methodology to examine the health experiences of 458 adult women with the premutation with and without a history of an FXPOI diagnosis. Results suggest similar findings to those reported in the literature with regard to the frequency of medical, emotional, and reproductive experiences of women with the premutation. In addition to expected reproductive differences, women with a diagnosis of FXPOI were also more likely to experience dizziness, nausea, and muscle weakness than women without a diagnosis of FXPOI. Women with and without FXPOI were more likely to have used reproductive assistance and were more likely to have experienced preeclampsia during at least one pregnancy than is reported in the general population. Having comorbid depression and anxiety was predictive of increased medical conditions and increased daily physical health symptoms.

  13. A Quantitative Assessment of Tremor and Ataxia in Female FMR1 Premutation Carriers Using CATSYS

    Directory of Open Access Journals (Sweden)

    Vivien Narcisa

    2011-01-01

    Full Text Available The fragile X-associated tremor/ataxia syndrome (FXTAS is a relatively common cause of balance problems leading to gait disturbances in older males (40% with the premutation. FXTAS is less common in females. We utilized the CATSYS system, a quantitative measure of movement, in 23 women with FXTAS (mean age 62.7; SD 12.3, 90 women with the premutation without FXTAS (mean age 52.9; SD 9.4, and 37 controls (mean age 56.53; SD 7.8. CATSYS distinguished differences between carriers with and without FXTAS in postural tremor, postural sway, hand coordination, and reaction time tasks. Differences were also seen between carriers without FXTAS and controls in finger tapping, reaction time, and one postural sway task. However, these differences did not persist after statistical correction for multiple comparisons. Notably, there were no differences across groups in intention tremor. This is likely due to the milder symptoms in females compared to males with FXTAS.

  14. Hypertension in FMR1 Premutation Males With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

    OpenAIRE

    Hamlin, Alyssa A.; Sukharev, Dina; Campos, Luis; Mu, Yi; Tassone, Flora; Hessl, David; Nguyen, Danh V.; Loesch, Danuta; Hagerman, Randi J.

    2012-01-01

    Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected ...

  15. Depression and anxiety symptoms among women who carry the FMR1 premutation: impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms.

    Science.gov (United States)

    Hunter, Jessica Ezzell; Leslie, Mary; Novak, Gloria; Hamilton, Debra; Shubeck, Lisa; Charen, Krista; Abramowitz, Ann; Epstein, Michael P; Lori, Adriana; Binder, Elisabeth; Cubells, Joseph F; Sherman, Stephanie L

    2012-07-01

    The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5'-untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55-199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self-report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State-Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation.

  16. Premutation in the Fragile X Mental Retardation 1 (FMR1 Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding

    Directory of Open Access Journals (Sweden)

    Eleonora eNapoli

    2016-04-01

    Full Text Available Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn homeostasis has been reported in fibroblasts from > 60 y old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3 in a knock-in (KI premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression in KI mice and human fibroblasts from carriers of the pre- and full mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210. A strong genotype x age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type x genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as

  17. Associated Clinical Disorders Diagnosed by Medical Specialists in 188 FMR1 Premutation Carriers Found in the Last 25 Years in the Spanish Basque Country: A Retrospective Study

    Science.gov (United States)

    Merino, Sonia; Ibarluzea, Nekane; Maortua, Hiart; Prieto, Begoña; Rouco, Idoia; López-Aríztegui, Maria-Asunción; Tejada, Maria-Isabel

    2016-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are definitely related to the fragile X mental retardation 1 (FMR1) premutation (PM). Additional medical problems have also been associated with the PM, such as fibromyalgia, endocrine, and psychiatric disorders. To improve our understanding in the field, we reviewed all PM carriers and their reasons for any medical referrals from 104 fragile X families molecularly diagnosed in our laboratory and living in the Spanish Basque Country. After signing the written informed consent, we studied their electronic medical records in order to identify the disorders associated with the PM and their frequencies. We obtained clinical data in 188 PM carriers (147 women and 41 men). In women, the frequency of FXPOI (22.61%) was similar to that previously reported in PM carriers. In men, the frequency of definite FXTAS (28.57%) was lower than reported elsewhere. Furthermore, thyroid pathology was associated with the PM, the frequency of hypothyroidism being much higher in the studied region than in the general population (8.84% vs. 0.93%). Finally, we found no association with fibromyalgia or psychiatric problems. These findings represent another population contribution in this field and may be useful for the clinical management of PM carriers. PMID:27775646

  18. The number of CGG repeats of the FMR1 locus in premutated and fully mutated heterozygotes and their offspring: Implications for the origin of mosaicism

    Energy Technology Data Exchange (ETDEWEB)

    Mingroni-Netto, R.C.; Vianna-Morgante, A.M. [Universidade de Sao Paulo (Brazil); Haddad, L.A. [Universidade Federal de Minas Gerais (Brazil)

    1996-08-09

    The size of the CGG repeat of the FMRl gene was investigated with probe StB12.3 in 154 transmissions to the offspring of heterozygotes for the premutation and the full mutation. Among the 135 offspring of premutated heterozygotes there were three decreases in size of the repeats: in two of these cases a full mutation was present along with the decreased premutation, and in a third mosaic (46,fra(X)(q27.3),Y), a normal allele was observed. In the 19 offspring of fully mutated females with no detected mosaicism, there were three mosaics and three individuals who had full mutations that included a number of repeats smaller than those present in their mothers. Among the 32 offspring who received a premutation from their premutated mothers, 27 alleles were increased in size and 5 remained unaltered. Among 11 mosaic offspring of premutated mothers, the premutation increased in 4, decreased in 3, and was unchanged in 4. In contrast to the trend of an increasing premutation size in the non-mosaic offspring, the premutation present in mosaics can be smaller, larger, or of unaltered size with approximately equal frequencies. These data suggest that the premutations present in mosaics result from mitotic instability of the inherited full mutations. This is further supported by the finding of a mosaic male with a normal sized allele. 17 refs., 3 figs., 1 tab.

  19. Segregation of the fragile X mutation from a male with a full mutation: Unusual somatic instability in the FMR-1 locus

    Energy Technology Data Exchange (ETDEWEB)

    Kambouris, M.; Bluhm, D.; Feldman, G.L. [Henry Ford Hospital, Detroit, MI (United States)] [and others

    1996-08-09

    Fragile X syndrome is associated with an unstable CGG-repeat in the FMR-1 gene. There are few reports of affected males transmitting the FMR-l gene to offspring. We report on a family in which the propositus and his twin sister each had a full mutation with abnormal methylation. Their mother had an FMR-1 allele in the normal range and a large premutation, with normal methylation. The maternal grandmother had two normal FMR-1 alleles. The maternal grandfather had an unusual somatic FMR-1 pattern, with allele size ranging from premutation to full mutation. No allele was detectable by PCR analysis. Multiple Southern blot analyses identified a hybridization pattern that originated at a distinct premutation band and extended into the full mutation range. Methylation studies revealed a mosaic pattern with both unmethylated premutations and methylated full mutations. This individual declined formal evaluation but did not finish high school and has difficulty in reading and writing. The size of the premutation FMR-1 allele passed to his daughter is larger than his most prominent premutation allele. This is most likely due to gonadal mosaicism similar to that in his peripheral lymphocytes. Alternatively, this expansion event may have occurred during his daughter`s early embryonic development and this large premutation allele is mitotically unstable. This pattern of FMR-1 alleles in a presumably mildly affected male is highly unusual. These findings are consistent with the absence of transmission of a full fragile X mutation through an expressing male. Studies of tissue-specific FMR-1 allele expansion and FMR-1 protein expression on this individual should help to determine the correlation of the molecular findings with the phenotypic effects. 18 refs., 2 figs.

  20. Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome.

    Science.gov (United States)

    Napoli, Eleonora; Song, Gyu; Wong, Sarah; Hagerman, Randi; Giulivi, Cecilia

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.

  1. Correlation of normal-range FMR1 repeat length or genotypes and reproductive parameters.

    Science.gov (United States)

    Maslow, Bat-Sheva L; Davis, Stephanie; Engmann, Lawrence; Nulsen, John C; Benadiva, Claudio A

    2016-09-01

    This study aims to ascertain whether the length of normal-ranged CGG repeats on the FMR1 gene correlates with abnormal reproductive parameters. We performed a retrospective, cross-sectional study of all FMR1 carrier screening performed as part of routine care at a large university-based fertility center from January 2011 to March 2014. Correlations were performed between normal-range FMR1 length and baseline serum anti-Müllerian hormone (AMH), cycle day 3 follicle stimulating hormone (FSH), ovarian volumes (OV), antral follicle counts (AFC), and incidence of diminished ovarian reserve (DOR), while controlling for the effect of age. Six hundred three FMR1 screening results were collected. One subject was found to be a pre-mutation carrier and was excluded from the study. Baseline serum AMH, cycle day 3 FSH, OV, and AFC data were collected for the 602 subjects with normal-ranged CGG repeats. No significant difference in median age was noted amongst any of the FMR1 repeat genotypes. No significant correlation or association was found between any allele length or genotype, with any of the reproductive parameters or with incidence of DOR at any age (p > 0.05). However, subjects who were less than 35 years old with low/low genotype were significantly more likely to have below average AMH levels compared to those with normal/normal genotype (RR 3.82; 95 % CI 1.38-10.56). This large study did not demonstrate any substantial association between normal-range FMR1 repeat lengths and reproductive parameters.

  2. Methylization analysis of the FMR1 gene in carrier females

    Energy Technology Data Exchange (ETDEWEB)

    Meyers, S.; Cappon, S.; Khalifa, M.M. [Kingston General Hospital (Canada)] [and others

    1994-09-01

    The fragile X syndrome mutation is associated with an expansion of a CGG repeat sequence and methylation of the CpG island in the promoter of the FMR1 gene. Methylation of the CpG island silences the FMR1 gene, thereby generating the disease phenotypes. Previous studies suggest that the normal FMR1 gene has the properties of an X-linked housekeeping gene that is subject to X inactivation, i.e., its CpG island is unmethylated on the active X chromosome and methylated on the inactive X. Because methylation of the mutant FMR1 gene occurs in both males and females with the full mutation, inactivating the FMR1 gene in these females might be a localized event independent from X inactivation. To test this hypothesis we compared the methylation pattern of two housekeeping genes, PGK1 and androgen receptor (AR) with that of the FMR1 in 46 female carriers of the fragile X syndrome. Twenty eight females were in the premutation range (63-193 repeats) and 16 were carriers of the full mutation (263-996 repeats). The data revealed complete correlation between the methylation pattern of PGK1 and AR. There was also a close correlation between X inactivation pattern detected by PGK1 and/or AR and that detected by FMR1 in female carriers of the premutation. In all female carriers of the full mutation there was complete methylation of the BssHII site in the expanded FMR1 allele. The X chromosome inactivation pattern in these females as detected by PGK1 and/or AR was as follows: in 10 cases the X inactivation was skewed in favor of the mutant FMR1, i.e. the mutant allele was on the inactive X chromosome, in 3 the inactivation was random and in 3 the inactivation was skewed in favor of the normal allele. These data suggest that the methylation of the FMR1 gene in females with the full mutation is a localized event and methylation of the FMR1 gene in these females cannot be used as a predictor of X inactivation.

  3. Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population

    Energy Technology Data Exchange (ETDEWEB)

    Snow, K.; Doud, L.K.; Thibodeau, S.N. (Mayo Clinic and Foundation, Rochester, MN (United States)); Hagerman, R. (Denver Children' s Hospital, CO (United States)); Pergolizzi, R.G.; Erster, S.H. (North Shore University Hospital, Manhasset, NY (United States))

    1993-12-01

    In this study, the authors have characterized a CGG repeat at the FMR-1 locus in more than 100 families (more than 500 individuals) presenting for fragile X testing and in 247 individuals from the general population. Both Southern blot and PCR-based assays were evaluated for their ability to detect premutations, full mutations, and variability in normal allele sizes. Among the Southern blot assays, the probes Ox1.09 or StB12.3 with a double restriction-enzyme digest were the most sensitive in detecting both small and large amplifications and, in addition, provided information on methylation of an adjacent CpG island. In the PCR-based assays, analysis of PCR products on denaturing DNA sequencing gels allowed the most accurate determination of CGG repeat number up to approximately 130 repeats. A combination of a Southern blot assay with a double digest and the PCR-sequencing-gel assay detected the spectrum of amplification-type mutations at the FMR-1 locus. In the patient population, a CGG repeat of 51 was the largest to be stably inherited, and a repeat of 57 was the smallest size of premutation to be unstably inherited. When premutations were transmitted by females, the size of repeat correlated with risk of expansion to a full mutation in the next generation. Full mutations (large repeats typically associated with an abnormal methylation pattern and mitotic instability) were associated with clinical and cytogenetic manifestations in males but not necessarily in females. In the control population, the CGG repeat changed from 13 to 61, but 94% of alleles had fewer than 40 repeats. The most frequent allele (34%) was a repeat of 30. One female had an allele (61 repeats) within a range consistent with fragile X premutations, while two other individuals each had a repeat of 52. This suggests that the frequency of unstable alleles in the general population may be [approximately]1%. 34 refs., 5 figs., 3 tabs.

  4. Distribution of FMR1 and FMR2 Repeats in Argentinean Patients with Primary Ovarian Insufficiency

    Science.gov (United States)

    Espeche, Lucía Daniela; Chiauzzi, Violeta; Ferder, Ianina; Arrar, Mehrnoosh; Solari, Andrea Paula; Bruque, Carlos David; Delea, Marisol; Belli, Susana; Fernández, Cecilia Soledad; Buzzalino, Noemí Delia; Charreau, Eduardo Hernán; Dain, Liliana Beatriz

    2017-01-01

    The premutation state of FMR1 (Fragile X Mental Retardation 1) has been associated with primary ovarian insufficiency (POI), and is the most common known genetic cause for 46,XX patients. Nevertheless, very few studies have analyzed its frequency in Latin American populations. Additionally, a relationship between alleles carrying a cryptic microdeletion in the 5’UTR of FMR2 and the onset of POI has only been studied in one population. Our aim was to analyze the incidence of FMR1 premutations and putative microdeletions in exon 1 of FMR2 in a cohort of Argentinean women with POI. We studied 133 patients and 84 controls. Fluorescent PCR was performed, and the FMR2 exon 1 was further sequenced in samples presenting less than 11 repeats. We found the frequency of FMR1 premutations to be 6.7% and 2.9% for familial and sporadic patients, respectively. Among controls, 1/84 women presented a premutation. In addition, although we did not find microdeletions in FMR2, we observed a change (T >C) adjacent to the repeats in two sisters with POI. Given the repetitive nature of the sequence involved, we could not ascertain whether this represents a single nucleotide polymorphism (SNP) or a deletion. Therefore, a relationship between FMR2 and POI could not be established for our population. PMID:28812997

  5. Clinical, molecular, and pharmacological aspects of FMR1 related disorders.

    Science.gov (United States)

    Pugin, A; Faundes, V; Santa María, L; Curotto, B; Aliaga, S; Salas, I; Soto, P; Bravo, P; Peña, M I; Alliende, M A

    2017-05-01

    Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Tissue-specific methylation differences and cognitive function in fragile X premutation females

    Energy Technology Data Exchange (ETDEWEB)

    Allingham-Hawkins, D.J.; Babul, R.; Chitayat, D. [Hospital for Sick Children, Toronto (Canada)] [and others

    1996-08-09

    Tissue-specific variation in (CGG){sub n} repeat size and methylation status of the FMR1 gene was investigated in 17 female premutation carriers. Minor variation in premutation repeat size among leukocyte, lymphoblast, and fibroblast tissues was noted in some subjects. One subject exhibited a premutation size allele of (CGG){sub 64} in leukocyte and fibroblast tissues by polymerase chain reaction analysis but a normal-size allele of (CGG){sub 46} in lymphoblast cells, suggesting low-level mosaicism in blood and clonality of the lymphoblast cell line. Six subjects exhibited differences in methylation pattern between leukocytes and lymphoblasts but not between leukocytes and fibroblasts, whereas 2 subjects showed large differences in methylation pattern between leukocytes and fibroblasts. Cognitive function was studied in 14 subjects using the Wechsler Adult Intelligence Scale-Revised. Mean Verbal and Performance IQs were well within the average range as was the mean Full Scale IQ; nevertheless, a trend toward lower Performance IQ compared with Verbal IQ was observed. No significant correlation was apparent between Full Scale IQ and (CGG){sub n} repeat size; however, a significant positive correlation was observed between Full Scale IQ and the proportion of the active X carrying the normal FMR1 allele in fibroblasts but not in leukocytes or lymphoblasts. 24 refs., 1 fig., 2 tabs.

  7. Low-Normal FMR1 CGG Repeat Length: Phenotypic Associations

    Directory of Open Access Journals (Sweden)

    Marsha eMailick

    2014-09-01

    Full Text Available This population-based study investigates genotype-phenotype correlations of low-normal CGG repeats in the fragile X mental retardation 1 (FMR1 gene. FMR1 plays an important role in brain development and function, and encodes FMRP (fragile X mental retardation protein, an RNA-binding protein that regulates protein synthesis impacting activity-dependent synaptic development and plasticity. Most past research has focused on CGG premutation expansions (41 to 200 CGG repeats and on fragile X syndrome (200+ CGG repeats, with considerably less attention on the other end of the spectrum of CGG repeats. Using existing data, older adults with 23 or fewer CGG repeats (2 SDs below the mean were compared with age-peers who have normal numbers of CGGs (24-40 with respect to cognition, mental health, cancer, and having children with disabilities. Men (n = 341 with an allele in the low-normal range and women (n = 46 with two low-normal alleles had significantly more difficulty with their memory and ability to solve day to day problems. Women with both FMR1 alleles in the low-normal category had significantly elevated odds of feeling that they need to drink more to get the same effect as in the past. These women also had two and one-half times the odds of having had breast cancer and four times the odds of uterine cancer. Men and women with low-normal CGGs had higher odds of having a child with a disability, either a developmental disability or a mental health condition. These findings are in line with the hypothesis that there is a need for tight neuronal homeostatic control mechanisms for optimal cognitive and behavioral functioning, and more generally that low numbers as well as high numbers of CGG repeats may be problematic for health.

  8. FMR1 alleles in Tasmania: a screening study of the special educational needs population.

    Science.gov (United States)

    Mitchell, R J; Holden, J J A; Zhang, C; Curlis, Y; Slater, H R; Burgess, T; Kirkby, K C; Carmichael, A; Heading, K D; Loesch, D Z

    2005-01-01

    The distribution of fragile X mental retardation-1 (FMR1) allele categories, classified by the number of CGG repeats, in the population of Tasmania was investigated in 1253 males with special educational needs (SEN). The frequencies of these FMR1 categories were compared with those seen in controls as represented by 578 consecutive male births. The initial screening was based on polymerase chain reaction analysis of dried blood spots. Inconclusive results were verified by Southern analysis of a venous blood sample. The frequencies of common FMR1 alleles in both samples, and of grey zone alleles in the controls, were similar to those in other Caucasian populations. Consistent with earlier reports, we found some (although insignificant) increase of grey zone alleles in SEN subjects compared with controls. The frequencies of predisposing flanking haplotypes among grey zone males FMR1 alleles were similar to those seen in other Caucasian SEN samples. Contrary to expectation, given the normal frequency of grey zone alleles, no premutation (PM) or full mutation (FM) allele was detected in either sample, with only 15 fragile X families diagnosed through routine clinical admissions registered in Tasmania up to 2002. An explanation of this discrepancy could be that the C19th founders of Tasmania carried few PM or FM alleles. The eight to ten generations since white settlement of Tasmania has been insufficient time for susceptible grey zone alleles to evolve into the larger expansions.

  9. A fragile X male with a broad smear on southern blot analysis representing 100-500 CGG repeats and no methylation at the EagI site of the FMR-1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Lachiewicz, A.M.; Spiridigliozzi, G.A.; McConkie-Rosell, A. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

    1996-08-09

    Fragile X DNA studies were carried out on all obligate carriers of a large fragile X family with 10 mentally retarded individuals. One 64-year-old carrier man with an altered FMR-1 allele was not described as being mentally retarded or as having any limitations in function. He was married, raised 8 children, and worked as an auto mechanic. On examination, he had macrocephaly and mild macroorchidism but few of the other typical physical findings of males with fragile X syndrome. His Full Scale IQ is 73, and his Vineland Adaptive Behavior Composite is 73. On the Woodcock-Johnson Psycho-Educational Battery-Revised, he achieved standard scores of 64 in Reading, 55 in Math, and 83 in Knowledge. His DNA findings showed a broad smear on Southern blot analysis of 100-500 CGG repeats and no methylation at the EagI site upstream of the FMR-1 protein coding region. His FMR-1 protein production is 12% of normal. His daughters all have large premutations, with somatic instability in the size of the CGG repeat lengths. They all have evidence of academic underachievement and 2 have physical characteristics frequently described in individuals with fragile X. 21 refs., 3 figs.

  10. Repeat-mediated epigenetic dysregulation of the FMR1 gene in the Fragile X-related disorders

    Directory of Open Access Journals (Sweden)

    Karen eUsdin

    2015-06-01

    Full Text Available The Fragile X-related disorders are members of the Repeat Expansion Diseases, a group of genetic conditions resulting from an expansion in the size of a tandem repeat tract at a specific genetic locus. The repeat responsible for disease pathology in the Fragile X-related disorders is CGG/CCG and the repeat tract is located in the 5’ UTR of the FMR1 gene, whose protein product FMRP, is important for the proper translation of dendritic mRNAs in response to synaptic activation. There are two different pathological FMR1 allele classes that are distinguished only by the number of repeats. Premutation alleles have 55-200 repeats and confer risk of Fragile X-associated tremor/ataxia syndrome and Fragile X-associated primary ovarian insufficiency. Full mutation alleles on the other hand have >200 repeats and result in Fragile X syndrome, a disorder that affects learning and behavior. Different symptoms are seen in carriers of premutation and full mutation alleles because the repeat number has paradoxical effects on gene expression: Epigenetic changes increase transcription from premutation alleles and decrease transcription from full mutation alleles. This review will cover what is currently known about the mechanisms responsible for these changes in FMR1 expression and how they may relate to other Repeat Expansion Diseases that also show repeat-mediated changes in gene expression.

  11. Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat.

    Science.gov (United States)

    Ferder, Ianina; Parborell, Fernanda; Sundblad, Victoria; Chiauzzi, Violeta; Gómez, Karina; Charreau, Eduardo H; Tesone, Marta; Dain, Liliana

    2013-04-01

    Fragile X mental retardation protein (FMRP) belongs to a small family of RNA-binding proteins. Its absence or inactivity is responsible for fragile X syndrome, the most common cause of inherited mental retardation. Despite its ubiquitous expression, FMRP function and expression remain almost understudied in non-neuronal tissues, though previous studies on germline development during oogenesis may suggest a special function of this protein also in ovarian tissue. In addition, the well-documented association of FMR1 premutation state with fragile X-related premature ovarian insufficiency adds interest to the role of FMRP in ovarian physiology. The aim of the present work was to investigate the expression of Fmr1 mRNA and its protein, FMRP, at different stages of rat follicular development. By immunohistochemical studies we demonstrated FMRP expression in granulosa, theca and germ cells in all stages of follicular development. In addition, changes in Fmr1 expression, both at the protein and mRNA levels, were observed. FMRP levels increased upon follicular development while preantral and early antral follicles presented similar levels of Fmr1 transcripts with decreased expression in preovulatory follicles. These observations suggest that Fmr1 expression in the ovary is regulated at different and perhaps independent levels. In addition, our results show expression of at least four different isoforms of FMRP during all stages of follicular growth with expression patterns that differ from those observed in brain and testis. Our study shows a regulated expression of Fmr1, both at mRNA and protein levels, during rat follicular development.

  12. Diagnostic, carrier and prenatal genetic testing for fragile X syndrome and other FMR-1-related disorders in Johannesburg, South Africa: a 20-year review.

    Science.gov (United States)

    Essop, Fahmida B; Krause, Amanda

    2013-10-11

    Fragile X syndrome (FXS), the most common inherited cause of intellectual disability (ID) worldwide, is caused by the expansion of a CGG repeat in the fragile X mental retardation gene (FMR-1) gene. OBJECTIVES; To review, retrospectively, the genetic services for FXS and other FMR-1-related disorders - including fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR-1-related primary ovarian insufficiency (POI) - at the Division of Human Genetics, Johannesburg, for diagnostic, carrier and prenatal genetic testing.Methods. The records of 2 690 patients with ID and suspected FXS (ID/?FXS) who had genetic testing for FMR-1 between 1992 and 2012 were reviewed. Of these, 2 239 had diagnostic testing, 430 carrier or cascade testing and 17 prenatal testing for FXS. Four had FXTAS or POI testing. Polymerase chain reaction (PCR) and/or Southern blotting techniques were used to test the patients' samples for FMR-1 and FMR-2 expansions. RESULTS; Of the 2 239 patients who had diagnostic testing, 128 (5.7%) had a full mutation, 12 (0.5%) had a premutation and 43 (1.9%) an intermediate allele. In 17 prenatal tests, eight fetuses tested positive for FXS. FMR-1 CGG repeat distribution analysis in 1 532 males negative for the FMR-1 expansion showed that 29 and 30 CGG repeats were the most common (61.1%), but distribution was significantly different in the black and white populations.CONCLUSION; The findings support the presence of FXS, as the most common cause of ID, in all local populations. The FMR-1 CGG repeat distribution varied from that found in other studies. The number of family members tested was relatively low suggesting that many at-risk individuals are not being referred.

  13. Role of CTCF protein in regulating FMR1 locus transcription.

    Directory of Open Access Journals (Sweden)

    Stella Lanni

    Full Text Available Fragile X syndrome (FXS, the leading cause of inherited intellectual disability, is caused by epigenetic silencing of the FMR1 gene, through expansion and methylation of a CGG triplet repeat (methylated full mutation. An antisense transcript (FMR1-AS1, starting from both promoter and intron 2 of the FMR1 gene, was demonstrated in transcriptionally active alleles, but not in silent FXS alleles. Moreover, a DNA methylation boundary, which is lost in FXS, was recently identified upstream of the FMR1 gene. Several nuclear proteins bind to this region, like the insulator protein CTCF. Here we demonstrate for the first time that rare unmethylated full mutation (UFM alleles present the same boundary described in wild type (WT alleles and that CTCF binds to this region, as well as to the FMR1 gene promoter, exon 1 and intron 2 binding sites. Contrariwise, DNA methylation prevents CTCF binding to FXS alleles. Drug-induced CpGs demethylation does not restore this binding. CTCF knock-down experiments clearly established that CTCF does not act as insulator at the active FMR1 locus, despite the presence of a CGG expansion. CTCF depletion induces heterochromatinic histone configuration of the FMR1 locus and results in reduction of FMR1 transcription, which however is not accompanied by spreading of DNA methylation towards the FMR1 promoter. CTCF depletion is also associated with FMR1-AS1 mRNA reduction. Antisense RNA, like sense transcript, is upregulated in UFM and absent in FXS cells and its splicing is correlated to that of the FMR1-mRNA. We conclude that CTCF has a complex role in regulating FMR1 expression, probably through the organization of chromatin loops between sense/antisense transcriptional regulatory regions, as suggested by bioinformatics analysis.

  14. Modeling fragile X syndrome in the Fmr1 knockout mouse.

    Science.gov (United States)

    Kazdoba, Tatiana M; Leach, Prescott T; Silverman, Jill L; Crawley, Jacqueline N

    2014-11-01

    Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS.

  15. Array-based FMR1 sequencing and deletion analysis in patients with a fragile X syndrome-like phenotype.

    Directory of Open Access Journals (Sweden)

    Stephen C Collins

    Full Text Available BACKGROUND: Fragile X syndrome (FXS is caused by loss of function mutations in the FMR1 gene. Trinucleotide CGG-repeat expansions, resulting in FMR1 gene silencing, are the most common mutations observed at this locus. Even though the repeat expansion mutation is a functional null mutation, few conventional mutations have been identified at this locus, largely due to the clinical laboratory focus on the repeat tract. METHODOLOGY/PRINCIPAL FINDINGS: To more thoroughly evaluate the frequency of conventional mutations in FXS-like patients, we used an array-based method to sequence FMR1 in 51 unrelated males exhibiting several features characteristic of FXS but with normal CGG-repeat tracts of FMR1. One patient was identified with a deletion in FMR1, but none of the patients were found to have other conventional mutations. CONCLUSIONS/SIGNIFICANCE: These data suggest that missense mutations in FMR1 are not a common cause of the FXS phenotype in patients who have normal-length CGG-repeat tracts. However, screening for small deletions of FMR1 may be of clinically utility.

  16. In Silico Analysis of FMR1 Gene Missense SNPs.

    Science.gov (United States)

    Tekcan, Akin

    2016-06-01

    The FMR1 gene, a member of the fragile X-related gene family, is responsible for fragile X syndrome (FXS). Missense single-nucleotide polymorphisms (SNPs) are responsible for many complex diseases. The effect of FMR1 gene missense SNPs is unknown. The aim of this study, using in silico techniques, was to analyze all known missense mutations that can affect the functionality of the FMR1 gene, leading to mental retardation (MR) and FXS. Data on the human FMR1 gene were collected from the Ensembl database (release 81), National Centre for Biological Information dbSNP Short Genetic Variations database, 1000 Genomes Browser, and NHLBI Exome Sequencing Project Exome Variant Server. In silico analysis was then performed. One hundred-twenty different missense SNPs of the FMR1 gene were determined. Of these, 11.66 % of the FMR1 gene missense SNPs were in highly conserved domains, and 83.33 % were in domains with high variety. The results of the in silico prediction analysis showed that 31.66 % of the FMR1 gene SNPs were disease related and that 50 % of SNPs had a pathogenic effect. The results of the structural and functional analysis revealed that although the R138Q mutation did not seem to have a damaging effect on the protein, the G266E and I304N SNPs appeared to disturb the interaction between the domains and affect the function of the protein. This is the first study to analyze all missense SNPs of the FMR1 gene. The results indicate the applicability of a bioinformatics approach to FXS and other FMR1-related diseases. I think that the analysis of FMR1 gene missense SNPs using bioinformatics methods would help diagnosis of FXS and other FMR1-related diseases.

  17. Mosaicism for FMR1 gene full mutation and intermediate allele in a female foetus: a postzygotic retraction event.

    Science.gov (United States)

    Ferreira, Susana Isabel; Pires, Luís Miguel; Ferrão, José; Sá, Joaquim; Serra, Armando; Carreira, Isabel Marques

    2013-09-15

    Fragile X syndrome is caused by the expansion of an unstable CGG repeat in the 5'UTR of FMR1 gene. The occurrence of mosaicism is not uncommon, especially in male patients, whereas in females it is not so often reported. Here we report a female foetus that was subject to prenatal diagnosis, because of her mother being a premutation carrier. The foetus was identified as being a mosaic for an intermediate allele and a full mutation of FMR1 gene, in the presence of a normal allele. The mosaic status was confirmed in three different tissues of the foetus--amniotic fluid, skin biopsy and blood--the last two obtained after pregnancy termination. Karyotype analysis and X-chromosome STR markers analysis do not support the mosaicism as inheritance of both maternal alleles. Oligonucleotide array-CGH excluded an imbalance that could contain the primer binding site with a different repeat size. The obtained results give compelling evidence for a postzygotic expansion mechanism where the foetus mosaic pattern originated from expansion of the mother's premutation into a full mutation and consequent regression to an intermediate allele in a proportion of cells. These events occurred in early embryogenesis before the commitment of cells into the different tissues, as the three tested tissues of the foetus have the same mosaic pattern. The couple has a son with Fragile X mental retardation syndrome and choose to terminate this pregnancy after genetic counselling.

  18. Generation and characterization of FMR1 knockout zebrafish.

    NARCIS (Netherlands)

    den Broeder, M.J.; van der Linde, H.; de Brouwer, J.F.C.; Oostra, B.A.; Willemsen, R.; Ketting, R.F.

    2009-01-01

    Fragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated two mutant al

  19. Generation and characterization of Fmr1 knockout zebrafish

    NARCIS (Netherlands)

    M.J. den Broeder (Marjo); H.C. van der Linde (Herma); J. Brouwer (Jaap); B.A. Oostra (Ben); R. Willemsen (Rob); R.F. Ketting (René)

    2009-01-01

    textabstractFragile X syndrome (FXS) is one of the most common known causes of inherited mental retardation. The gene mutated in FXS is named FMR1, and is well conserved from human to Drosophila. In order to generate a genetic tool to study FMR1 function during vertebrate development, we generated t

  20. A nonsense mutation in FMR1 causing fragile X syndrome

    DEFF Research Database (Denmark)

    Grønskov, Karen; Brøndum-Nielsen, Karen; Dedic, Alma

    2011-01-01

    Fragile X syndrome is a common cause of inherited intellectual disability. It is caused by lack of the FMR1 gene product FMRP. The most frequent cause is the expansion of a CGG repeat located in the 5'UTR of FMR1. Alleles with 200 or more repeats become hypermethylated and transcriptionally silent...... mutation p.Ser27X, in a patient with classical clinical symptoms of fragile X syndrome. The mother who carried the mutation in heterozygous form presented with mild intellectual impairment. We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should....... Only few patients with intragenic point mutations in FMR1 have been reported and, currently, routine analysis of patients referred for fragile X syndrome includes solely analysis for repeat expansion and methylation status. We identified a substitution in exon 2 of FMR1, c.80C>A, causing a nonsense...

  1. RNA binding proteins hnRNP A2/B1 and CUGBP1 suppress Fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS

    OpenAIRE

    Sofola, Oyinkan A.; Jin, Peng; QIN, YUNLONG; Duan, Ranhui; LIU, Huijie; de Haro, Maria; Nelson,David L.; Botas, Juan

    2007-01-01

    Fragile X associated tremor ataxia syndrome (FXTAS) is a recently described neurodegenerative disorder of older adult carriers of premutation alleles (60-200 CGG repeats) in the fragile-X mental retardation gene (FMR1). It has been proposed that FXTAS is an RNA mediated neurodegenerative disease caused by the titration of RNA binding proteins by the CGG repeats. To test this hypothesis, we utilize a transgenic Drosophila model of FXTAS that expresses premutation length repeat (90 CGG repeats)...

  2. A neuropsychological investigation of male premutation carriers of fragile X syndrome.

    Science.gov (United States)

    Moore, Caroline J; Daly, Eileen M; Schmitz, Nicole; Tassone, Flora; Tysoe, Carolyn; Hagerman, Randi J; Hagerman, Paul J; Morris, Robin G; Murphy, Kieran C; Murphy, Declan G M

    2004-01-01

    It is currently thought that fragile X syndrome (FraX; the most common inherited form of learning disability) results from having more than 200 cytosine-guanine-guanine (CGG) trinucleotide repeats, with consequent methylation of the fragile X mental retardation (FMR1) gene and loss of FMR1 protein (FMRP). It was also considered that premutation carriers (with 55-200 CGG repeats) are unaffected, although a tremor/ataxia syndrome has recently been described in older adult male carriers. We reported that premutation expansion of CGG trinucleotide repeats affects brain anatomy, which, together with other studies, indicates that the molecular model for FraX needs modification. However, there are few studies on the cognitive ability of adult male premutation carriers. Thus, we selected 20 male premutation carriers on the basis of their genetic phenotype, and compared them to 20 male controls matched on age, IQ and handedness. We investigated intellectual functioning, executive function, memory, attention, visual and spatial perception, and language and pragmatics. The premutation carriers had significant impairments on tests of executive function (Verbal Fluency, Trail Making Test and Tower of London) and memory (Names sub-test of the Doors and People, Verbal Paired Associates Immediate Recall and Visual Paired Associates Delayed Recall sub-tests of the WMS-R, and Category Fluency Test for natural kinds). We therefore suggest that CGG trinucleotide repeats in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychological phenotype of premutation FraX.

  3. Modeling fragile X syndrome in the Fmr1 knockout mouse

    OpenAIRE

    Kazdoba, Tatiana M.; Leach, Prescott T.; Silverman, Jill L.; Crawley, Jacqueline N

    2014-01-01

    Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively si...

  4. Estudios de la región 5'UTRTR del gen FMR-1 en pacientes con falla ovárica prematura Studies of the 5' - UTRTR region in the FMR-1 gene in patients withe Premature Ovarian Failure

    Directory of Open Access Journals (Sweden)

    V.A. Chiauzzi

    2010-12-01

    Full Text Available La falla ovárica prematura (FOP es un síndrome de patogénesis multicausal que afecta aproximadamente al 1% de las mujeres en edad reproductiva. Numerosos estudios asocian el estado de premutación (amplificación del número de tripletes CGG entre 50/55 y 200 repeticiones en el gen FMR-1 y FOP. Alrededor de un 4% de las pacientes FOP presentan alelos con premutación. La amplificación del número de tripletes por encima de 200 repeticiones causa el Síndrome de Fragilidad del X (SFX. El objetivo del presente trabajo fue estudiar la región 5´ no codificante del gen en un grupo de pacientes FOP de Argentina. La región de interés se amplificó por PCR a partir de muestras de ADN de 100 pacientes FOP y 145 mujeres controles. Los alelos de las pacientes y controles fueron agrupados en 7 categorías de acuerdo al número de tripletes obtenidos. Se observó que el número de repeticiones más frecuente se encuentra en el rango de 26 a 30 tripletes, tanto en pacientes como en controles. En el grupo de pacientes FOP, 5/197 (2.6% alelos no relacionados estudiados presentaron un número de tripletes CGG mayor a 50, mientras que sólo 1 de 290 (0.34% para el grupo control. Todas las pacientes FOP con valores de tripletes CGG mayor a 50 presentaron amenorrea secundaria. Estos resultados están en concordancia con lo comunicado para otras poblaciones acerca de la existencia de una asociación entre la premutación del gen FMR-1 y el desarrollo de FOP. Asimismo, los resultados obtenidos refuerzan la importancia de la genotipificación del gen FMR-1 en las pacientes FOP, a los efectos de estimar el riesgo de su descendencia para el SFX.Premature ovarian failure (POF is a syndrome of multicausal pathogenesis that affects 1% of women before the age of 40. Several studies associate the premutation state (CGG repeats increased in number between 50/55 and 200 in the FMR-1 gene and POF. About 4% of POF women have alleles in the FMR-1 gene in the permutation

  5. Genetic and systems level analysis of Drosophila sticky/citron kinase and dFmr1 mutants reveals common regulation of genetic networks

    Directory of Open Access Journals (Sweden)

    Zarnescu Daniela C

    2008-11-01

    Full Text Available Abstract Background In Drosophila, the genes sticky and dFmr1 have both been shown to regulate cytoskeletal dynamics and chromatin structure. These genes also genetically interact with Argonaute family microRNA regulators. Furthermore, in mammalian systems, both genes have been implicated in neuronal development. Given these genetic and functional similarities, we tested Drosophila sticky and dFmr1 for a genetic interaction and measured whole genome expression in both mutants to assess similarities in gene regulation. Results We found that sticky mutations can dominantly suppress a dFmr1 gain-of-function phenotype in the developing eye, while phenotypes produced by RNAi knock-down of sticky were enhanced by dFmr1 RNAi and a dFmr1 loss-of-function mutation. We also identified a large number of transcripts that were misexpressed in both mutants suggesting that sticky and dFmr1 gene products similarly regulate gene expression. By integrating gene expression data with a protein-protein interaction network, we found that mutations in sticky and dFmr1 resulted in misexpression of common gene networks, and consequently predicted additional specific phenotypes previously not known to be associated with either gene. Further phenotypic analyses validated these predictions. Conclusion These findings establish a functional link between two previously unrelated genes. Microarray analysis indicates that sticky and dFmr1 are both required for regulation of many developmental genes in a variety of cell types. The diversity of transcripts regulated by these two genes suggests a clear cause of the pleiotropy that sticky and dFmr1 mutants display and provides many novel, testable hypotheses about the functions of these genes. As both of these genes are implicated in the development and function of the mammalian brain, these results have relevance to human health as well as to understanding more general biological processes.

  6. Aging in Fragile X Premutation Carriers.

    Science.gov (United States)

    Lozano, Reymundo; Saito, Naomi; Reed, Dallas; Eldeeb, Marwa; Schneider, Andrea; Hessl, David; Tassone, Flora; Beckett, Laurel; Hagerman, Randi

    2016-10-01

    It is now recognized that FMR1 premutation carriers (PC) are at risk to develop a range of neurological, psychiatric, and immune-mediated disorders during adulthood. There are conflicting findings regarding the incidence of hypertension, hypothyroidism, diabetes, and cancer in these patients that warrant further study. A retrospective controlled study was performed in a convenience sample of 248 controls (130 men, 118 women) and 397 FMR1 PC with and without fragile X-associated tremor ataxia syndrome (FXTAS) (176 men, 221 women); all participants were at least 45 years old (men: mean 62.4, SD 9.5; women: mean 62.8, SD 9.9; p = 0.63). Memory and cognitive assessments (Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III)) and molecular testing (CGG repeats and FMR1-mRNA levels) were performed. Additional data included body mass index (BMI), cholesterol levels, blood pressure, hemoglobin A1c (HbA1c) levels, and medical history. A higher percentage of PC subjects self-reported having a diagnosis of hypertension (50.0 vs. 35.0 %, p = 0.006) and thyroid problems (20.4 vs. 10.0 %, p = 0.012) than control subjects. When comparing controls versus PC with FXTAS, the association was higher for diabetes (p = 0.043); however, the effect was not significant after adjusting for demographic predictors. Blood pressure, blood glucose levels, HbA1c, and BMI values were not significantly different between the two groups. The PC with FXTAS group performed consistently lower in neuropsychological testing compared with the PC without FXTAS group, but the differences were very small for all but the WAIS full-scale IQ. Based on these findings, it appears that the risk for hypertension, thyroid problems, and diabetes may be more frequent in PC with FXTAS, which will require verification in future studies.

  7. CGG repeat in the FMR1 gene: Size matters

    NARCIS (Netherlands)

    R.A. Willemsen (Ralph); G.J. Levenga (Josien); B.A. Oostra (Ben)

    2011-01-01

    textabstractThe FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs (full

  8. Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Steven D Sheridan

    Full Text Available Fragile X syndrome (FXS is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5' untranslated region of the Fragile X Mental Retardation (FMR1 gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP. Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid

  9. Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency.

    Science.gov (United States)

    Hoyos, Luis R; Thakur, Mili

    2016-12-19

    Fragile X premutation carriers have 55-200 CGG repeats in the 5' untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI.

  10. Improved Methodology for Assessment of mRNA Levels in Blood of Patients with FMR1 Related Disorders

    Directory of Open Access Journals (Sweden)

    Godler David E

    2009-06-01

    Full Text Available Abstract Background Elevated levels of FMR1 mRNA in blood have been implicated in RNA toxicity associated with a number of clinical conditions. Due to the extensive inter-sample variation in the time lapse between the blood collection and RNA extraction in clinical practice, the resulting variation in mRNA quality significantly confounds mRNA analysis by real-time PCR. Methods Here, we developed an improved method to normalize for mRNA degradation in a sample set with large variation in rRNA quality, without sample omission. Initially, RNA samples were artificially degraded, and analyzed using capillary electrophoresis and real-time PCR standard curve method, with the aim of defining the best predictors of total RNA and mRNA degradation. Results We found that: (i the 28S:18S ratio and RNA quality indicator (RQI were good predictors of severe total RNA degradation, however, the greatest changes in the quantity of different mRNAs (FMR1, DNMT1, GUS, B2M and GAPDH occurred during the early to moderate stages of degradation; (ii chromatographic features for the 18S, 28S and the inter-peak region were the most reliable predictors of total RNA degradation, however their use for target gene normalization was inferior to internal control genes, of which GUS was the most appropriate. Using GUS for normalization, we examined in the whole blood the relationship between the FMR1 mRNA and CGG expansion in a non-coding portion of this gene, in a sample set (n = 30 with the large variation in rRNA quality. By combining FMR1 3' and 5' mRNA analyses the confounding impact of mRNA degradation on the correlation between FMR1 expression and CGG size was minimized, and the biological significance increased from p = 0.046 for the 5' FMR1 assay, to p = 0.018 for the combined FMR1 3' and 5' mRNA analysis. Conclusion Our observations demonstrate that, through the use of an appropriate internal control and the direct analysis of multiple sites of target mRNA, samples that

  11. Development of Genetic Testing for Fragile X Syndrome and Associated Disorders, and Estimates of the Prevalence of FMR1 Expansion Mutations

    Directory of Open Access Journals (Sweden)

    James N. Macpherson

    2016-11-01

    Full Text Available The identification of a trinucleotide (CGG expansion as the chief mechanism of mutation in Fragile X syndrome in 1991 heralded a new chapter in molecular diagnostic genetics and generated a new perspective on mutational mechanisms in human genetic disease, which rapidly became a central paradigm (“dynamic mutation” as more and more of the common hereditary neurodevelopmental disorders were ascribed to this novel class of mutation. The progressive expansion of a CGG repeat in the FMR1 gene from “premutation” to “full mutation” provided an explanation for the “Sherman paradox,” just as similar expansion mechanisms in other genes explained the phenomenon of “anticipation” in their pathogenesis. Later, FMR1 premutations were unexpectedly found associated with two other distinct phenotypes: primary ovarian insufficiency and tremor-ataxia syndrome. This review will provide a historical perspective on procedures for testing and reporting of Fragile X syndrome and associated disorders, and the population genetics of FMR1 expansions, including estimates of prevalence and the influence of AGG interspersions on the rate and probability of expansion.

  12. Neuropsychological profiles of three sisters homozygous for the fragile X premutation

    Energy Technology Data Exchange (ETDEWEB)

    Mazzocco, M.M.M. [Johns Hopkins School of Medicine, Baltimore, MD (United States); Holden, J.J.A. [Ongwanada Resource Centre, Kingston, Ontario (Canada)

    1996-08-09

    Fragile X syndrome (fraX) is associated with an amplification of a CGG repeat within the fraX mental retardation (FMR-1) gene. We describe an exceptional family in which 3 adult sisters are homozygous for the FMR-1 premutation. Each sister inherited 2 premutation alleles (ca. 80 CGG repeats) from their biologically unrelated parents. The 3 sisters were administered measures of executive function, visual spatial, memory, and verbal skills. Deficiencies in the first 2 of these domains have been reported among females with the full mutation. The sisters` performances were compared with available normative data and with published group means for females affected by fraX. These women did not appear to have verbal or memory difficulties. None of the women demonstrated a global executive function deficit, and none had global deficits in spatial ability. The profiles of these sisters are consistent with reports that the fragile X premutation does not affect cognitive performance. 31 refs., 1 fig., 4 tabs.

  13. Brief Report: Altered Social Behavior in Isolation-Reared "Fmr1" Knockout Mice

    Science.gov (United States)

    Heitzer, Andrew M.; Roth, Alexandra K.; Nawrocki, Lauren; Wrenn, Craige C.; Valdovinos, Maria G.

    2013-01-01

    Social behavior abnormalities in Fragile X syndrome (FXS) are characterized by social withdrawal, anxiety, and deficits in social cognition. To assess these deficits, a model of FXS, the "Fmr1" knockout mouse ("Fmr1" KO), has been utilized. This mouse model has a null mutation in the fragile X mental retardation 1 gene ("Fmr1") and displays…

  14. Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

    Directory of Open Access Journals (Sweden)

    Indhu-Shree Rajan-Babu

    2016-10-01

    Full Text Available Fragile X syndrome (FXS is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI and fragile X-associated tremor/ataxia syndrome (FXTAS relies on a combination of polymerase chain reaction (PCR and Southern blot (SB for the fragile X mental retardation 1 (FMR1 CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGGn expansion screening in newborns, women of reproductive age and high-risk populations.

  15. Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

    Science.gov (United States)

    Wang, Lu; Wang, Yan; Zhou, Shimeng; Yang, Liukun; Shi, Qixin; Li, Yujiao; Zhang, Kun; Yang, Le; Zhao, Minggao; Yang, Qi

    2016-01-01

    Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment. PMID:27517961

  16. The association of CGG repeats in the FMR1 gene and timing of natural menopause

    NARCIS (Netherlands)

    Voorhuis, M.; Onland-Moret, N. C.; Fauser, B. C. J. M.; van Amstel, H. K. Ploos; van der Schouw, Y. T.; Broekmans, F. J.

    2013-01-01

    Is there an association between the number of CGG repeats in the FMR1 gene in the normal and intermediate range and age at natural menopause? The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. Excessive triple CGG repeats

  17. Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

    Directory of Open Access Journals (Sweden)

    Lu Wang

    2016-08-01

    Full Text Available Fragile X syndrome (FXS is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP, the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO mice, the factors released by astrocytes are still unclear. We cultured wild type (WT cortical neurons in astrocyte-conditioned medium (ACM from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA levels using high-performance liquid chromatography (HPLC. The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB, a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment.

  18. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.

    Science.gov (United States)

    Myrick, Leila K; Deng, Pan-Yue; Hashimoto, Hideharu; Oh, Young Mi; Cho, Yongcheol; Poidevin, Mickael J; Suhl, Joshua A; Visootsak, Jeannie; Cavalli, Valeria; Jin, Peng; Cheng, Xiaodong; Warren, Stephen T; Klyachko, Vitaly A

    2015-01-27

    Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

  19. Hyperactivity and lack of social discrimination in the adolescent Fmr1 knockout mouse

    DEFF Research Database (Denmark)

    Sørensen, Emilie M; Bertelsen, Freja; Weikop, Pia;

    2015-01-01

    The aims of this study were to investigate behaviour relevant to human autism spectrum disorder (ASD) and the fragile X syndrome in adolescent Fmr1 knockout (KO) mice and to evaluate the tissue levels of striatal monoamines. Fmr1 KO mice were evaluated in the open field, marble burying and three......-chamber test for the presence of hyperactivity, anxiety, repetitive behaviour, sociability and observation of social novelty compared with wild-type (WT) mice. The Fmr1 KO mice expressed anxiety and hyperactivity in the open field compared with WT mice. This increased level of hyperactivity was confirmed...... in the three-chamber test. Fmr1 KO mice spent more time with stranger mice compared with the WT. However, after a correction for hyperactivity, their apparent increase in sociability became identical to that of the WT. Furthermore, the Fmr1 KO mice could not differentiate between a familiar or a novel mouse...

  20. Effects of clonidine and methylphenidate on motor activity in Fmr1 knockout mice.

    Science.gov (United States)

    Wrenn, Craige C; Heitzer, Andrew M; Roth, Alexandra K; Nawrocki, Lauren; Valdovinos, Maria G

    2015-01-12

    Fragile X syndrome (FXS), a disorder caused by a mutation in the FMR1 gene, is often associated with Attention Deficit Hyperactivity Disorder (ADHD). Common treatments for the hyperactivity often seen in ADHD involve the use of stimulants and α2-adrenergic agonists. The Fmr1 knockout (KO) mouse has been found to be a valid model for FXS both biologically and behaviorally. Of particular interest to our research, the Fmr1 KO mouse has been demonstrated to show increased locomotion in comparison to wild type (WT) littermates. In the present study, we assessed the effects of clonidine (0.05 mg/kg) and methylphenidate (5 mg/kg) on motor activity in Fmr1 KO mice and their WT littermates in the open field test. Results showed that methylphenidate increased motor activity in both genotypes. Clonidine decreased motor activity in both genotypes, but the effect was delayed in the Fmr1 KO mice.

  1. How the FMR1 gene became relevant to female fertility and reproductive medicine

    Directory of Open Access Journals (Sweden)

    Norbert eGleicher

    2014-08-01

    Full Text Available This manuscript describes the 6-year evolution of our center’s research into ovarian functions of the FMR1 gene, which led to the identification of a new normal CGGn range of 26-34. This new normal range, in turn, led to definitions of different alleles (haplotypes based on whether no, one or both alleles are within range. Specific alleles then were demonstrated to represent distinct ovarian aging patterns, suggesting an important FMR1 function in follicle recruitment and ovarian depletion of follicles. So called low alleles, characterized by CGGn34 alleles. Because low FMR1 alleles present in approximately 25% of all females, FMR1 testing at young ages may offer an opportunity for earlier diagnosis of OPOI than current practice allows. Earlier diagnosis of OPOI, in turn, would give young women the options of reassessing their reproductive schedules and/or pursue fertility preservation via oocyte cryopreservation when most effective.

  2. Histone Modifications Depict an Aberrantly Heterochromatinized FMR1 Gene in Fragile X Syndrome

    OpenAIRE

    Coffee, Bradford; Zhang, Fuping; Ceman, Stephanie; Warren, Stephen T.; Reines, Daniel

    2002-01-01

    Fragile X syndrome is caused by an expansion of a polymorphic CGG triplet repeat that results in silencing of FMR1 expression. This expansion triggers methylation of FMR1's CpG island, hypoacetylation of associated histones, and chromatin condensation, all characteristics of a transcriptionally inactive gene. Here, we show that there is a graded spectrum of histone H4 acetylation that is proportional to CGG repeat length and that correlates with responsiveness of the gene to DNA demethylation...

  3. Behavioral analysis of male and female Fmr1 knockout mice on C57BL/6 background.

    Science.gov (United States)

    Ding, Qi; Sethna, Ferzin; Wang, Hongbing

    2014-09-01

    Fragile X syndrome (FXS) is a monogenic disease caused by mutations in the FMR1 gene. The Fmr1 knockout (KO) mice show many aspects of FXS-related phenotypes, and have been used as a major pre-clinical model for FXS. Although FXS occurs in both male and female patients, most studies on the mouse model use male animals. Few studies test whether gender affects the face validity of the mouse model. Here, we examined multiple behavioral phenotypes with male hemizygous and female homozygous Fmr1 KO mice on C57BL/6 background. For each behavioral paradigm, we examined multiple cohorts from different litters. We found that both male and female Fmr1 KO mice displayed significant audiogenic seizures, hyperactivity in the open field test, deficits in passive avoidance and contextual fear memory, and significant enhancement of PPI at low stimulus intensity. Male and female Fmr1 KO mice also showed more transitional movement between the lit and dark chambers in the light-dark tests. The lack of gender effects suggests that the Fmr1 KO mouse is a reasonable tool to test the efficacy of potential FXS therapies. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Germinal mosaicism for a deletion of the FMR1 gene leading to fragile X syndrome.

    Science.gov (United States)

    Jiraanont, P; Hagerman, R J; Neri, G; Zollino, M; Murdolo, M; Tassone, F

    2016-09-01

    Aberrant CGG trinucleotide amplification within the FMR1 gene, which spans approximately 38 Kb of genomic DNA is almost always what leads to fragile X syndrome (FXS). However, deletions of part or the entire FMR1 gene can also cause FXS. Both CGG amplification-induced silencing and deletions result in the absence of the FMR1 gene product, FMRP. Here, we report a rare case of germinal mosaicism of a deletion encompassing approximately 300 Kb of DNA, which by removing the entire FMR1 gene led to FXS. The male proband, carrying the deletion, presented in clinic with the typical features of FXS. His mother was analyzed by FISH on metaphase chromosomes with cosmid probe c22.3 spanning the FMR1 locus, and she was found not to carry the deletion on 30 analyzed cells from peripheral blood lymphocytes. Prenatal examination of the mother's third pregnancy showed that the male fetus also had the same deletion as the proband. Following this prenatal diagnosis, FISH analysis in the mother was expanded to 400 metaphases from peripheral lymphocytes, and a heterozygous FMR1 deletion was found in three. Although this result could be considered questionable from a diagnostic point of view, it indicates that the deletion is in the ovary's germinal cells.

  5. Expression of GAD of cochlea in FMR1 gene Knock-out mice%Fmr1基因敲除小鼠耳蜗GAD的表达

    Institute of Scientific and Technical Information of China (English)

    李敏雄; 杜娜; 孙卫文; 黄月玲; 沈岩松; 戴丽军; 陈盛强; 马钊恩; 张建国

    2012-01-01

    目的 对4 周龄Fmr1 基因敲除小鼠的耳蜗的GAD 表达进行观察,探讨耳蜗GAD 的表达是否受FMRP 的影响.方法 使用PCR 技术对Fmr1 基因敲除小鼠鉴定后对4 周龄的Fmr1 基因敲除小鼠和野生型小鼠各15 只进行耳蜗的苏木精-伊红(HE) 染色和GAD 免疫组织化学的表达观察,数据采用多因素方差分析处理.结果 耳蜗HE 染色结果:4 周龄组KO 鼠较WT 鼠形态学观察无差异.4 周龄KO 小鼠的耳蜗中GAD 表达的平均阳性细胞数均高于WT 小鼠,P<0.01,差异具有统计学意义.结论 GAD 表达的改变可能与FMR1 基因KO 小鼠听源性惊厥发病有关.

  6. Risk of cognitive impairment in female premutation carriers of fragile X premutation: analysis by means of robust segmented linear regression models.

    Science.gov (United States)

    Mínguez, Mónica; Ibáñez, Berta; Ribate, Maria-Pilar; Ramos, Feliciano; García-Alegría, Eva; Fernández-Rivas, Aránzazu; Ruiz-Parra, Eduardo; Poch, Marisa; Alonso, Angel; Martinez-Bouzas, Cristina; Beristain, Elena; Tejada, Maria-Isabel

    2009-03-05

    This report describes a study focused on the relationship between CGG repeat length, FMRP, mRNA levels and cognitive functioning in premutation carriers (PM) carriers of Fragile X Syndrome (FXS). We studied 60 females-43 with PM and 17 with normal (N) alleles-from 25 FXS Spanish families. The Wechsler scales were administered to all subjects and new blood samples and hair roots were taken to study mRNA and FMRP levels. Using lowess curves together with segmented models we showed that within the premutation range, IQ scores tend to decrease when the number of CGG repeats increases and the FMRP values decrease. Furthermore, we discovered cut-off points in the molecular variables that seem to change the probability of having some cognitive impairment. Specifically, for those PM females in the upper premutation range (CGG > or = 100) and with FMRP expression < 60% in hair roots, a 10% decrement of FMRP expression represents a significant decrease in IQ scores of about six points, which is more evident for Full-Scale IQ (P-value = 0.035) and Performance IQ (P-value = 0.045) than for Verbal IQ (P-value = 0.074). On the contrary, we did not find any significant correlation between FMR1 mRNA levels and the IQ scores, probably due to the fact that mRNA levels were measured in blood. In conclusion, our findings suggest that the PM can have some effect on cognitive ability in female carriers, although these effects may be subtle. In these cases, it would be advisable to carry out a hair root analysis of FMRP.

  7. FMR1 genotype with autoimmunity-associated polycystic ovary-like phenotype and decreased pregnancy chance.

    Science.gov (United States)

    Gleicher, Norbert; Weghofer, Andrea; Lee, Irene H; Barad, David H

    2010-12-16

    The FMR1 gene partially appears to control ovarian reserve, with a specific ovarian sub-genotype statistically associated with a polycystic ovary (PCO)- like phenotype. Some forms of PCO have been associated with autoimmunity. We, therefore, investigated in multiple regression analyses associations of ovary-specific FMR1 genotypes with autoimmunity and pregnancy chances (with in vitro fertilization, IVF) in 339 consecutive infertile women (455 IVF cycles), 75 with PCO-like phenotype, adjusted for age, race/ethnicity, medication dosage and number of oocytes retrieved. Patients included 183 (54.0%) with normal (norm) and 156 (46%) with heterozygous (het) FMR1 genotypes; 133 (39.2%) demonstrated laboratory evidence of autoimmunity: 51.1% of het-norm/low, 38.3% of norm and 24.2% het-norm/high genotype and sub-genotypes demonstrated autoimmunity (p=0.003). Prevalence of autoimmunity increased further in PCO-like phenotype patients with het-norm/low genotype (83.3%), remained unchanged with norm (34.0%) and decreased in het-norm/high women (10.0%; PPregnancy rates were significantly higher with norm (38.6%) than het-norm/low (22.2%, p=0.001). FMR1 sub-genotype het-norm/low is strongly associated with autoimmunity and decreased pregnancy chances in IVF, reaffirming the importance of the distal long arm of the X chromosome (FMR1 maps at Xq27.3) for autoimmunity, ovarian function and, likely, pregnancy chance with IVF.

  8. Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout Mice.

    Science.gov (United States)

    Deng, Pan-Yue; Klyachko, Vitaly A

    2016-09-20

    Altered neuronal excitability is one of the hallmarks of fragile X syndrome (FXS), but the mechanisms underlying this critical neuronal dysfunction are poorly understood. Here, we find that pyramidal cells in the entorhinal cortex of Fmr1 KO mice, an established FXS mouse model, display a decreased AP threshold and increased neuronal excitability. The AP threshold changes in Fmr1 KO mice are caused by increased persistent sodium current (INaP). Our results indicate that this abnormal INaP in Fmr1 KO animals is mediated by increased mGluR5-PLC-PKC (metabotropic glutamate receptor 5/phospholipase C/protein kinase C) signaling. These findings identify Na(+) channel dysregulation as a major cause of neuronal hyperexcitability in cortical FXS neurons and uncover a mechanism by which abnormal mGluR5 signaling causes neuronal hyperexcitability in a FXS mouse model.

  9. Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout Mice

    Directory of Open Access Journals (Sweden)

    Pan-Yue Deng

    2016-09-01

    Full Text Available Altered neuronal excitability is one of the hallmarks of fragile X syndrome (FXS, but the mechanisms underlying this critical neuronal dysfunction are poorly understood. Here, we find that pyramidal cells in the entorhinal cortex of Fmr1 KO mice, an established FXS mouse model, display a decreased AP threshold and increased neuronal excitability. The AP threshold changes in Fmr1 KO mice are caused by increased persistent sodium current (INaP. Our results indicate that this abnormal INaP in Fmr1 KO animals is mediated by increased mGluR5-PLC-PKC (metabotropic glutamate receptor 5/phospholipase C/protein kinase C signaling. These findings identify Na+ channel dysregulation as a major cause of neuronal hyperexcitability in cortical FXS neurons and uncover a mechanism by which abnormal mGluR5 signaling causes neuronal hyperexcitability in a FXS mouse model.

  10. Deletion in the FMR1 gene in a fragile-X male

    Energy Technology Data Exchange (ETDEWEB)

    Mannermaa, A.; Pulkkinen, L.; Kajanoja, E. [Kuopio Univ., Hospital (Finland)] [and others

    1996-08-09

    The pathogenesis of fragile-X syndrome is a consequence of absence of the FMR1 gene product associated with expansion of the CGG repeat and abnormal methylation of this and a CpG island 250 hp proximal to the CGG repeat located at exon 1 in the FMR1 gene. While this is usually the case, some suspected fragile-X syndrome patients have been described with a mutation other than CGG expansion. We describe here an affected fragile-X male, who was found to be mosaic of a full mutation of the CGG expansion and a deletion in the FMR1 gene. The patient`s phenotype is probably mainly due to the effect of the full mutation of the repeat sequence. Thus, the influence of the deletion is difficult to evaluate. 20 refs., 2 figs.

  11. Failed stabilization for long-term potentiation in the auditory cortex of FMR1 knockout mice.

    Directory of Open Access Journals (Sweden)

    Sungchil Yang

    Full Text Available Fragile X syndrome is a developmental disorder that affects sensory systems. A null mutation of the Fragile X Mental Retardation protein 1 (Fmr1 gene in mice has varied effects on developmental plasticity in different sensory systems, including normal barrel cortical plasticity, altered ocular dominance plasticity and grossly impaired auditory frequency map plasticity. The mutation also has different effects on long-term synaptic plasticity in somatosensory and visual cortical neurons, providing insights on how it may differentially affect the sensory systems. Here we present evidence that long-term potentiation (LTP is impaired in the developing auditory cortex of the Fmr1 knockout (KO mice. This impairment of synaptic plasticity is consistent with impaired frequency map plasticity in the Fmr1 KO mouse. Together, these results suggest a potential role of LTP in sensory map plasticity during early sensory development.

  12. Epigenetic Characterization of the FMR1 Promoter in Induced Pluripotent Stem Cells from Human Fibroblasts Carrying an Unmethylated Full Mutation

    Science.gov (United States)

    de Esch, Celine E.F.; Ghazvini, Mehrnaz; Loos, Friedemann; Schelling-Kazaryan, Nune; Widagdo, W.; Munshi, Shashini T.; van der Wal, Erik; Douben, Hannie; Gunhanlar, Nilhan; Kushner, Steven A.; Pijnappel, W.W.M. Pim; de Vrij, Femke M.S.; Geijsen, Niels; Gribnau, Joost; Willemsen, Rob

    2014-01-01

    Summary Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene. PMID:25358783

  13. Epigenetic Characterization of the FMR1 Promoter in Induced Pluripotent Stem Cells from Human Fibroblasts Carrying an Unmethylated Full Mutation

    Directory of Open Access Journals (Sweden)

    Celine E.F. de Esch

    2014-10-01

    Full Text Available Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs of an unmethylated full mutation (uFM individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene.

  14. Differential Impact of the "FMR1" Gene on Visual Processing in Fragile X Syndrome

    Science.gov (United States)

    Kogan, Cary S.; Boutet, Isabelle; Cornish, Kim; Zangenehpour, Shahin; Mullen, Kathy T.; Holden, Jeanette J. A.; Kaloustian, Vazken M. Der; Andermann, Eva; Chaudhuri, Avi

    2004-01-01

    Fragile X syndrome (FXS) is the most common form of heritable mental retardation, affecting (~ around) 1 in 4000 males. The syndrome arises from expansion of a trinucleotide repeat in the 5'-untranslated region of the fragile X mental retardation 1 ("FMR1") gene, leading to methylation of the promoter sequence and lack of the fragile X mental…

  15. Microdeletions Including FMR1 in Three Female Patients with Intellectual Disability – Further Delineation of the Phenotype and Expression Studies

    Science.gov (United States)

    Zink, A.M.; Wohlleber, E.; Engels, H.; Rødningen, O.K.; Ravn, K.; Heilmann, S.; Rehnitz, J.; Katzorke, N.; Kraus, C.; Blichfeldt, S.; Hoffmann, P.; Reutter, H.; Brockschmidt, F.F.; Kreiß-Nachtsheim, M.; Vogt, P.H.; Prescott, T.E.; Tümer, Z.; Lee, J.A.

    2014-01-01

    Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1. PMID:24715853

  16. The -413C > G substitution in the promoter of the FMR1 gene is not associated with the fragile X syndrome phenotype.

    Science.gov (United States)

    Grasso, Marina; Cecconi, Massimiliano; Boni, Stefania; Forzano, Francesca; Barbaresi, Maurizio; Memo, Luigi; Perroni, Lucia; Faravelli, Francesca; Di Maria, Emilio

    2010-04-01

    Most common inherited form of intellectual disability, fragile X syndrome is associated to an expansion of greater than 200 CGG repeats in the 5' untranslated region of the FMR1 gene on the X chromosome which causes transcriptional silencing and deficiency of the encoded protein FMRP. Molecular diagnosis is performed through a combination of PCR to identify fewer than 100-150 repeats and of Southern blot analysis to identify longer alleles and the methylation status of the FMR1 promoter. We present a family with one patient with mild mental retardation who showed an atypical profile at Southern analysis due to the -413C > G transversion located in the FMR1 promoter which had been described as possibly associated with mental retardation. We demonstrated this variant in other four family members along three generations, including the maternal grandfather who did not manifest any pathological feature. Though the -413C > G substitution was not found in a large control series, these findings allowed to exclude its role in determining the disease phenotype.

  17. FMR1 genotype with autoimmunity-associated polycystic ovary-like phenotype and decreased pregnancy chance.

    Directory of Open Access Journals (Sweden)

    Norbert Gleicher

    Full Text Available The FMR1 gene partially appears to control ovarian reserve, with a specific ovarian sub-genotype statistically associated with a polycystic ovary (PCO- like phenotype. Some forms of PCO have been associated with autoimmunity. We, therefore, investigated in multiple regression analyses associations of ovary-specific FMR1 genotypes with autoimmunity and pregnancy chances (with in vitro fertilization, IVF in 339 consecutive infertile women (455 IVF cycles, 75 with PCO-like phenotype, adjusted for age, race/ethnicity, medication dosage and number of oocytes retrieved. Patients included 183 (54.0% with normal (norm and 156 (46% with heterozygous (het FMR1 genotypes; 133 (39.2% demonstrated laboratory evidence of autoimmunity: 51.1% of het-norm/low, 38.3% of norm and 24.2% het-norm/high genotype and sub-genotypes demonstrated autoimmunity (p=0.003. Prevalence of autoimmunity increased further in PCO-like phenotype patients with het-norm/low genotype (83.3%, remained unchanged with norm (34.0% and decreased in het-norm/high women (10.0%; P<0.0001. Pregnancy rates were significantly higher with norm (38.6% than het-norm/low (22.2%, p=0.001. FMR1 sub-genotype het-norm/low is strongly associated with autoimmunity and decreased pregnancy chances in IVF, reaffirming the importance of the distal long arm of the X chromosome (FMR1 maps at Xq27.3 for autoimmunity, ovarian function and, likely, pregnancy chance with IVF.

  18. Identifying intrinsic and extrinsic determinants that regulate internal initiation of translation mediated by the FMR1 5' leader

    Directory of Open Access Journals (Sweden)

    Timmerman Stephanie

    2008-10-01

    Full Text Available Abstract Background Regulating synthesis of the Fragile X gene (FMR1 product, FMRP alters neural plasticity potentially through its role in the microRNA pathway. Cap-dependent translation of the FMR1 mRNA, a process requiring ribosomal scanning through the 5' leader, is likely impeded by the extensive secondary structure generated by the high guanosine/cytosine nucleotide content including the CGG triplet nucleotide repeats in the 5' leader. An alternative mechanism to initiate translation – internal initiation often utilizes secondary structure to recruit the translational machinery. Consequently, studies were undertaken to confirm and extend a previous observation that the FMR1 5' leader contains an internal ribosomal entry site (IRES. Results Cellular transfection of a dicistronic DNA construct containing the FMR1 5' leader inserted into the intercistronic region yielded significant translation of the second cistron, but the FMR1 5' leader was also found to contain a cryptic promoter possibly confounding interpretation of these results. However, transfection of dicistronic and monocistronic RNA ex vivo or in vitro confirmed that the FMR1 5' leader contains an IRES. Moreover, inhibiting cap-dependent translation ex vivo did not affect the expression level of endogenous FMRP indicating a role for IRES-dependent translation of FMR1 mRNA. Analysis of the FMR1 5' leader revealed that the CGG repeats and the 5' end of the leader were vital for internal initiation. Functionally, exposure to potassium chloride or intracellular acidification and addition of polyinosinic:polycytidylic acid as mimics of neural activity and double stranded RNA, respectively, differentially affected FMR1 IRES activity. Conclusion Our results indicate that multiple stimuli influence IRES-dependent translation of the FMR1 mRNA and suggest a functional role for the CGG nucleotide repeats.

  19. Fragile X syndrome: a pilot proton magnetic resonance spectroscopy study in premutation carriers

    LENUS (Irish Health Repository)

    Hallahan, Brian P

    2012-08-30

    AbstractPurposeThere is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX.MethodsWe used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals.ResultsThere was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls.ConclusionsThis is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.

  20. Spatiotemporal expression of PSD-95 in Fmr1 knockout mice brain.

    Science.gov (United States)

    Zhu, Zhi-Wei; Xu, Qin; Zhao, Zheng-Yan; Gu, Wei-Zhong; Wu, Ding-Wen

    2011-06-01

    To investigate and compare the spatial and temporal expression of post-synaptic density-95 (PSD-95) in Fmr1 knockout mice (the animal model of fragile X syndrome, FXS) and wild-type mice brain, on postnatal day 7 (P7), P14, P21, P28 and P90, mice from each group were decapitated, and three principal brain regions (cerebral cortex, hippocampus and cerebellum) were obtained and stored for later experiments. PSD-95 mRNA in the three brain areas was analyzed with quantitative RT-PCR. PSD-95 protein was measured by immunohistochemical staining and Western blot. In the three principal brain areas of Fmr1 knockout mice and wild-type mice, the expression of PSD-95 mRNA and protein were detected at the lowest levels on P7, and then significantly increased on P14, reaching the peak levels in adolescents or adults. Moreover, it was found that PSD-95 mRNA and protein in the hippocampus were significantly decreased in Fmr1 knockout mice during the developmental period (P7, P14, P21 and P28) as well as at adulthood (P90) (P PSD-95 in the cortex and cerebellum between Fmr1 knockout and wild mice. The expression of PSD-95 in the hippocampus might be regulated by fragile X mental retardation protein (FMRP) during mice early developmental and adult periods. It is suggested that impairment of PSD-95 is possibly involved in hippocampal-dependent learning defects, which are common in people with FXS. © 2010 Japanese Society of Neuropathology.

  1. FIRING PROPERTY OF INFERIOR COLLICULUS NEURONS AFFECTED BY FMR1 GENE MUTATION

    Institute of Scientific and Technical Information of China (English)

    Brittany Mott; SUN Wei

    2014-01-01

    Fragile X syndrome is the most common form of inherited mental retardation affecting up to 1 in 4000 individuals. The syn-drome is induced by a mutation in the FMR1 gene, causing a deficiency in its gene by-product FMRP. Impairment in the nor-mal functioning of FMRP leads to learning and memory deficits and heightened sensitivity to sensory stimuli, including sound (hyperacusis). The molecular basis of fragile X syndrome is thoroughly understood;however, the neural mechanisms underly-ing hyperacusis have not yet been determined. As the inferior colliculus (IC) is the principal midbrain nucleus of the auditory pathway, the current study addresses the questions underlying the neural mechanism of hyperacusis within the IC of fragile X mice. Acute experiments were performed in which electrophysiological recordings of the IC in FMR1-KO and WT mice were measured. Results showed that Q-values for WT were significantly larger than that of FMR-1 KO mice, indicating that WT mice exhibit sharper tuning curves than FMR1-KO mice. We also found the ratio of the monotonic neurons in the KO mice was much higher than the WT mice. These results suggest that lack of FMRP in the auditory system affects the developmental maturation and function of structures within the auditory pathway, and in this case specifically the IC. The dysfunction ob-served within the auditory neural pathway and in particular the IC may be related to the increased susceptibility to sound as seen in individuals with fragile X syndrome. Our study may help on understanding the mechanisms of the fragile X syndrome and hyperacusis.

  2. Behavioral effects of chronic stress in the Fmr1 mouse model for fragile X syndrome.

    Science.gov (United States)

    Lemaire-Mayo, Valerie; Subashi, Enejda; Henkous, Nadia; Beracochea, Daniel; Pietropaolo, Susanna

    2017-03-01

    Fragile X Syndrome (FXS) is a pervasive developmental disorder due to a mutation in the FMR1 X-linked gene. Despite its clear genetic cause, the expression of FXS symptoms is known to be modulated by environmental factors, including stress. Furthermore, several studies have shown disturbances in stress regulatory systems in FXS patients and Fmr1 mice. These studies have mostly focused on the hormonal responses to stress, using the acute exposure to a single type of stressor. Hence, little is known about the behavioral effects of stress in FXS, and the importance of the nature of the stressing procedure, especially in the context of a repeated exposure that more closely resembles real life conditions. Here we evaluated the effects of chronic exposure to different types of stress (i.e., either repeated restraint or unpredictable stress) on the behavioral phenotype of adult Fmr1 mice. Our results demonstrated that chronic stress induced deficits in social interaction and working memory only in WT mice and the impact of stress depended on the type of stressors and the specific behavior tested. Our data suggest that the behavioral sensitivity to stress is dramatically reduced in FXS, opening new views on the impact of gene-environment interactions in this pathology.

  3. Molecular-clinical correlations in males with an expanded FMR1 mutation

    Energy Technology Data Exchange (ETDEWEB)

    Merenstein, S.A.; Sobesky, W.E.; Tran, H.X. [Children`s Hospital, Denver, CO (United States)] [and others

    1996-08-09

    Fragile X syndrome is caused by an expansion of a CGG repeat in the FMR1 gene. The CGG repeat number of the FMR1 mutation and the percentage of cells with methylation of the gene were studied in 218 male patients. Physical and cognitive measurements were also performed. Patients were divided into three groups; those with full mutation and complete methylation (n = 160), those with full mutation and partial methylation (n = 12), and those with a mosaic pattern (n = 46). Statistical comparisons were made between males with the fully methylated full mutation and those with a mosaic pattern. Males having full mutation with complete methylation had the lowest IQ scores and greatest physical involvement. These significant differences were seen only in ages after puberty. CGG repeat length did not correlate with IQ or the physical index score in any group. These findings suggest that a partial production of FMR1 protein may predict milder clinical involvement in some males with fragile X syndrome. 39 refs., 4 tabs.

  4. Genetic variation of the FMR1 gene among four Mexican populations: Mestizo, Huichol, Purepecha, and Tarahumara.

    Science.gov (United States)

    Barros-Núñez, Patricio; Rosales-Reynoso, Mónica Alejandra; Sandoval, Lucila; Romero-Espinoza, Pavel; Troyo-Sanromán, Rogelio; Ibarra, Bertha

    2008-01-01

    Fragile X syndrome is the most common cause of inherited mental retardation; it is caused by expansion of CGG repeats in the first exon of the FMR1 gene. The number of CGG repeats varies between 6 and 50 triplets in normal individuals; the most common alleles have 29 or 30 repeats. Allelic patterns in the global populations are similar; however; some reports show statistical differences among several populations. In Mexico, except by a single report on a western Mestizo population, the allelic frequencies of the FMR1 gene are unknown. In this study, we analyze 207, 140, 138, and 40 chromosomes from Mestizos, Tarahumaras, Huichols, and Purepechas respectively. After PCR amplification on DNA modified by sodium bisulfite treatment, molecular analysis of the FMR1 gene showed 30 different alleles among the 525 chromosomes evaluated. Trinucleotide repeat number in the different Mexican populations varied from 15 to 87, with modal numbers of 32 and 30 in Mestizos and Tarahumaras, 29 and 32 in Purepechas and 30 among Huichols. Together, these allelic patterns differ significantly from those reported for Caucasian, Chinese, African, Indonesian, Brazilian, and Chilean populations. The increased number of the unusual allele of 32 repeats observed in the Mexican mestizo population can be explained from its frequency in at least two Mexican native populations.

  5. MicroRNA-130b targets Fmr1 and regulates embryonic neural progenitor cell proliferation and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Gong, Xi [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China); Zhang, Kunshan [Department of Regenerative Medicine, Stem Cell Center, Tongji University School of Medicine, Shanghai 200092 (China); Wang, Yanlu; Wang, Junbang; Cui, Yaru [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China); Li, Siguang, E-mail: siguangli@163.com [Department of Regenerative Medicine, Stem Cell Center, Tongji University School of Medicine, Shanghai 200092 (China); Luo, Yuping, E-mail: luoyuping@163.com [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China)

    2013-10-04

    Highlights: •We found that the 3′ UTR of the Fmr1 mRNA is a target of miR-130b. •MiR-130b suppresses the expression of Fmr1 in mouse embryonic stem cell. •MiR-130b alters the proliferation of mouse embryonic stem cell. •MiR-130b alters fate specification of mouse embryonic stem cell. -- Abstract: Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by expansion of the CGG repeat in the 5′-untranslated region of the X-linked Fmr1 gene, which results in transcriptional silencing and loss of expression of its encoded protein FMRP. The loss of FMRP increases proliferation and alters fate specification in adult neural progenitor cells (aNPCs). However, little is known about Fmr1 mRNA regulation at the transcriptional and post-transcriptional levels. In the present study, we report that miR-130b regulated Fmr1 expression by directly targeting its 3′-untranslated region (3′ UTR). Up-regulation of miR-130b in mouse embryonic neural progenitor cells (eNPCs) decreased Fmr1 expression, markedly increased eNPC proliferation and altered the differentiation tendency of eNPCs, suggesting that antagonizing miR-130b may be a new therapeutic entry point for treating Fragile X syndrome.

  6. Cortisol Response to Behavior Problems in FMR1 Premutation Mothers of Adolescents and Adults with Fragile X Syndrome: A Diathesis-Stress Model

    Science.gov (United States)

    Hartley, Sigan L.; Seltzer, Marsha Mailick; Hong, Jinkuk; Greenberg, Jan S.; Smith, Leann; Almeida, David; Coe, Chris; Abbeduto, Leonard

    2012-01-01

    Mothers of adolescents and adults with fragile X syndrome (FXS) are faced with high levels of parenting stress. The extent to which mothers are negatively impacted by this stress, however, may be influenced by their own genetic status. The present study uses a diathesis-stress model to examine the ways in which a genetic vulnerability in mothers…

  7. Cortisol Response to Behavior Problems in FMR1 Premutation Mothers of Adolescents and Adults with Fragile X Syndrome: A Diathesis-Stress Model

    Science.gov (United States)

    Hartley, Sigan L.; Seltzer, Marsha Mailick; Hong, Jinkuk; Greenberg, Jan S.; Smith, Leann; Almeida, David; Coe, Chris; Abbeduto, Leonard

    2012-01-01

    Mothers of adolescents and adults with fragile X syndrome (FXS) are faced with high levels of parenting stress. The extent to which mothers are negatively impacted by this stress, however, may be influenced by their own genetic status. The present study uses a diathesis-stress model to examine the ways in which a genetic vulnerability in mothers…

  8. FMR-1 CGG transitions in male and female carriers of fragile X

    Energy Technology Data Exchange (ETDEWEB)

    Nolin, S.L.; Lewis, F.A. III; Ye, L.L. [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)] [and others

    1994-09-01

    We have conducted a preliminary analysis of the CGG transitions observed among the offspring of fragile X male and female carriers using the PCR method of Brown et al. A strong familial clustering was observed in maternal inheritance of the fragile X chromosome. Fifty-eight premutation females passed their fragile X alleles to mutiple offspring (total 134). Forty-nine of these women had 106 children with the full mutation. Nine mothers (2 in the 60-69 repeat range, 6 in the 80-89 range, 1 in the 90-99 range) had a total of 19 premutation and 3 full mutation children. These data suggest that a premutation carrier with 1 premutation child has a reduced risk for full mutation offspring independent of her CGG repeat size. Familial clustering was also observed in transmitting males. The daughters of transmitting males showed surprisingly little variation in CGG repeat size among each set of daughters. In twelve sibling sets, the daughters were within 10 CGGs of each other, 6 sets were within 11-18 repeats, and one set was within 40 repeats. Taken together, the male and female carrier data support the concept of a sequence or structure within or close to the CGG repeat which influences the expansion of the repeat during its transmission from parent to child. We also found that in transmitting males with > 90 repeats, the repeat was often meiotically unstable. In 5 of these males, 44% (7/16) meioses showed a reduction 2-20 CGGs inherited and all 5 fathers had at least 1 daughter with a size reduction. This finding suggests that repeats > 90 may not be stably transmitted in spermatocytes.

  9. Translation of the FMR1 mRNA is not influenced by AGG interruptions

    OpenAIRE

    Ludwig, Anna L.; Raske, Christopher; Tassone, Flora; Garcia-Arocena, Dolores; Hershey, John W.; Hagerman, Paul J.

    2009-01-01

    The fragile X mental retardation 1 (FMR1) gene contains a CGG-repeat element within its 5′ untranslated region (5′UTR) which, for alleles with more than ∼40 repeats, increasingly affects both transcription (up-regulation) and translation (inhibition) of the repeat-containing RNA with increasing CGG-repeat length. Translational inhibition is thought to be due to impaired ribosomal scanning through the CGG-repeat region, which is postulated to form highly stable secondary/tertiary structure. On...

  10. Implicancias del gen FMR1 en la función ovárica

    OpenAIRE

    2014-01-01

    El gen FMR1, responsable del Síndrome de Fragilidad del X (SFX), se localiza en el sitio FRAXA en el brazo largo del cromosoma X (Xq27.3), está compuesto por 17 exones, abarca aproximadamente 38 kilobases (kb) y su producto transcripcional es un ARN mensajero de 3,9 kb que puede sufrir splicing alternativo. En su región 5’ no codificante presenta una zona de tripletes CGG que puede variar en longitud. Según el tamaño de la expansión, los alelos se clasifican en normales (5- 44 repeticiones), ...

  11. Fmr1基因敲除小鼠耳蜗的GABAα1受体的表达%Expression of GABAα1 receptor of cochlea in FMR1 gene knock-out mice

    Institute of Scientific and Technical Information of China (English)

    李敏雄; 杜娜; 孙卫文; 黄月玲; 沈岩松; 戴丽军; 陈盛强; 马钊恩; 张建国

    2012-01-01

    Objective To observe cochlea morphology and expression of GABA a 1 receptor of cochlea in 4 weeks FMR1 KO mice and WT mice. Methods Four-week old Fmrl knockout mice were identified using the PCR technique.and immunohistochemistry to compare with the changes of expression of GABA a 1 receptor between FMR1 KO mice and WT mice cochlea. Results There were no difference in cochlea morphology between FMR1 KO mice and WT mice by HE dyeing. The expression of GABA a 1 receptor in cochlear in FMR-1K0 mice was decreased. Conclusion The expression of GABA a 1 receptor is incerased in cochlear in four-week old FMR-1K0 mice that might be associated with audiogenic seizure susceptibility of Fmrl knockout mice.%目的 对4周龄Fmr1基因敲除小鼠耳蜗的GABAα1受体表达进行观察,探讨耳蜗GABAα1受体的表达是否受FMRP的影响.方法 使用PCR技术对Fmr1基因敲除小鼠鉴定后,对4周龄的Fmr1基因敲除小鼠和野生型小鼠进行耳蜗的GABAα1受体免疫组织化学的表达观察,数据采用多因素方差分析处理.结果 耳蜗HE染色结果:4周龄组KO鼠较WT鼠形态学观察无差异.4周龄KO小鼠的耳蜗中GABAα1受体表达的平均阳性细胞数均低于WT小鼠,P<0.01,差异具有统计学意义.结论 GABAα1受体表达的降低可能与FMR1基因KO小鼠听源性惊厥发病有关.

  12. Distribution of FMR-1 and associated microsatellite alleles in a normal Chinese population

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, N.; Houck, G.E. Jr.; Li, S.; Dobkin, C.; Brown, W.T. [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States); Xixian Liu; Shen Gou [Tongji Medical Univ., Wuhan (China)

    1994-07-15

    The CGG repeat size distribution of the fragile X mental retardation gene (FMR-1) was studied in a population of normal Chinese X chromosomes along with that of two proximal microsatellite polymorphic markers: FRAXAC1 and DXS548. The most common CGG repeat allele was 29 (47.2%) with 30 being second most common (26%). This distribution was different from that seen in Caucasian controls, where the most common allele was 30 repeats. Other differences with Caucasian controls included a secondary model peak at 36 repeats and the absence of peaks at 20 or 23 repeats. There were only two FRAXAC1 and five DXS548 alleles found in the Chinese sample. A striking linkage disequilibrium of FMR-1 alleles with FRAXAC1 alleles was observed, in that 90% of the 29 CGG repeat alleles but only 41% of the 30 CGG repeat alleles had the FRAXAC1 152 bp allele (18 AC repeats). This disequilibrium suggests that slippage between the closely spaced normal CGG repeat alleles, 29 and 30, and between 152 and 154 FRAXAC1 alleles is very rare. This study lays the groundwork for an understanding of founder chromosome effects in comparing Asian and Caucasian populations. 29 refs., 5 tabs.

  13. Analysis of FMR1 (CGG)(n) alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia.

    Science.gov (United States)

    Larsen, L A; Vuust, J; Nystad, M; Evseeva, I; Van Ghelue, M; Tranebjaerg, L

    2001-09-01

    Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)(n) repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)(n) alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)(n) repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)(n) repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9-10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)(n) alleles and haplotype 7-3.

  14. Observation of tail suspension test in Fmr1 gene knockout mice%Fmr1基因敲除小鼠悬尾实验的观察

    Institute of Scientific and Technical Information of China (English)

    胡丽婵; 黄海樱; 郭艺; 孙祺章; 余国汉; 黄月玲; 戴丽军; 党亚梅; 黄雄; 陈盛强

    2016-01-01

    Objective To observe tail suspension test in Fmr1 gene knockout mice and to explore whether there are differences in mobility of KO and WT mice. Methods 1 80 test mice were divided into two groups:① KO group (4,6,8 weeks old,each age group of mice is 30,male and female in half,a total of 90)② WT group (4,6,8 weeks old,each group of mice is 30,male and female on half,a total of 90).Through forced swimming test and tail suspension test to observe gender, age effect on immobility time. Results With the same age of the same sex,the KO mice’s immobility time was longer than WT mice’s.P <0.05.With the same age,the male mice’s immobility time was shorter than female mice’s.With the age in-crease,the immobility time of KO mice was longer than WT mice.P <0.05. Conclusion Fmr1 gene knockout mice have anxiety and depressive behavior.%目的:对不同周龄的 KO 小鼠与 WT 小鼠进行悬尾实验进行观察,探讨 KO 小鼠与 WT 小鼠的行为差别。方法采用健康的试验动物180只分两组:①KO 组(4、6、8周龄,各周龄30只,雌雄各半,共90只)②WT 组(4、6、8周龄,各周龄30只,雌雄各半,共90只);通过悬尾实验观察性别,年龄对不动时间的影响。结果同龄 KO 雌性小鼠比雄性小鼠的静止时间差别不大;随着年龄增大,静止时间增长。同龄同性别的 KO 鼠比 WT 鼠的不动时间长。P <0.05;同龄雄性小鼠比雌性小鼠的不动时间短;随年龄增长各种系小鼠不动时间增长,KO 鼠的不动时间比 WT 鼠长,P <0.05。结论 KO 小鼠存在抑郁行为表型。

  15. Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

    Science.gov (United States)

    Zhang, Yu; Bonnan, Audrey; Bony, Guillaume; Ferezou, Isabelle; Pietropaolo, Susanna; Ginger, Melanie; Sans, Nathalie; Rossier, Jean; Oostra, Ben; LeMasson, Gwen; Frick, Andreas

    2014-12-01

    Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

  16. FMR1基因敲除对雄性小鼠生殖功能的影响%The influence of FMR1 gene knockout on the reproduction of male mice

    Institute of Scientific and Technical Information of China (English)

    祝亚桥; 周兴; 陈盛强

    2012-01-01

    Objective To investigate the influence of fragile x mental retardation-1 (FMR1) gene on the spermatogenesis and reproduction of male mice. Methods FMR1 knockout (KO) male mice and wild type (WT) male mice were mated with wt female mice. The number of litters, pregnancy rate and male mice having offsprings were counted. Serum T, FSH and LH concentrations were also measured. The density, mortality and morphology of the left cauda epididymis sperms were analyzed, HE staining was performed on the right side. Results The pregnance rate of wt female mice mated with FMR1K0 males was significantly lower than the control group (41.7% vs. 87. 5% , P 0.05). Male fertility showed that 41.7% of KO mice had pups, whereas 91.7% of the mice had pups in the control group (P 0.05).两组小鼠血清T,FSH,LH浓度无统计学差异.KO组的睾丸附睾病理切片与WT组比较未见明显异常,其精子活率及各种畸形率与WT小鼠比较均没有统计学差异(P>0.05).结论:可以推测FMR1基因对雄性生殖系统发育有一定的影响,Fmr1基因的缺失降低了雄性小鼠生育率,但对精子生成、畸形率等未见明显影响,其对雄性生殖系统影响机制还有待进一步的实验研究.

  17. Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.

    Science.gov (United States)

    Matic, Katarina; Eninger, Timo; Bardoni, Barbara; Davidovic, Laetitia; Macek, Boris

    2014-10-03

    Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS.

  18. Molecular-intelligence correlations in young fragile X males with a mild CGG repeat expansion in the FMR1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Steyaert, J. [Central of Clinical Genetics, Maastricht (Netherlands); Borghgraef, M.; Legius, E. [University Hospital Gasthuisberg, Leuven (Belgium)] [and others

    1996-08-09

    Several mechanisms can explain the occurrence of full-mutation fragile X males with an IQ level above -2 SD below mean, also called {open_quotes}high-functioning fragile X males.{close_quotes} Incomplete methylation of the CpG island at the 5{prime} end of the FMR1 gene is one of these mechanisms. The present study describes the physical and behavior phenotypes in 7 fragile X boys with CGG repeat insertions in the FMR1 gene between 600-2,400 base pairs. The degree of methylation at the FMR1-associated CpG island ranges in peripheral blood lymphocytes from 0-95%. Subjects with a low degree of methylation at this site have mild or absent physical characteristics of the fragile X syndrome, while subjects with a high degree of methylation at this site have more severe physical characteristics. In this range of CGG repeat insertion (600-2,400 base pairs), the degree of methylation at the FMR1-associated CpG island is a good predictor of intelligence, while CGG repeat insertion length is not. 13 refs., 1 fig., 1 tab.

  19. The DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells.

    Science.gov (United States)

    Gerhardt, Jeannine; Tomishima, Mark J; Zaninovic, Nikica; Colak, Dilek; Yan, Zi; Zhan, Qiansheng; Rosenwaks, Zev; Jaffrey, Samie R; Schildkraut, Carl L

    2014-01-09

    Fragile X syndrome (FXS) is caused by a CGG repeat expansion in the FMR1 gene that appears to occur during oogenesis and during early embryogenesis. One model proposes that repeat instability depends on the replication fork direction through the repeats such that (CNG)n hairpin-like structures form, causing DNA polymerase to stall and slip. Examining DNA replication fork progression on single DNA molecules at the endogenous FMR1 locus revealed that replication forks stall at CGG repeats in human cells. Furthermore, replication profiles of FXS human embryonic stem cells (hESCs) compared to nonaffected hESCs showed that fork direction through the repeats is altered at the FMR1 locus in FXS hESCs, such that predominantly the CCG strand serves as the lagging-strand template. This is due to the absence of replication initiation that would typically occur upstream of FMR1, suggesting that altered replication origin usage combined with fork stalling promotes repeat instability during early embryonic development.

  20. Fmr1 knockout mice show reduced anxiety and alterations in neurogenesis that are specific to the ventral dentate gyrus.

    Science.gov (United States)

    Eadie, B D; Zhang, W N; Boehme, F; Gil-Mohapel, J; Kainer, L; Simpson, J M; Christie, B R

    2009-11-01

    Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the selective loss of the expression of the Fmr1 gene. Key symptoms in FXS include intellectual impairment and abnormal anxiety-related behaviors. Fmr1 knockout (KO) mice exhibited reduced anxiety on two behavioral tests as well as a blunted corticosterone response to acute stress. Spatial learning and memory was not impaired when tested with both the classic Morris water and Plus-shaped mazes. Adult hippocampal neurogenesis has been associated with spatial learning and memory and emotions such as anxiety and depression. The process of neurogenesis appears abnormal in young adult Fmr1 KO mice, with significantly fewer bromodeoxyuridine-positive cells surviving for at least 4 weeks in the ventral subregion of the dentate gyrus (DG), a hippocampal subregion more closely associated with emotion than the dorsal DG. Within this smaller pool of surviving cells, we observed a concomitant increase in the proportion of surviving cells that acquire a neuronal phenotype. We did not observe a clear difference in cell proliferation using both endogenous and exogenous markers. This work indicates that loss of Fmr1 expression can alter anxiety-related behaviors in mice as well as produce region-specific alterations in hippocampal adult neurogenesis.

  1. Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies

    DEFF Research Database (Denmark)

    Zink, A M; Wohlleber, E; Engels, H;

    2014-01-01

    Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide...... clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random...... in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute...

  2. Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons

    Directory of Open Access Journals (Sweden)

    Chul-Yong Park

    2015-10-01

    Full Text Available Fragile X syndrome (FXS is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1 gene. Here, we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders.

  3. Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

    Directory of Open Access Journals (Sweden)

    Karen eUsdin

    2014-07-01

    Full Text Available AbstractThe Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor and ataxia syndrome (FXTAS, the fertility disorder, Fragile X-associated primary ovarian insufficiency (FXPOI and the intellectual disability, Fragile X syndrome (FXS. The pathology in all these diseases is related to the number of CGG/CCG-repeats in the 5’ UTR of the FMR1 gene. The repeats are prone to continuous expansion and the increase in repeat number has paradoxical effects on gene expression increasing transcription on mid-sized alleles and decreasing it on longer ones. In some cases the repeats can simultaneously both increase FMR1 mRNA production and decrease the levels of the FMR1 gene product, FMRP. Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by reduced FMRP levels, the clinical picture is turning out to be more complex than once appreciated. Added complications are generated by the fact that increasing repeat numbers make the alleles somatically unstable, generating resulting in individuals sometimes having a complex mixture of different sized alleles. Furthermore, it has become apparent that the eponymous fragile site, once thought to be no more than a useful diagnostic criterion, may have clinical consequences for females who inherit chromosomes that express this site. This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility. It will also touch on what current and future options are for ameliorating some of these effects.

  4. Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits.

    Science.gov (United States)

    Uutela, M; Lindholm, J; Louhivuori, V; Wei, H; Louhivuori, L M; Pertovaara, A; Akerman, K; Castrén, E; Castrén, M L

    2012-07-01

    Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age-dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus-dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  5. Young adult male carriers of the fragile X premutation exhibit genetically modulated impairments in visuospatial tasks controlled for psychomotor speed

    Directory of Open Access Journals (Sweden)

    Wong Ling M

    2012-11-01

    Full Text Available Abstract Background A previous study reported enhanced psychomotor speed, and subtle but significant cognitive impairments, modulated by age and by mutations in the fragile X mental retardation 1 (FMR1 gene in adult female fragile X premutation carriers (fXPCs. Because male carriers, unlike females, do not have a second, unaffected FMR1 allele, male fXPCs should exhibit similar, if not worse, impairments. Understanding male fXPCs is of particular significance because of their increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS. Methods Male fXPCs (n = 18 and healthy control (HC adults (n = 26 aged less than 45 years performed two psychomotor speed tasks (manual and oral and two visuospatial tasks (magnitude comparison and enumeration. In the magnitude comparison task, participants were asked to compare and judge which of two bars was larger. In the enumeration task, participants were shown between one and eight green bars in the center of the screen, and asked to state the total number displayed. Enumeration typically proceeds in one of two modes: subitizing, a fast and accurate process that works only with a small set of items, and counting, which requires accurate serial-object detection and individuation during visual search. We examined the associations between the performance on all tasks and the age, full-scale intelligent quotient, and CGG repeat length of participants. Results We found that in the magnitude comparison and enumeration tasks, male fXPCs exhibited slower reaction times relative to HCs, even after controlling for simple reaction time. Conclusions Our results indicate that male fXPCs as a group show impairments (slower reaction times in numerical visuospatial tasks, which are consistent with previous findings. This adds to a growing body of literature characterizing the phenotype in fXPCs who are asymptomatic for FXTAS. Future longitudinal studies are needed to determine how these impairments

  6. Fmr1基因敲除雄性小鼠生长指标的变化%Observation on the results of body weight and length of male mince with Fmr1 gene knockout.

    Institute of Scientific and Technical Information of China (English)

    杨乙; 刘国彬; 刘绪红; 林波; 黄月玲; 沈岩松; 张维雯; 孙卫文; 李敏雄; 陈盛强

    2011-01-01

    目的 对出生后0~56d的清洁级FVB小鼠和Fmr1基因敲除雄性小鼠的体重和体长指标进行分析比较,同时比较出生后28d的睾丸大小变化.方法 挑选10周龄FVB小鼠和Fmr1基因敲除小鼠各20只(雌、雄各半),采取1:I同居,全同胞兄妹近交繁殖,测定雄性子代生长发育指标,进行统计分析.结果 出生后0~56d清洁级Fmr1基因敲除雄性小鼠体重与体长的增长与FVB小鼠差异无统计学意义(t=0.93,t=1.24,P>0.05),但出生后28d的FVB小鼠和Fmr1基因敲除雄性小鼠睾丸大小差别有统计学意义(t=4.12,P<0.05).结论 Fmr1基因敲除不影响雄性小鼠正常的体重和体长的发育,但出生后28d的Fmr1基因敲除小鼠有巨睾征.%Objective To characterize the growth performance of FVB mice and Fmrl gene knockout mice. Methods There 20 seed FVB micedO males and 10 females,aged 10 weeks)were chosen and monogamously mated. The parameters of growth performance were analyzed. And these analysis also conducted on male Fmrl gene knockout mice. Results There no significant statistical differences in average weight and length of the newboms FVB and Fmrl gene knockout mice within 56 days after borth were observed. While significant differences were observed in size of testes of FVB mice and Fmrl gene knockout mice 28 days after birth. Conclusion Fmrl gene knockout does not affect the growth and weight of the mice but the mice may have giant testes.

  7. Detection of the CGG repeats and methylation of Fragile X mental retardation gene 1 (FMR1)%脆性X综合征FMR1基因CGG重复序列与甲基化的检测

    Institute of Scientific and Technical Information of China (English)

    花茂方; 刘小云; 王文; 陈红; 刘福民; 严晓南

    2012-01-01

    目的 建立一种快速、可靠的脆性X综合征的群体筛查方法.方法 应用热启动PCR和甲基化特异性PCR ( MS - PCR)方法对62例智力低下儿童、12例父母外周血液以及5例高危胎儿的脐带血中FMRl基因CGG重复序列与甲基化状态进行检测.结果 采用热启动PCR方法检测79例标本,77例标本的CGG重复数在21 ~40之间,与正常对照组无明显差异;2例标本未扩增出明显条带.采用MS-PCR方法检测出2例FMRl基因甲基化但CGG重复数在正常范围的患者.结论 应用热启动PCR结合MS - PCR方法检测FMR1基因CGG重复数和甲基化,能提高诊断效率,可作为筛查脆性X综合征的首选方法.%Objective: To establish a time - efficient and sensitive method for screening the CGG repeats and methylation of Fragile X mental retardation gene 1 (FMR1). Methods: The Hot - start PCR and methylation specific PCR ( MS - PCR) were used to detect the CGG repeats and methylation in FMR1 gene of the Mental Retardation (MR) children, their parents and fetus of pregnancy women who had given birth MR children. Results; Detected by the Hot - start PCR, CGG repeats number in FMR1 gene of MR children and the control group were 21 -40, 15-34 respectively and no significant difference were observed between two groups. The CGG repeats number in FMR1 gene of two MR children did not be detected. However, the two MR children were observed methylated FMR1 gene but normal CGG repeats by MS - PCR. Conclusion : The Hot - start PCR and MS - PCR are efficient and sensitive methods for screening fragile X syndrome.

  8. FMR1基因敲除对雌性小鼠生殖功能的影响%Influence of FMR1 gene knockout on the reproduction of female mice

    Institute of Scientific and Technical Information of China (English)

    肖国宏; 叶球仙; 杨洁; 陈盛强; 孙卫文; 黄晓虹; 甘婷

    2014-01-01

    目的 利用FMR1基因敲除小鼠,研究FMR1基因缺失对雌性小鼠生殖功能的影响,并对其影响机制进行探讨.方法 将成年的KO纯合子、KO杂合子、WT雌鼠分别和成年的WT雄鼠合笼,观察合笼时间及产仔数;随机取10周的上述3种基因型雌鼠,HE染色观察卵巢形态;免疫组化测定NPY和GABA在下丘脑的分布,Image Pro Plus 6.0分析平均光密度值;ELISA测定血清NPY水平.结果 3组小鼠中,KO纯合子雌鼠的产仔数少于WT雌鼠(6.39±2.30)、(7.60±2.69)和(8.00±1.88);KO纯合子雌鼠的卵泡总数少于WT雌鼠(36.00±5)、(39.33±7.87)和(45.45±7.85);KO纯合子雌鼠下丘脑NPY的表达弱于WT雌鼠(0.27±0.016)、(0.29±0.04)和(0.31±0.041);血清NPY及下丘脑GABA的表达三组间差异均无显著性(P>0.05).结论 FMR1基因敲除可导致雌鼠生育功能下降,FMR1基因可能是通过下调NPY的表达来降低其生殖功能的.

  9. Behavioural comparision on Fmr1 knockout mice at 30 days age in spontaneous activity test%30日龄Fmr1基因敲除小鼠的自主活动观察

    Institute of Scientific and Technical Information of China (English)

    张伟雯; 黄越玲; 刘国彬; 沈岩松; 孙卫文; 李敏雄; 戴丽军; 陈盛强

    2011-01-01

    Objective To compare the behavioural differences at 30 days age in spontaneous activity test. Methods Fmr1 knockout mice were identified using the PCR technica. and spontaneous activity test was used in the study .The data was analyzed with Multifactor Variance Analysis. Results Activities in their own experiments, as compared with WT mice, KO mice in the experiment of self-activity increase in the number of activities and reduction in the number of standing, with statistical significance ( P<0.05 ), but there were no significant differences on manure behaviour between two groups. Conclusion Fmr1 knockout animals exhibited higher locomotor activity in the spontaneous activity test at 30 days age.%目的 对30日龄的Fmr1基因敲除小鼠的自主活动进行观察.方法 采用30日龄的KO鼠和WT鼠分别连续进行2天的自主活动实验,根据所获得的数据进行多因素方差分析处理.结果 通过第1天的学习与第2天的记忆再现,在自主活动实验中,与WT鼠相比,KO鼠在自主活动实验中的活动和站立次数均增多,具有统计学意义(P<0.05),粪便数相比无明显差异.结论 30日龄Fmr1基因敲除小鼠的自主活动异常,运动性和兴奋性较野生型小鼠增高.

  10. BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26 FMR1 sub-genotypes: explanation for the "BRCA paradox"?

    Directory of Open Access Journals (Sweden)

    Andrea Weghofer

    Full Text Available BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm, heterozygous (het and homozygous (hom, and of their respective sub-genotypes (high/low, in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG (n<26 alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001. These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG (n<26 FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.

  11. Depressed nNOS expression during spine transition in the developing hippocampus of FMR1 KO mice

    Directory of Open Access Journals (Sweden)

    Qin Xu

    2012-12-01

    Full Text Available Nitric oxide (NO, synthesized as needed by NO synthase (NOS, is involved in spinogenesis and synaptogenesis. Immature spine morphology is characteristic of fragile X syndrome (FXS. The objective of this research was to investigate and compare changes of postnatal neuronal NOS (nNOS expression in the hippocampus of male fragile X mental retardation 1 gene knockout mice (FMR1 KO mice, the animal model of FXS and male wild-type mice (WT at postnatal day 7 (P7, P14, P21, and P28. nNOS mRNA levels were analyzed by real-time quantitative PCR (N = 4-7 and nNOS protein was estimated by Western blot (N = 3 and immunohistochemistry (N = 1. In the PCR assessment, primers 5’-GTGGCCATCGTGTCCTACCATAC-3’ and 5’-GTTTCGAGGCAGGTGGAAGCTA-3’ were used for the detection of nNOS and primers 5’-CCGTTTCTCCTGGCTCAGTTTA-3’ and 5’-CCCCAATACCACATCATCCAT-3’ were used for the detection of β-actin. Compared to the WT group, nNOS mRNA expression was significantly decreased in FMR1 KO mice at P21 (KO: 0.2857 ± 0.0150, WT: 0.5646 ± 0.0657; P < 0.05. Consistently, nNOS immunoreactivity also revealed reduced staining intensity at P21 in the FMR1 KO group. Western blot analysis validated the immunostaining results by demonstrating a significant reduction in nNOS protein levels in the FMR1 KO group compared to the WT group at P21 (KO: 0.3015 ± 0.0897, WT: 1.7542 ± 0.5455; P < 0.05. These results suggest that nNOS was involved in the postnatal development of the hippocampus in FXS and impaired NO production may retard spine maturation in FXS.

  12. Depressed nNOS expression during spine transition in the developing hippocampus of FMR1 KO mice

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Qin; Zhu, Zhiwei; Xu, Jialu [Department of Children' s Health Care, Children' s Hospital, Zhejiang University, Hangzhou Zhejiang (China); Gu, Weizhong [Department of Pathology, Children' s Hospital, Zhejiang University, Hangzhou Zhejiang (China); Zhao, Zhengyan [Department of Children' s Health Care, Children' s Hospital, Zhejiang University, Hangzhou Zhejiang (China)

    2012-10-05

    Nitric oxide (NO), synthesized as needed by NO synthase (NOS), is involved in spinogenesis and synaptogenesis. Immature spine morphology is characteristic of fragile X syndrome (FXS). The objective of this research was to investigate and compare changes of postnatal neuronal NOS (nNOS) expression in the hippocampus of male fragile X mental retardation 1 gene knockout mice (FMR1 KO mice, the animal model of FXS) and male wild-type mice (WT) at postnatal day 7 (P7), P14, P21, and P28. nNOS mRNA levels were analyzed by real-time quantitative PCR (N = 4-7) and nNOS protein was estimated by Western blot (N = 3) and immunohistochemistry (N = 1). In the PCR assessment, primers 5′-GTGGCCATCGTGTCCTACCATAC-3′ and 5′-GTTTCGAGGCAGGTGGAAGCTA-3′ were used for the detection of nNOS and primers 5′-CCGTTTCTCCTGGCTCAGTTTA-3′ and 5′-CCCCAATACCACATCATCCAT-3′ were used for the detection of β-actin. Compared to the WT group, nNOS mRNA expression was significantly decreased in FMR1 KO mice at P21 (KO: 0.2857 ± 0.0150, WT: 0.5646 ± 0.0657; P < 0.05). Consistently, nNOS immunoreactivity also revealed reduced staining intensity at P21 in the FMR1 KO group. Western blot analysis validated the immunostaining results by demonstrating a significant reduction in nNOS protein levels in the FMR1 KO group compared to the WT group at P21 (KO: 0.3015 ± 0.0897, WT: 1.7542 ± 0.5455; P < 0.05). These results suggest that nNOS was involved in the postnatal development of the hippocampus in FXS and impaired NO production may retard spine maturation in FXS.

  13. Towards a Better Molecular Diagnosis of FMR1-Related Disorders—A Multiyear Experience from a Reference Lab

    Directory of Open Access Journals (Sweden)

    Sylwia Olimpia Rzońca

    2016-09-01

    Full Text Available The article summarizes over 20 years of experience of a reference lab in fragile X mental retardation 1 gene (FMR1 molecular analysis in the molecular diagnosis of fragile X spectrum disorders. This includes fragile X syndrome (FXS, fragile X-associated primary ovarian insufficiency (FXPOI and fragile X-associated tremor/ataxia syndrome (FXTAS, which are three different clinical conditions with the same molecular background. They are all associated with an expansion of CGG repeats in the 5′UTR of FMR1 gene. Until 2016, the FMR1 gene was tested in 9185 individuals with the pre-screening PCR, supplemented with Southern blot analysis and/or Triplet Repeat Primed PCR based method. This approach allowed us to confirm the diagnosis of FXS, FXPOI FXTAS in 636/9131 (6.96%, 4/43 (9.3% and 3/11 (27.3% of the studied cases, respectively. Moreover, the FXS carrier status was established in 389 individuals. The technical aspect of the molecular analysis is very important in diagnosis of FXS-related disorders. The new methods were subsequently implemented in our laboratory. This allowed the significance of the Southern blot technique to be decreased until its complete withdrawal. Our experience points out the necessity of implementation of the GeneScan based methods to simplify the testing procedure as well as to obtain more information for the patient, especially if TP-PCR based methods are used.

  14. The fragile x mental retardation syndrome 20 years after the FMR1 gene discovery: an expanding universe of knowledge.

    Science.gov (United States)

    Rousseau, François; Labelle, Yves; Bussières, Johanne; Lindsay, Carmen

    2011-08-01

    The fragile X mental retardation (FXMR) syndrome is one of the most frequent causes of mental retardation. Affected individuals display a wide range of additional characteristic features including behavioural and physical phenotypes, and the extent to which individuals are affected is highly variable. For these reasons, elucidation of the pathophysiology of this disease has been an important challenge to the scientific community. 1991 marks the year of the discovery of both the FMR1 gene mutations involved in this disease, and of their dynamic nature. Although a mouse model for the disease has been available for 16 years and extensive research has been performed on the FMR1 protein (FMRP), we still understand little about how the disease develops, and no treatment has yet been shown to be effective. In this review, we summarise current knowledge on FXMR with an emphasis on the technical challenges of molecular diagnostics, on its prevalence and dynamics among populations, and on the potential of screening for FMR1 mutations.

  15. Towards a Better Molecular Diagnosis of FMR1-Related Disorders-A Multiyear Experience from a Reference Lab.

    Science.gov (United States)

    Rzońca, Sylwia Olimpia; Gos, Monika; Szopa, Daniel; Sielska-Rotblum, Danuta; Landowska, Aleksandra; Szpecht-Potocka, Agnieszka; Milewski, Michał; Czekajska, Jolanta; Abramowicz, Anna; Obersztyn, Ewa; Maciejko, Dorota; Mazurczak, Tadeusz; Bal, Jerzy

    2016-09-02

    The article summarizes over 20 years of experience of a reference lab in fragile X mental retardation 1 gene (FMR1) molecular analysis in the molecular diagnosis of fragile X spectrum disorders. This includes fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which are three different clinical conditions with the same molecular background. They are all associated with an expansion of CGG repeats in the 5'UTR of FMR1 gene. Until 2016, the FMR1 gene was tested in 9185 individuals with the pre-screening PCR, supplemented with Southern blot analysis and/or Triplet Repeat Primed PCR based method. This approach allowed us to confirm the diagnosis of FXS, FXPOI FXTAS in 636/9131 (6.96%), 4/43 (9.3%) and 3/11 (27.3%) of the studied cases, respectively. Moreover, the FXS carrier status was established in 389 individuals. The technical aspect of the molecular analysis is very important in diagnosis of FXS-related disorders. The new methods were subsequently implemented in our laboratory. This allowed the significance of the Southern blot technique to be decreased until its complete withdrawal. Our experience points out the necessity of implementation of the GeneScan based methods to simplify the testing procedure as well as to obtain more information for the patient, especially if TP-PCR based methods are used.

  16. Resilience to audiogenic seizures is associated with p-ERK1/2 dephosphorylation in the subiculum of Fmr1 knockout mice

    Directory of Open Access Journals (Sweden)

    Giulia eCuria

    2013-04-01

    Full Text Available Young, but not adult, Fmr1 knockout (KO mice display audiogenic seizures (AGS that can be prevented by inhibiting extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation. In order to identify the cerebral regions involved in these phenomena, we characterized the response to AGS in Fmr1 KO mice and wild type (WT controls at postnatal day (P 45 and P90. To characterize the diverse response to AGS in various cerebral regions, we evaluated the activity markers FosB/ΔFosB and phosphorylated ERK1/2 (p-ERK1/2. Wild running (100% of tested mice followed by clonic/tonic seizures (30% were observed in P45 Fmr1 KO mice, but not in WT mice. In P90 Fmr1 KO mice, wild running was only present in 25% of tested animals. Basal FosB/ΔFosB immunoreactivity was higher (P<0.01 vs WT in the CA1 and subiculum of P45 Fmr1 KO mice. Following the AGS test, FosB/ΔFosB expression consistently increased in most of the analyzed regions in both groups at P45, but not at P90. Interestingly, FosB/ΔFosB immunoreactivity was significantly higher in P45 Fmr1 KO mice in the medial geniculate body (P<0.05 vs WT and CA3 (P<0.01. Neurons presenting with immunopositivity to p-ERK1/2 were more abundant in the subiculum of Fmr1 KO mice in control condition (P<0.05 vs WT, in both age groups. In this region, p-ERK1/2-immunopositive cells significantly decreased (-75%, P<0.01 in P90 Fmr1 KO mice exposed to the AGS test, but no changes were found in P45 mice or in other brain regions. In both age groups of WT mice, p-ERK1/2-immunopositive cells increased in the subiculum after exposure to the acoustic test. Our findings illustrate that FosB/ΔFosB markers are overexpressed in the medial geniculate body and CA3 in Fmr1 KO mice experiencing AGS, and that p-ERK1/2 is markedly decreased in the subiculum of Fmr1 KO mice resistant to AGS induction. These findings suggest that resilience to AGS is associated with dephosphorylation of p-ERK1/2 in the subiculum of mature Fmr1 KO mice.

  17. The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro

    Directory of Open Access Journals (Sweden)

    Tabolacci Elisabetta

    2012-03-01

    Full Text Available Abstract Background Fragile X syndrome (FXS, the leading cause of inherited mental retardation, is due to expansion and methylation of a CGG sequence in the FMR1 gene, which result in its silencing and consequent absence of FMRP protein. This absence causes loss of repression of metabotropic glutamate receptor 5 (mGluR5-mediated pathways resulting in the behavioral and cognitive impairments associated with FXS. In a randomized, double-blind trial it was recently demonstrated a beneficial effect of AFQ056, a selective inhibitor of metabotrobic glutamate receptor type 5 (mGluR5, on fully methylated FXS patients respect to partially methylated FXS ones. Methods To determine whether AFQ056 may have secondary effects on the methylation and transcription of FMR1, here we treated three FXS lymphoblastoid cell lines and one normal control male line. A quantitative RT-PCR was performed to assess transcriptional reactivation of the FMR1 gene. To assess the methylation status of the FMR1 gene promoter it was carried out a bisulphite sequencing analysis. Results Both FMR1-mRNA levels and DNA methylation were unmodified with respect to untreated controls. Conclusions These results demonstrate that the AFQ056 effect on fully methylated FXS patients is not due to a secondary effect on DNA methylation and consequent transcriptional activation of FMR1.

  18. Differences in ovarian aging patterns between races are associated with ovarian genotypes and sub-genotypes of the FMR1 gene

    Directory of Open Access Journals (Sweden)

    Gleicher Norbert

    2012-09-01

    Full Text Available Abstract Background Ovarian aging patterns differ between races, and appear to affect fertility treatment outcomes. What causes these differences is, however, unknown. Variations in ovarian aging patterns have recently been associated with specific ovarian genotypes and sub-genotypes of the FMR1 gene. We, therefore, attempted to determine differences in how functional ovarian reserve (FOR changes with advancing age between races, and whether changes are associated with differences in distribution of ovarian genotypes and sub-genotypes of the FMR1 gene. Methods We determined in association with in vitro fertilization (IVF FOR in 62 young Caucasian, African and Asian oocyte donors and 536 older infertility patients of all three races, based on follicle stimulating hormone (FSH, anti-Müllerian hormone (AMH and oocyte yields, and investigated whether differences between races are associated with differences in distribution of FMR1 genotypes and sub-genotypes. Results Changes in distribution of mean FSH, AMH and oocyte yields between young donors and older infertility patients were significant (all P FMR1 genotypes and sub-genotypes in patients varied significantly between races, with Asians demonstrating fewer het-norm/low sub-genotypes than Caucasians and Africans (P = 0.012. Conclusion FOR changes in different races at different rates, and appears to parallel ovarian FMR1 genotypes and sub-genotype distributions. Differences in ovarian aging between races may, therefore, be FMR1-associated.

  19. A viable model for the study of GABAergic neurons in fmr1 knockout mice%fmr1基因敲除小鼠中间神经元发育研究的新方法

    Institute of Scientific and Technical Information of China (English)

    欧阳梅; 徐明明; 卢韬; 黄越玲; 易咏红

    2011-01-01

    目的:通过杂交技术获得能表达GAD67 -GFP的fmr1基因敲除小鼠模型.方法:fmr1基因敲除(fmr1-ko)雌性小鼠(X-X-)和GAD67-GFP敲入基因杂合雄性小鼠(2+2-)杂交.鼠尾巴提取基因组DNA,用PCR方法鉴定所有子代基因型.对杂交后代小鼠进行行为学观察,并行脑组织切片观察绿色荧光蛋白在γ-氨基丁酸能神经元的表达.结果:PCR方法证实通过杂交繁殖出四种基因型小鼠:同时带有杂合fmr1 ko及GAD67-GFP位点的雌性小鼠(X+ X-/2 +2-)、带有纯合fmr1-ko及GAD67-GFP位点的雄性小鼠(X-Y/2 +2-)、不带有GAD67-GFP的雌性和雄性小鼠(X+X-/2-2-,X-Y/2-2-).观察发现X-Y/2+2-小鼠具有fmr1 -ko小鼠类似的行为学表现,同时在显微镜下观察到X-Y/2+2-小鼠脑组织切片有发绿色荧光的GABA神经元.结论:该杂交小鼠成功表达了GAD67-GFP,为研究γ-氨基丁酸能神经元在脆性X综合征发病机制中的作用提供一种可靠的模型.%Objective: To obtain Fragile X syndrome rat models with GAD67-GFP expression by hybridization technique. Methods; One fmrl-knockout female (X~X~) rat was mated with GAD67-CFP heterozygous male (2 + 2-). All hybrid offspring were genotyped by polymerase chain reaction ( PCR) according to genomic DNA extracted from the tail. The behaviors and the expression of GFP on GABAergic neurons of brain slice were also observed. Results: Four genotypes of mice have been generated: the heterozygous female mice with both the fmrl-gfp-ko and GAD67-GFP locus (X+XV2-2-) , fmrl-ko male mice heterozygous with GAD67-GFP locus (X-Y/2+2-) .female and male mice without GAD67-GFP locus(X+ X/-2-2-,X-Y/2-2-). Mice X-Y2+2-were noted to have similar behaviors with fmrl ko mice. Morphological observation of GABAergic neuron had a good match between the mice X-Y/2+2~and fmrl ko mice. Conclusions:The hybrid mice X-Y/2-2- successfully expressed the GAD67-GFP protein, which provides a viable model for the study on the pathogenetic effect of

  20. Investigation on the mechanism of descended reproductive function in FMR1 gene knockout male mice%FMR1基因敲除雄鼠生殖功能下降的机制探讨

    Institute of Scientific and Technical Information of China (English)

    叶球仙; 杨洁; 罗虹; 陈盛强; 黄晓虹; 甘婷; 陈燕; 肖国宏

    2013-01-01

    Objective To investigate the mechanism of descended reproductive function induced by FMR1 gene knockout in male FMR1 gene knockout mice (KO) and male wild mice (WT).Methods The morphology of the testis of 10 weeks old KO and WT male mice were observed by HE staining.The mean optical density (MOD) of the expressions of neuropeptide Y (NPY) and gamma aminobutyricacid (GABA) in hypothalamus were tested and analyzed by immunohistochemistry and Image Pro Plus 6.0.Serum NPY concentrations were measured by ELISA.Results No obvious pathological differences in testis were found between KO and WT mice.The MOD of NPY in hypothalamus and the expression of NPY in serum in KO mice were weaken than those in WT mice,respectively [0.27 ± 0.031 vs.0.31 ± 0.031,P < 0.05; (179.21 ± 50.773)ng/L vs.(225.24 ± 52.293) ng/L,P <0.05].There was no significant difference in the MOD of GABA in hypothalamus between KO and WT mice (0.29 ±0.017 vs.0.28 ± 0.009,P > 0.05).Conclusions FMR1 gene may down-regulate the reproductive function of male mice through reducing the expression of NPY.%目的:利用FMR1基因敲除鼠(KO)和野生型FVB鼠(WT),研究FMR1基因敲除引起雄鼠生殖功能下降的可能机制.方法:随机取10周的KO及WT雄鼠,HE染色观察睾丸形态;免疫组化及Image ProPlus 6.0测定分析下丘脑神经肽Y(NPY)及γ-氨基丁酸(GABA)表达的平均光密度值;ELISA测定血清NPY水平.结果:KO、WT小鼠睾丸形态未见明显不同;KO雄鼠下丘脑NPY的表达弱于WT雄鼠(0.27±0.031,0.31±0.031,P<0.05);KO雄鼠血清NPY的表达弱于WT雄鼠(179.21±50.773,225.24±52.293,P< 0.05);两种基因型小鼠下丘脑GABA的表达差异无统计学意义(0.29±0.017,0.28±0.009,P> 0.05).结论:FMR1基因可能是通过下调NPY的表达来降低雄鼠生殖功能的.

  1. 2-Methyl-6-(phenylethynyl pyridine (MPEP reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice.

    Directory of Open Access Journals (Sweden)

    Réno Michelle Gandhi

    2014-03-01

    Full Text Available Fragile X syndrome (FXS is caused by the lack of expression of the fragile X mental retardation protein (FMRP, which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR signalling, which is a target for putative treatments. The Hebb-Williams (H-W mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioural deficits in Fmr1 KO mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl pyridine (MPEP; n = 11 or an equivalent dose of saline (n = 11 prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioural deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed PSD-95 protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioural functioning following pharmacological

  2. Cell-Type Specific Channelopathies in the Prefrontal Cortex of the fmr1-/y Mouse Model of Fragile X Syndrome.

    Science.gov (United States)

    Kalmbach, Brian E; Johnston, Daniel; Brager, Darrin H

    2015-01-01

    Fragile X syndrome (FXS) is caused by transcriptional silencing of the fmr1 gene resulting in the loss of fragile X mental retardation protein (FMRP) expression. FXS patients display several behavioral phenotypes associated with prefrontal cortex (PFC) dysfunction. Voltage-gated ion channels, some of which are regulated by FMRP, heavily influence PFC neuron function. Although there is evidence for brain region-specific alterations to the function a single type of ion channel in FXS, it is unclear whether subtypes of principal neurons within a brain region are affected uniformly. We tested for alterations to ion channels critical in regulating neural excitability in two subtypes of prefrontal L5 pyramidal neurons. Using somatic and dendritic patch-clamp recordings, we provide evidence that the functional expression of h-channels (Ih) is down-regulated, whereas A-type K(+) channel function is up-regulated in pyramidal tract-projecting (PT) neurons in the fmr1-/y mouse PFC. This is the opposite pattern of results from published findings from hippocampus where Ih is up-regulated and A-type K(+) channel function is down-regulated. Additionally, we find that somatic Kv1-mediated current is down-regulated, resulting in increased excitability of fmr1-/y PT neurons. Importantly, these h- and K(+) channel differences do not extend to neighboring intratelencephalic-projecting neurons. Thus, the absence of FMRP has divergent effects on the function of individual types of ion channels not only between brain regions, but also variable effects across cell types within the same brain region. Given the importance of ion channels in regulating neural circuits, these results suggest cell-type-specific phenotypes for the disease.

  3. A novel methylation PCR that offers standardized determination of FMR1 methylation and CGG repeat length without southern blot analysis.

    Science.gov (United States)

    Grasso, Marina; Boon, Elles M J; Filipovic-Sadic, Stela; van Bunderen, Patrick A; Gennaro, Elena; Cao, Ru; Latham, Gary J; Hadd, Andrew G; Coviello, Domenico A

    2014-01-01

    Fragile X syndrome and associated disorders are characterized by the number of CGG repeats and methylation status of the FMR1 gene for which Southern blot (SB) historically has been required for analysis. This study describes a simple PCR-only workflow (mPCR) to replace SB analysis, that incorporates novel procedural controls, treatment of the DNA in separate control and methylation-sensitive restriction endonuclease reactions, amplification with labeled primers, and two-color amplicon sizing by capillary electrophoresis. mPCR was evaluated in two independent laboratories with 76 residual clinical samples that represented typical and challenging fragile X alleles in both males and females. mPCR enabled superior size resolution and analytical sensitivity for size and methylation mosaicism compared to SB. Full mutation mosaicism was detected down to 1% in a background of 99% normal allele with 50- to 100-fold less DNA than required for SB. A low level of full mutation mosaicism in one sample was detected using mPCR but not observed using SB. Overall, the sensitivity for detection of full mutation alleles was 100% (95% CI: 89%-100%) with an accuracy of 99% (95% CI: 93%-100%). mPCR analysis of DNA from individuals with Klinefelter and Turner syndromes, and DNA from sperm and blood, were consistent with SB. As such, mPCR enables accurate, sensitive, and standardized methods of FMR1 analysis that can harmonize results across different laboratories.

  4. The impact in older women of ovarian FMR1 genotypes and sub-genotypes on ovarian reserve.

    Directory of Open Access Journals (Sweden)

    Norbert Gleicher

    Full Text Available We recently associated ovarian FMR1genotypes and sub-genotypes with distinct ovarian aging patterns. How they impact older females is, however, unknown. We, therefore, investigated 217 consecutive first in vitro fertilization (IVF cycles in women >40 assessing oocyte yields, stratified for better (anti-Müllerian hormone, AMH >1.05 ng/mL or poorer (AMH ≤ 1.05 ng/mL functional reserve (FOR. Mean age was 42.4 ± 2.0 years, mean AMH 0.76 ± 0.92 ng/mL and mean oocyte yield 5.3 ± 5.4. Overall, and in women with better FOR, FMR1 did not affect oocyte yields. With poorer FOR (AMH ≤ 1.05 ng/mL women with het-norm/high, however, demonstrated higher oocyte yields (5.0 ± 3.8 than those with het-norm/low sub-genotype 3.1 ± 2.5; P = 0.03, confirmed after log conversion. Known associated with low FOR at young age, het-norm/high, thus, appears to preserve FOR into older age, and both het sub-genotypes appear to expand female reproductive lifespan into opposite directions.

  5. eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors.

    Science.gov (United States)

    Huynh, Thu N; Shah, Manan; Koo, So Yeon; Faraud, Kirsten S; Santini, Emanuela; Klann, Eric

    2015-11-01

    Autism spectrum disorder (ASD) is a group of heritable disorders with complex and unclear etiology. Classic ASD symptoms include social interaction and communication deficits as well as restricted, repetitive behaviors. In addition, ASD is often comorbid with intellectual disability. Fragile X syndrome (FXS) is the leading genetic cause of ASD, and is the most commonly inherited form of intellectual disability. Several mouse models of ASD and FXS exist, however the intellectual disability observed in ASD patients is not well modeled in mice. Using the Fmr1 knockout mouse and the eIF4E transgenic mouse, two previously characterized mouse models of fragile X syndrome and ASD, respectively, we generated the eIF4E/Fmr1 double mutant mouse. Our study shows that the eIF4E/Fmr1 double mutant mice display classic ASD behaviors, as well as cognitive dysfunction. Importantly, the learning impairments displayed by the double mutant mice spanned multiple cognitive tasks. Moreover, the eIF4E/Fmr1 double mutant mice display increased levels of basal protein synthesis. The results of our study suggest that the eIF4E/Fmr1 double mutant mouse may be a reliable model to study cognitive dysfunction in the context of ASD. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Impaired Dendritic Expression and Plasticity of h-Channels in the fmr1−/y Mouse Model of Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Darrin H. Brager

    2012-03-01

    Full Text Available Despite extensive research into both synaptic and morphological changes, surprisingly little is known about dendritic function in fragile X syndrome (FXS. We found that the dendritic input resistance of CA1 neurons was significantly lower in fmr1−/y versus wild-type mice. Consistent with elevated dendritic Ih, voltage sag, rebound, and resonance frequency were significantly higher and temporal summation was lower in the dendrites of fmr1−/y mice. Dendritic expression of the h-channel subunit HCN1, but not HCN2, was higher in the CA1 region of fmr1−/y mice. Interestingly, whereas mGluR-mediated persistent decreases in Ih occurred in both wild-type and fmr1−/y mice, persistent increases in Ih that occurred after LTP induction in wild-type mice were absent in fmr1−/y mice. Thus, chronic upregulation of dendritic Ih in conjunction with impairment of homeostatic h-channel plasticity represents a dendritic channelopathy in this model of mental retardation and may provide a mechanism for the cognitive impairment associated with FXS.

  7. 三十日龄Fmr1基因敲除小鼠的水迷宫实验观察%Behavioural comparision on Fmr1 knockout mice at 30 days age in Morris water maze experiment

    Institute of Scientific and Technical Information of China (English)

    孙卫文; 黄越玲; 张维雯; 刘国彬; 沈岩松; 李敏雄; 戴丽军; 陈盛强

    2011-01-01

    目的 实验对30日龄的Fmr1基因敲除(KO)小鼠的经典Morris水迷宫实验进行观察.方法 采用Morris水迷宫实验,测试1月龄KO小鼠与WT小鼠的学习记忆功能.水迷宫实验共训练4 d,记录每天的潜伏期与游泳轨迹,第5天去除平台,记录小鼠停留各象限的时间百分比.根据所获得的数据进行多因素方差分析处理.结果 ①空间航行实验第1天至第3天实验中KO鼠与WT鼠的潜伏期和穿越平台次数差异无统计学意义(P>0.05);在第4天实验中KO鼠的潜伏期和穿越平台次数比WT鼠差异有统计学意义(JP<0.05).②空间搜索实验4周龄WT鼠在目标象限停留时间比其它象限停留时间长;4周龄KO鼠在第二象限停留时间长.结论 30日龄KO小鼠存在认知功能障碍.%Objective To compare the behaviour defferences at 30 days age in Morris water maze experiment.Methods Fmr1 knockout mice were identified using the PCR technique , and Morris water maze experiment were used in the study.The data was analyzed with Multifactor Variance Analysis.Results ①space navigation experiment from the first day to the third day, KO mice have no obviously difference with the WT mice in the Latency and number of crossing platform (P> 0.05) , but on the fourth day , there was a statistical significance (P< 0.05) ; ②Space search experiment.The four-week WT mice will stay longer than the other mice at the target quadrants; the four-week KO mice stay at the second quadrant longer.Conclusion Fmr1 knockout animals exhihited low ability of learning and memorizing in the Morris water maze task at 30 days Age.

  8. The fragile X phenotype in a mosaic male with a deletion showing expression of the FMR1 protein in 28% of the cells

    Energy Technology Data Exchange (ETDEWEB)

    Graaf, E. de; Vries, B.B.A. de; Willemsen, R. [Erasmus Univ., Rotterdam (Netherlands)] [and others

    1996-08-09

    The instability of the CGG repeat region of FMR1 is not restricted to the CGG repeat but expands to flanking sequences as well. A mosaic fragile X male is reported with a deletion of part of the CGG repeat and 30 bp immediately 3{prime} of the repeat, thus confirming the presence of a hotspot for deletions in the CGG region of FMR1. The deletion, detected in 28% of his lymphocytes, did not impair the transcription and translation of FMR1, suggesting that regulatory elements are not present in the deleted region. The patient has the characteristic fragile X phenotype and assuming that the mosaic pattern detected in the lymphocytes reflects the mosaic pattern in brain, 28% expression of FMRP may not be sufficient for normal cognitive functioning. 43 refs., 3 figs.

  9. A distinct DNA-methylation boundary in the 5'- upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.

    Science.gov (United States)

    Naumann, Anja; Hochstein, Norbert; Weber, Stefanie; Fanning, Ellen; Doerfler, Walter

    2009-11-01

    We have discovered a distinct DNA-methylation boundary at a site between 650 and 800 nucleotides upstream of the CGG repeat in the first exon of the human FMR1 gene. This boundary, identified by bisulfite sequencing, is present in all human cell lines and cell types, irrespective of age, gender, and developmental stage. The same boundary is found also in different mouse tissues, although sequence homology between human and mouse in this region is only 46.7%. This boundary sequence, in both the unmethylated and the CpG-methylated modes, binds specifically to nuclear proteins from human cells. We interpret this boundary as carrying a specific chromatin structure that delineates a hypermethylated area in the genome from the unmethylated FMR1 promoter and protecting it from the spreading of DNA methylation. In individuals with the fragile X syndrome (FRAXA), the methylation boundary is lost; methylation has penetrated into the FMR1 promoter and inactivated the FMR1 gene. In one FRAXA genome, the upstream terminus of the methylation boundary region exhibits decreased methylation as compared to that of healthy individuals. This finding suggests changes in nucleotide sequence and chromatin structure in the boundary region of this FRAXA individual. In the completely de novo methylated FMR1 promoter, there are isolated unmethylated CpG dinucleotides that are, however, not found when the FMR1 promoter and upstream sequences are methylated in vitro with the bacterial M-SssI DNA methyltransferase. They may arise during de novo methylation only in DNA that is organized in chromatin and be due to the binding of specific proteins.

  10. A Distinct DNA-Methylation Boundary in the 5′- Upstream Sequence of the FMR1 Promoter Binds Nuclear Proteins and Is Lost in Fragile X Syndrome

    Science.gov (United States)

    Naumann, Anja; Hochstein, Norbert; Weber, Stefanie; Fanning, Ellen; Doerfler, Walter

    2009-01-01

    We have discovered a distinct DNA-methylation boundary at a site between 650 and 800 nucleotides upstream of the CGG repeat in the first exon of the human FMR1 gene. This boundary, identified by bisulfite sequencing, is present in all human cell lines and cell types, irrespective of age, gender, and developmental stage. The same boundary is found also in different mouse tissues, although sequence homology between human and mouse in this region is only 46.7%. This boundary sequence, in both the unmethylated and the CpG-methylated modes, binds specifically to nuclear proteins from human cells. We interpret this boundary as carrying a specific chromatin structure that delineates a hypermethylated area in the genome from the unmethylated FMR1 promoter and protecting it from the spreading of DNA methylation. In individuals with the fragile X syndrome (FRAXA), the methylation boundary is lost; methylation has penetrated into the FMR1 promoter and inactivated the FMR1 gene. In one FRAXA genome, the upstream terminus of the methylation boundary region exhibits decreased methylation as compared to that of healthy individuals. This finding suggests changes in nucleotide sequence and chromatin structure in the boundary region of this FRAXA individual. In the completely de novo methylated FMR1 promoter, there are isolated unmethylated CpG dinucleotides that are, however, not found when the FMR1 promoter and upstream sequences are methylated in vitro with the bacterial M-SssI DNA methyltransferase. They may arise during de novo methylation only in DNA that is organized in chromatin and be due to the binding of specific proteins. PMID:19853235

  11. 钙结合蛋白Calbindin在FMR1基因敲除小鼠脑组织中的表达%The expression of calcium combined with protein Calbindin in little FMR-1 gene knockout rat brain tissue

    Institute of Scientific and Technical Information of China (English)

    郭阳; 易咏红; 孙卫文

    2006-01-01

    目的探讨脆性X综合征中钙结合蛋白Calbindin在神经元树突棘形态异常中的作用.方法我们选用FVB品系的FMR1基因敲除型(KO)和野生型(WT)小鼠,分别取新生1、3、5、7、10、14 d,及成年(6周)的KO小鼠以及WT小鼠用免疫组织化学方法检测钙结合蛋白Calbindin在脑组织中的分布和表达情况,分别对大脑纹状皮质、海马、颞叶听区、梨状皮质、丘脑及小脑的免疫阳性显色细胞进行检测.结果在新生1 d龄WT型及KO型小鼠中Calbindin免疫阳性细胞首先出现于梨状皮质和小脑皮质中,随着天龄的增长脑内其他各区逐渐出现Calbindin免疫阳性细胞的表达,且≤10 dKO型小鼠Calbindin免疫阳性细胞平均光密度均显著高于WT型小鼠(P<0.05). 结论FMRP通过负性调节脑内钙结合蛋白Calbindin的表达,这推测与FMR1基因敲除小鼠神经元树突和树突棘形态异常有关.

  12. DNA diagnosis of the fragile X syndrome in a series of 236 mentally retarded subjects and evidence for a reversal of mutation in the FMR-1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Ouweland, A.M.W. van den; Vries, B.B.A. de; Bakker, P.L.G.; Deelen, W.H.; Graaff, E. de; Hemel, J.O. van; Oostra, B.A.; Niermeijer, M.F.; Halley, D.J.J. [Erasmus Univ., Rotterdam (Netherlands)

    1994-07-15

    The cloning of the FMR-1 gene and the identification of an expanded CGG repeat in DNA of fragile X patients has made reliable DNA diagnosis feasible. Southern blotting and PCR assays of the CGG repeat in an unselected series of 236 mentally retarded subjects resulted in the identification of 10 new fragile X families. Reevaluation of previously assessed fragile X families resulted in the first observation of the presence of a reversal of mutation in the FMR-1 gene. 21 refs., 1 fig., 1 tab.

  13. Slight instability of a FMR-1 allele over three generations in a family from the general population

    Energy Technology Data Exchange (ETDEWEB)

    Abramowicz, M.J.; Parma, J.; Cochaux, P. [Brussels Univ. Clinic-Erasme Hospital, Brussels (Belgium)

    1996-08-09

    We report on a family segregating a FMR-1 allele within the {open_quotes}grey zone{close_quotes} of triplet repeat length (n = 51). The allele showed a 1-unit increment when transmitted through a female meiosis and a 1-unit increment when transmitted through a male of the next generation. At the following generation, a pregnant woman had amniocentesis performed. The latter showed she transmitted the allele unchanged (n = 53) to her male fetus. This family was not ascertained through an affected subject, and there was no family history of mental retardation. Thus our observation reflects the natural history of an unstable allele in the general population. Systematic analysis of such alleles may help refine our understanding of the grey zone of triplet repeat length. 5 refs., 1 fig.

  14. FMR1 CGG repeat distribution and linked microsatellite-SNP haplotypes in normal Mexican Mestizo and indigenous populations.

    Science.gov (United States)

    Felix-López, Xóchitl Adriana; Argüello-García, Raúl; Cerda-Flores, Ricardo M; Peñaloza-Espinoza, Rosenda I; Buentello-Malo, Leonor; Estrada-Mena, Francisco Javier; Ramos-Kuri, Manuel; Gómez, Fabio Salamanca; Arenas-Aranda, Diego Julio

    2006-10-01

    The (CGG)n repeat size distribution in the FMR1 gene was studied in healthy individuals: 80 X chromosomes of Mexican Mestizos from Mexico City and 33 X chromosomes of Mexican Amerindians from three indigenous communities (Purepechas, Nahuas, and Tzeltales), along with alleles and haplotypes defined by two microsatellite polymorphic markers (DXS548 and FRAXAC1) and two single nucleotide polymorphisms (FMRA and FMRB). Genetic frequencies of Mestizo and Amerindian subpopulations were statistically similar in almost all cases and thus were considered one population for comparisons with other populations. Sixteen (CGG)n alleles in the 17-38 size range were observed, and the most common were the 25 (38.0%), 26 (28.3%), and 24 (12.3%) repeat alleles. This pattern differs from most other populations reported, but a closer relation to Amerindian, European, and African populations was found, as expected from the historical admixture that gave rise to Mexican Mestizos. The results of the CA repeats analysis at DXS548-FRAXAC1 were restricted to nine haplotypes, of which haplotypes 7-4 (52.2%), 8-4 (23.8%), and 7-3 (11.5%) were predominant. The modal haplotype 7-4, instead of the nearly universal haplotype 7-3, had been reported exclusively in Eastern Asian populations. Likewise, only seven different FRAXAC1-FMRA-FMRB haplotypes were observed, including five novel haplotypes (3TA, 4TA, 3 - A, 4 - A, and 5 - A), compared with Caucasians. Of these, haplotypes - A (78.7%) and 3 - A (13.2%) were the most common in the Mexican population. These data suggest a singular but relatively low genetic diversity at FMR1 in the studied Mexican populations that may be related to the recent origin of Mestizos and the low admixture rate of Amerindians.

  15. Temporal dynamics of attentional selection in adult male carriers of the fragile X premutation allele and adult controls

    Directory of Open Access Journals (Sweden)

    Ling Mei Wong

    2015-02-01

    Full Text Available Carriers of the fragile X premutation allele (fXPCs have an expanded CGG trinucleotide repeat size within the emph{FMR1} gene and are at increased risk of developing Fragile X-associated Tremor Ataxia Syndrome (FXTAS. Previous research has shown that male fXPCs with FXTAS exhibit cognitive decline, predominantly in executive functions such as inhibitory control and working memory. Recent evidence suggests fXPCs may also exhibit impairments in processing temporal information. The attentional blink (AB task is often used to examine the dynamics of attentional selection, but disagreements exist as to whether the AB is due to excessive or insufficient attentional control. In this study, we used a variant of the AB task and neuropsychological testing to explore the dynamics of attentional selection, relate AB performance to attentional control, and determine whether fXPCs exhibited temporal and/or attentional control impairments. Participants were adult male fXPCs, aged 18--48 years and asymptomatic for FXTAS (emph{n} = 19 and age-matched male controls (emph{n} = 20. We found that fXPCs did not differ from controls in the AB task, indicating that the temporal dynamics of attentional selection were intact. However, they were impaired in the letter-number sequencing task, a test of attentional control. In the combined fXPC and control group, letter-number sequencing performance correlated positively with AB magnitude. This finding supports models that posit the AB is due to excess attentional control. In our two-pronged analysis approach, we contribute to the theoretical literature in controls by extending the AB literature, and we enhance our understanding of fXPCs by demonstrating that at least some aspects of temporal processing may be spared.

  16. 针刺长强穴对FMR1基因敲除小鼠海马CA1区BDNF和SYN表达的影响%Effects of Acupuncturing at Changqiang on Expressions of BDNF and SYN in Hippocampal CA1 Area of FMR1 Gene Knockout Mice

    Institute of Scientific and Technical Information of China (English)

    韩平; 俞萍; 陈可爱; 林栋; 张学君; 吴强

    2012-01-01

    目的 研究针刺长强穴对FMR1基因敲除小鼠海马CA1区脑源性神经营养因子(BDNF)与突触素(SYN)的表达. 方法 选取28日龄脆性X智力低下基因1(FMR1)缺失KO小鼠与野生型(WT)小鼠各30只,分为KO长强组、KO非穴组、KO空白组和WT长强组、WT非穴组、WT空白组,每组10只,检测小鼠海马CA1区BDNF、SYN蛋白的表达. 结果 FMR1基因敲除小鼠海马区BDNF的表达低于野生型小鼠;FMR1基因敲除小鼠长强组BDNF的表达明显高于非穴组和空白组;FMR1基因敲除小鼠海马区SYN的表达低于野生型小鼠;FMR1基因敲除小鼠长强组SYN的表达明显高于非穴组和空白组. 结论 针刺长强穴能上调FMR1基因敲除小鼠海马CA1区BDNF和SYN的表达.

  17. The RNA-binding proteins FMR1, rasputin and caprin act together with the UBA protein lingerer to restrict tissue growth in Drosophila melanogaster.

    Science.gov (United States)

    Baumgartner, Roland; Stocker, Hugo; Hafen, Ernst

    2013-01-01

    Appropriate expression of growth-regulatory genes is essential to ensure normal animal development and to prevent diseases like cancer. Gene regulation at the levels of transcription and translational initiation mediated by the Hippo and Insulin signaling pathways and by the TORC1 complex, respectively, has been well documented. Whether translational control mediated by RNA-binding proteins contributes to the regulation of cellular growth is less clear. Here, we identify Lingerer (Lig), an UBA domain-containing protein, as growth suppressor that associates with the RNA-binding proteins Fragile X mental retardation protein 1 (FMR1) and Caprin (Capr) and directly interacts with and regulates the RNA-binding protein Rasputin (Rin) in Drosophila melanogaster. lig mutant organs overgrow due to increased proliferation, and a reporter for the JAK/STAT signaling pathway is upregulated in a lig mutant situation. rin, Capr or FMR1 in combination as double mutants, but not the respective single mutants, display lig like phenotypes, implicating a redundant function of Rin, Capr and FMR1 in growth control in epithelial tissues. Thus, Lig regulates cell proliferation during development in concert with Rin, Capr and FMR1.

  18. The RNA-binding proteins FMR1, rasputin and caprin act together with the UBA protein lingerer to restrict tissue growth in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Roland Baumgartner

    Full Text Available Appropriate expression of growth-regulatory genes is essential to ensure normal animal development and to prevent diseases like cancer. Gene regulation at the levels of transcription and translational initiation mediated by the Hippo and Insulin signaling pathways and by the TORC1 complex, respectively, has been well documented. Whether translational control mediated by RNA-binding proteins contributes to the regulation of cellular growth is less clear. Here, we identify Lingerer (Lig, an UBA domain-containing protein, as growth suppressor that associates with the RNA-binding proteins Fragile X mental retardation protein 1 (FMR1 and Caprin (Capr and directly interacts with and regulates the RNA-binding protein Rasputin (Rin in Drosophila melanogaster. lig mutant organs overgrow due to increased proliferation, and a reporter for the JAK/STAT signaling pathway is upregulated in a lig mutant situation. rin, Capr or FMR1 in combination as double mutants, but not the respective single mutants, display lig like phenotypes, implicating a redundant function of Rin, Capr and FMR1 in growth control in epithelial tissues. Thus, Lig regulates cell proliferation during development in concert with Rin, Capr and FMR1.

  19. 中国女性对于FMR1突变产前筛查的态度调查%Acceptance of prenatal screening for FMR1 mutation in Chinese female population

    Institute of Scientific and Technical Information of China (English)

    张岚; 章远志

    2012-01-01

    Objective Study the attitude of Chinese female population on prenatal screening of FXS in order to investigate the feasibility of offering prenatal screening.Methods Two hundred and eighty four women with no family history of mental retardation or FXS were recruited in the study.They were grouped into:females married with child (ren) (67/284),females married without child (54/284),unmarried single women (163/284).Then the participants were tested whether they retained the basic genetic knowledge of fragile X by using the adapted questionnaire.Results The proportions of the women who preferred to have prenatal screening for FXS in each group were 77.6%,66.7% and 74.9%.Further more,95.5% of the women in the first female group would like to terminate the pregnancy if a positive result of FXS was reported,so did 92.6% of the women in the second female group and 90.2% of women in the third female group.Conclusion There is a big acceptance of prenatal screening for FMR1 mutation in Chinese female population.Most people would like to take prenatal screening of fragile X syndrome.%目的 调查中国女性对于脆性X综合征产前筛查的态度.方法 随机调查284位没有智力发育障碍及脆性X综合征家族史的女性,分为已婚已育(67/284)、已婚未育(54/284)及未婚未育(163/284)三组.结果 各组愿意接受产前筛查的比率分别为77.6%、66.7%及74.9%.而各组选择在得知产前筛查结果阳性时愿意终止妊娠的比率分别为95.5%、92.6%及90.2%.结论 在中国女性群体中对FMR1基因突变进行产前筛查有较高的接受度.大多数人选择接受针对脆X综合征的产前筛查.

  20. 30日龄Fmr1基因敲除小鼠的跳台实验观察%Behavioural Comparison of Fmr1 Knockout Mice at 30 Days Age in Step-down Test

    Institute of Scientific and Technical Information of China (English)

    黄月玲; 沈岩松; 张维雯; 孙卫文; 李敏雄; 陈盛强; 戴丽军

    2011-01-01

    目的 对30日龄的Fmr1基因敲除小鼠的跳台实验进行观察.方法 采用30日龄的KO鼠和WT鼠分别连续进行2d的跳台实验,根据所获得的数据进行多因素方差分析处理.结果 同周龄KO鼠的潜伏期比WT鼠明显少(P<0.05);而KO鼠的错误次数比WT鼠明显多(P<0.05);不同周龄KO鼠或WT鼠的潜伏期、错误次数无差异(P>0.05);第1天KO鼠的潜伏期和错误次数与第2天相比无差异(P>0.05);第1天WT鼠的潜伏期和错误次数与第2天相比有显著差异(P<0.05).结论 30日龄Fmr1基因敲除小鼠存在认知功能障碍.%Objective This study was designed to observe the cognition of Fmrl knockout mice at 30 days Age instep-down test. Method Fmrl knockout mice were identified using the PCR technical and step-down test were used in the study. Animals were tested for two days. The latency and the number of errors were recorded. The data was analyzed with multifactor variance analysis. Result KO mice obviously had the shorter latency than WT mice, and KO mice obviously had more errors than WT mice ( P 0. 05 ) ; On the first day, the latency and number of errors of WT mice had significant difference compared with the second day ( P < 0.05 ). Conclusion Fmrl knockout mice displayed cognitive impairment in the step-down test.

  1. Extended gene diversity at the FMR1 locus and neighbouring CA repeats in a sub-Saharan population

    Energy Technology Data Exchange (ETDEWEB)

    Chiurazzi, Genuardi, M.; Neri, G. [Instituto di Genetica Medica, Roma (Italy)] [and others

    1996-07-12

    We report on the allele distributions in a normal black African population at two microsatellite loci neighbouring the FRAXA locus and at the CGG repeat in the 5{prime} end of the FMR1 gene, which causes the fragile X syndrome. The CGG repeat distribution was found to be similar to that of other ethnic groups, as well as to that of other non-human primates, possibly predicting a comparable prevalence of fragile X in Africa. Significant linkage disequilibrium has been observed between fragile X mutations and alleles of the DXS548 and FRAXAC1 loci in European and Asian populations, and some founder chromosomes may be extremely old. Those associated with FRAXAC1-A and DXS548-2 alleles are not present in the Asian fragile X samples. We searched for these alleles and their frequency in the well defined Bamileke population of Cameroon. All previously described alleles and some new ones were found in this sample, supporting the hypothesis of their pre-existence and subsequent loss in Asian populations. Finally, the heterozygosity of the Bamileke sample was significantly higher at both marker loci and comparable to that of Europeans at the CGG repeat, confirming the notion that genetic diversity is greater in Africans than in other groups and supporting the view that evolution of modern man started in Africa. 31 refs., 1 fig., 1 tab.

  2. Cell-Type Specific Channelopathies in the Prefrontal Cortex of the fmr1-/y Mouse Model of Fragile X Syndrome 1,2,3

    OpenAIRE

    Kalmbach, Brian E.; Johnston, Daniel; Brager, Darrin H.

    2015-01-01

    Abstract Fragile X syndrome (FXS) is caused by transcriptional silencing of the fmr1 gene resulting in the loss of fragile X mental retardation protein (FMRP) expression. FXS patients display several behavioral phenotypes associated with prefrontal cortex (PFC) dysfunction. Voltage-gated ion channels, some of which are regulated by FMRP, heavily influence PFC neuron function. Although there is evidence for brain region-specific alterations to the function a single type of ion channel in FXS, ...

  3. Distribution of the FMR1 gene in females by race/ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study).

    Science.gov (United States)

    Pastore, Lisa M; Young, Steven L; Manichaikul, Ani; Baker, Valerie L; Wang, Xin Q; Finkelstein, Joel S

    2017-01-01

    To study whether reported, but inconsistent, associations between the FMR1 CGG repeat lengths in the intermediate, high normal, or low normal range differentiate women diagnosed with diminished ovarian reserve (DOR) from population controls and whether associations vary by race/ethnic group. Case-control study. Academic and private fertility clinics. DOR cases (n = 129; 95 Whites, 22 Asian, 12 other) from five U.S. fertility clinics were clinically diagnosed, with regular menses and no fragile X syndrome family history. Normal fertility controls (n = 803; 386 Whites, 219 African-Americans, 102 Japanese, 96 Chinese) from the United States-based SWAN Study had one or more menstrual period in the 3 months pre-enrollment, one or more pregnancy, no history of infertility or hormone therapy, and menopause ≥46 years. Previously, the SWAN Chinese and Japanese groups had similar FMR1 CGG repeat lengths, thus they were combined. None. FMR1 CGG repeat lengths. Median CGG repeats were nearly identical by case/control group. DOR cases had fewer CGG repeats in the shorter FMR1 allele than controls among Whites, but this was not significant among Asians. White cases had fewer CGG repeats in the shorter allele than Asian cases. No significant differences were found in the high normal/intermediate range between cases and controls or by race/ethnic group within cases in the longer allele. This study refutes prior reports of an association between DOR and high normal/intermediate repeats and confirms an association between DOR and low normal repeats in Whites. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  4. Fmr1基因在大鼠快速眼动睡眠剥夺后脑皮质、海马和丘脑区的表达%Expressions of gene Fmr1 in rat cortex, hippocampus and thalamus areas after the rapid eyes movement sleep deprivation

    Institute of Scientific and Technical Information of China (English)

    范贵民; 武冬梅; 王培君; 熊慧; 杨迎峰; 范洪儒; 王景涛

    2014-01-01

    Objective To investigate the expression of gene Fmr1 in rats cortex, hippocampus and hypothalamus areas after the rapid eyes movement ( REM ) sleep deprivation .Methods Using the modified multiple platform method (MMPM), 126 rats were randomly and averagely divided into three groups , the normal control group ( CC), the environmental control group (TC) and the sleep deprivation group (SD).Each group was detected on day 1, day 2, day 3, day 5, day 7, and day 9, and the sample tissues were extracted from 7 rats at each time point.Immunohistochemistry and RT-PCR were operated to analysis the expression of gene Fmr 1.Results The expressions of gene Fmr1 were increased gradually in the cortex and thalamus of the SD group after 3 days ( P 0.05).The expressions of gene Fmr1 were decreased gradually in hippocampus for SD after 3 days ( P 0.05 ) . Conclusion The expressions of gene Fmr 1 were increased gradually in the cortex and thalamus but decreased in the hippocampus in the SD group after 3 days.%目的:探讨快速眼动( REM)睡眠剥夺过程中Fmr1基因在大鼠皮质、海马和丘脑区的表达及变化。方法采用改良多平台水环境法( MMPM )制作大鼠睡眠剥夺模型,采用免疫组织化学法及RT-PCR方法检测Fmr1基因的表达变化。结果在皮质和丘脑中,与CC组和TC组相比,SD1d和SD2d组的Fmr1基因表达无明显变化,SD3d组开始增高(P<0.05),SD5d、SD7d组和SD9d组显著增高(P<0.01);在海马中,与CC组和TC组相比,SD1d和SD2d组的Fmr1基因表达无明显变化,SD3d组开始降低(P<0.05),SD5d、SD7d组和SD9d组显著降低(P<0.01)。结论Fmr1基因在大鼠睡眠剥夺第3天开始表达发生变化,在皮质和丘脑中表达增高,在海马中表达降低。

  5. Expression of neuregulin 1 and its significance in brain tissues of FMR1 gene knockout mice%Fmr1基因敲除小鼠脑组织神经调节蛋白1表达的改变及其意义

    Institute of Scientific and Technical Information of China (English)

    卢韬; 欧阳梅; 周林涛; 易咏红

    2013-01-01

    目的 明确神经调节蛋白1 (NRG1)在Fmr1基因敲除(KO)小鼠中的变化,探讨其在脆性X综合征发病机制中的作用. 方法 应用免疫组织化学染色法检测FVB近交系雄性2周龄Fmr1 KO小鼠(KO2w)、4周龄Fmr1 KO小鼠(KO4w)和同龄野生型(WT)小鼠大脑皮层及海马CA1区、CA3区、齿状回中神经调节蛋白1的阳性神经元的数量;Western blotting检测上述小鼠大脑皮层和海马组织NRG1蛋白的含量. 结果 与同龄WT小鼠相比,KO2w、KO4w小鼠大脑皮层、海马CA1和CA3区NRG1阳性神经元的数量明显减少,在海马齿状回却明显增多,差异均有统计学意义(P<0.05);KO2w、KO4w小鼠大脑皮层、海马中NRG1含量(相对分子质量为55 000亚型)分别较同龄的WT小鼠明显减少,差异亦有统计学意义(P<0.05). 结论 Fmr1 KO小鼠大脑皮层和海马组织NRG1阳性神经元及NRG1蛋白表达明显减少,NRG1可能参与脆性X综合征发病机制.%Objective To explore the expression changes ofneuregulin 1 (NRG1) in Fmr1 gene knockout (Fmr1 KO) mice,and its possible role in fragile X syndrome pathogenesis.Methods Immunohistochemistry and Western blotting were simultaneously employed to detect the expression levels of NRG 1 in the hippocampus and the cortex of FVB strain Fmr1 KO mice and wild type (WT) controls at the age of 2 and 4 weeks.Results The number of NRG1-positive cells in the CA1 and CA3 regions of hippocampus and the cortex of Fmr1 KO mice at the age of 2 and 4 weeks was significantly smaller than that in the age-matched WT mice (P<0.05).The NRG1 protein levels in the hippocampus and cerebral cortex of Fmr1 KO mice at the age of 2 and 4 weeks were also decreased as compared with those in the age-matched WT mice (P<0.05).Conclusion The number of NRG1-positive cells and NRG1 protein levels in the CA1 and CA3 regions of hippocampus and the cortex of Fmr1 KO mice are decreased,indicating that NRG 1 might involve in the pathogenesis of Fragile X

  6. Biophysical characterization of G-quadruplex forming FMR1 mRNA and of its interactions with different fragile X mental retardation protein isoforms.

    Science.gov (United States)

    Blice-Baum, Anna C; Mihailescu, Mihaela-Rita

    2014-01-01

    Fragile X syndrome, the most common form of inherited mental impairment in humans, is caused by the absence of the fragile X mental retardation protein (FMRP) due to a CGG trinucleotide repeat expansion in the 5'-untranslated region (UTR) and subsequent translational silencing of the fragile x mental retardation-1 (FMR1) gene. FMRP, which is proposed to be involved in the translational regulation of specific neuronal messenger RNA (mRNA) targets, contains an arginine-glycine-glycine (RGG) box RNA binding domain that has been shown to bind with high affinity to G-quadruplex forming mRNA structures. FMRP undergoes alternative splicing, and the binding of FMRP to a proposed G-quadruplex structure in the coding region of its mRNA (named FBS) has been proposed to affect the mRNA splicing events at exon 15. In this study, we used biophysical methods to directly demonstrate the folding of FMR1 FBS into a secondary structure that contains two specific G-quadruplexes and analyze its interactions with several FMRP isoforms. Our results show that minor splice isoforms, ISO2 and ISO3, created by the usage of the second and third acceptor sites at exon 15, bind with higher affinity to FBS than FMRP ISO1, which is created by the usage of the first acceptor site. FMRP ISO2 and ISO3 cannot undergo phosphorylation, an FMRP post-translational modification shown to modulate the protein translation regulation. Thus, their expression has to be tightly regulated, and this might be accomplished by a feedback mechanism involving the FMRP interactions with the G-quadruplex structures formed within FMR1 mRNA.

  7. Effects of FMR1 Gene Knockout on Reproductive Performance of C57BL/6 Mice Based on Gene Identification%基于子代基因型鉴定技术研究FMR1敲除对C57BL/6小鼠繁殖性能的影响

    Institute of Scientific and Technical Information of China (English)

    谢金东; 杨燕燕; 林玮; 俞春英; 周建华; 刘德强; 王训立

    2015-01-01

    为探讨FMR1基因敲除对C57BL/6小鼠繁殖性能的影响,将FMR1基因敲除杂合子小鼠饲养于SPF环境,依照遗传学规则进行繁育,并采用PCR法利用小鼠尾部组织鉴定子代小鼠的基因型.结果表明,PCR技术可以检测小鼠的基因型,且具有方便快捷、直观可靠的特点.子代经过检测可得野生型、杂合子和纯合子3种基因型;在此鉴定基础上,挑选10周龄C57BL/6 FMR1 KO和同源SPF级C57BL/6种鼠各10对,采取1∶1全同胞兄妹近亲繁殖的方法,测定各对第2胎仔鼠的繁殖性能,并进行比较分析.结果显示,C57BL/6 FMR1 KO小鼠在窝产仔数、离乳率、初生鼠体重和体长、离乳体长及雌雄比例等数值偏低,但均差异不显著(P>0.05);而两者的离乳体重差异极显著(P<0.01).

  8. FMR1基因敲除小鼠脑组织微白蛋白表达的改变及其意义%Changes and significance of expression of parvalbumin in brain tissues of FMR1 gene knockout mice

    Institute of Scientific and Technical Information of China (English)

    邸伟; 易咏红; 曾志涌; 徐明明; 王玉良; 孙卫文; 廖卫平

    2010-01-01

    目的 探讨微白蛋白(PV)阳性中间神经元在脆性X综合征(FXS)癫痫易感性增加中的作用. 方法 应用免疫组织化学染色检测FVB近交系雄性2、4、6 W龄FMR1基因敲除型(KO)(KO2W、KO4W、KO6W)和同龄野生型(WT)(WT2W、WT4W、WT6W)小鼠大脑纹状皮质、颞听皮质、梨状皮质及海马CA1区、CA3区、齿状回中PV的表达(n=6);应用Western blot法检测上述小鼠大脑皮层、海马组织PV的含量(n=6). 结果 KO2W、KO44W小鼠的大脑纹状皮质、颞听皮质、梨状皮质、海马CA1和CA3区PV阳性中间神经元的数量分别较WT2W、WT4-小鼠减少,差异有统计学意义(P<0.05);KO2W和KO4W小鼠大脑皮层、海马中PV含量分别较WT2W、WT4W小鼠减少,差异有统计学意义(P<0.05). 结论 PV阳性中间神经元及PV含量的减少.可能是引起FXS模型鼠癫痫易感性增加的主要原因.%Objective To explore the possible role of parvalbumin (PV)-positive interneuron in the pathogenesis of increased susceptibility to epileptic seizures in FMR1 gene knockout (FMR1 KO)mice. Methods Immunohistochemistry was employed to determine the expression of PV in CA1 and CA3 regions of the hippocampus, the striate cortex, the temporal auditory cortex and the piriform cortex of FVB strain FMR1 KO mice and wild type (WT) controls at the age of 2, 4 and 6 w. Western blotting was used to detect the level of PV in the cerebral cortex and hippocampus of the above mice. Results The numbers of PV-positive interneuron in CA1 and CA3 regions of the hippocampus, the striate cortex,the temporal auditory cortex and the piriform cortex of FMR1 KO mice at the age of 2 and 4 w were significantly decreased as compared with those in the age-matched WT mice (P<0.05). The level of PV in the cerebral cortex and hippocampus in FMR1 KO mice at the age of 2 and 4 w was also significantly decreased than that in the age-matched WT mice (P<0.05). Conclusion Decreased numbers of PV-positive interneuron and level of PV

  9. Intervention Effect of α-Asarone on the Locomotor Activity in Fmr1 Gene Knockout Mice%α-细辛醚对Fmr1基因敲除小鼠的自主活动的干预作用

    Institute of Scientific and Technical Information of China (English)

    吴杰贤; 陈希; 张伟雯; 黄月玲; 孙祺章; 黄小燕; 陈盛强; 孙卫文; 戴丽军

    2014-01-01

    目的 探讨α-细辛醚对Fmr1基因敲除小鼠的自主活动的干预作用.方法 选取30日龄Fmr1基因敲除小鼠(KO小鼠)和FVB野生型小鼠(WT小鼠)为研究对象,将KO和WT两种类型的小鼠分别分为7小组,每组15只.其中1组作为对照组给予生理盐水,另外6小组连续腹腔注射不同剂量α-细辛醚(3 mg/kg、6 mg/kg、9 mg/kg、12 mg/kg、24 mg/kg、36mg/kg)5天,用药第5天进行自主活动行为学实验,观察α-细辛醚能否改善KO鼠的过度活动的表型.结果 在行为学自主活动实验中,KO鼠的活动次数比WT鼠的活动次数多,站立次数比WT鼠的站立次数少,差异具有统计学意义(P<0.05);使用α-细辛醚后,KO鼠的活动次数明显减少,站立次数明显增多,差异均具有统计学意义(P均<0.05).结论 α-细辛醚能改善KO鼠的的活动过度的表型,可能对Fmr1基因敲除小鼠有治疗作用.

  10. 柴胡桂枝汤挥发油对Fmr1基因敲除小鼠脑组织超氧化物歧化酶和丙二醛及一氧化氮的影响%Influence of Bupleuri and Ramuli Cinnamomi Decoction on Levels of Malondialdehyde,Nitrogen Monoxidum and Superoxide Dismutase in FMR-1 Gene Knockout Mice

    Institute of Scientific and Technical Information of China (English)

    高飞; 黄庆晖; 黄越玲; 孙卫文; 戴丽军; 沈岩松; 李敏雄; 陈盛强; 刘忠民

    2010-01-01

    目的 利用超临界二氧化碳(CO2)萃取法获取柴胡桂枝汤挥发油,并在Fmr1基因敲除小鼠(脆性基因敲除小鼠)模型上观察柴胡桂枝汤挥发油的抗癫痫作用,及其与超氧化物歧化酶(SOD )、丙二醛(MDA)、一氧化氮(NO)的关系.方法 将30只30日龄的Fmr1基因敲除小鼠(KO)和30只30日龄的野生型小鼠(WT)分别分成两组(KO空白组和KO用药组,WT空白组和WT用药组),按1.7 ml/kg的剂量腹腔注射柴胡桂枝汤挥发油,观察柴胡桂枝汤挥发油对小鼠旷场行为的影响,并取不同部位的小鼠脑组织制成1∶ 10(重量体积比) 的组织匀浆,测定SOD活性及MDA、NO的水平.结果 与空白组比较,用药组小鼠在旷场实验中运动的平均速度、总路程、穿过各区的次数减少;脑组织中SOD活性增高,而MDA、NO水平均降低,差异有统计学意义(P<0.05).结论 柴胡桂枝汤挥发油对Fmr1基因敲除小鼠的探索性、兴奋性、运动性均有抑制作用;其抗癫痫作用与清除自由基、阻止过氧化物生成,减少NO的神经毒性相关.

  11. Normal number of CGG repeats in the FMR-1 gene and abnormal incorporation of fibrillin into the extracellular matrix in Lujan Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Greenhaw, G.A.; Stone, C.; Milewicz, D. [Univ. of Texas Health Science Center, Houston, TX (United States)

    1994-09-01

    Lujan syndrome is an X-linked condition that includes mild-to-moderate mental retardation, poor social integration, normal secondary sexual development with normal testicular size, generalized hypotonia, hypernasal voice and dolichostenomelia. Major cardiac complications and lens dislocation have not been reported although severe myopia may occur. All reported cases have had negative cytogenetic screening for fra(X) syndrome but establishing this constellation of findings as a distinctive entity has been difficult. We report 4 males in two sibships with clinical findings consistent with Lujan syndrome, normal karyotypes, negative cytogenetic screening for fra(X) syndrome and a normal number of CGG repeats in the FMR-1 gene. Dermal fibroblasts explanted from one of the affected males were used to study fibrillin synthesis secretion and extracellular matrix incorporation into microfibrils. Cells from the affected individual showed normal synthesis and secretion of fibrillin when compared to control cells, but the fibrillin was not incorporated into the extracellular matrix. These results suggest the presence of a gene on the X chromosome which may play a role in microfibril assembly and when deficient may disrupt the incorporation of fibrillin into microfibrils. This may be important not only in normal body morphogenesis but also in the development/function of the brain. More affected individuals are needed to investigate these findings further.

  12. A single nucleotide variant in the FMR1 CGG repeat results in a "Pseudodeletion" and is not associated with the fragile X syndrome phenotype.

    Science.gov (United States)

    Cecconi, Massimiliano; Forzano, Francesca; Rinaldi, Rosanna; Cappellacci, Sandra; Grammatico, Paola; Faravelli, Francesca; Dagna Bricarelli, Franca; Di Maria, Emilio; Grasso, Marina

    2008-05-01

    The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype.

  13. A Single Nucleotide Variant in the FMR1 CGG Repeat Results in a “Pseudodeletion” and Is Not Associated with the Fragile X Syndrome Phenotype

    Science.gov (United States)

    Cecconi, Massimiliano; Forzano, Francesca; Rinaldi, Rosanna; Cappellacci, Sandra; Grammatico, Paola; Faravelli, Francesca; Dagna Bricarelli, Franca; Di Maria, Emilio; Grasso, Marina

    2008-01-01

    The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype. PMID:18403614

  14. Premutation huntingtin allele adopts a non-B conformation and contains a hot spot for DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Jarem, Daniel A. [Department of Chemistry, Brown University, Providence, RI 02912 (United States); Delaney, Sarah, E-mail: sarah_delaney@brown.edu [Department of Chemistry, Brown University, Providence, RI 02912 (United States)

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer First structural and thermodynamic analysis of premutation allele of HD. Black-Right-Pointing-Pointer Premutation allele of HD adopts a stem-loop non-B conformation. Black-Right-Pointing-Pointer Healthy and premutation length stem-loops are hyper-susceptible to oxidative damage. Black-Right-Pointing-Pointer Stability of stem-loop structures increases linearly with repeat length. Black-Right-Pointing-Pointer Thermodynamic stability, not the ability to adopt non-B conformation, distinguishes DNA prone to expansion from stable DNA. -- Abstract: The expansion of a CAG trinucleotide repeat (TNR) sequence has been linked to several neurological disorders, for example, Huntington's disease (HD). In HD, healthy individuals have 5-35 CAG repeats. Those with 36-39 repeats have the premutation allele, which is known to be prone to expansion. In the disease state, greater than 40 repeats are present. Interestingly, the formation of non-B DNA conformations by the TNR sequence is proposed to contribute to the expansion. Here we provide the first structural and thermodynamic analysis of a premutation length TNR sequence. Using chemical probes of nucleobase accessibility, we found that similar to (CAG){sub 10}, the premutation length sequence (CAG){sub 36} forms a stem-loop hairpin and contains a hot spot for DNA damage. Additionally, calorimetric analysis of a series of (CAG){sub n} sequences, that includes repeat tracts in both the healthy and premutation ranges, reveal that thermodynamic stability increases linearly with the number of repeats. Based on these data, we propose that while non-B conformations can be formed by TNR tracts found in both the healthy and premutation allele, only sequences containing at least 36 repeats have sufficient thermodynamic stability to contribute to expansion.

  15. Lack of expansion of triplet repeats in the FMR1, FRAXE, and FRAXF loci in male multiplex families with autism and pervasive developmental disorders

    Energy Technology Data Exchange (ETDEWEB)

    Holden, J.J.A.; Julien-Inalsingh, C. [Queen`s Univ., Kingston (Canada); Wing, M. [Ongwanada Resource Centre, Kingston (Canada)] [and others

    1996-08-09

    Sib, twin, and family studies have shown that a genetic cause exists in many cases of autism, with a portion of cases associated with a fragile X chromosome. Three folate-sensitive fragile sites in the Xq27{r_arrow}Xq28 region have been cloned and found to have polymorphic trinucleotide repeats at the respective sites; these repeats are amplified and methylated in individuals who are positive for the different fragile sites. We have tested affected boys and their mothers from 19 families with two autistic/PDD boys for amplification and/or instability of the triplet repeats at these loci and concordance of inheritance of alleles by affected brothers. In all cases, the triplet repeat numbers were within the normal range, with no individuals having expanded or premutation-size alleles. For each locus, there was no evidence for an increased frequency of concordance, indicating that mutations within these genes are unlikely to be responsible for the autistic/PDD phenotypes in the affected boys. Thus, we think it is important to retest those autistic individuals who were cytogenetically positive for a fragile X chromosome, particularly cases where there is no family history of the fragile X syndrome, using the more accurate DNA-based testing procedures. 29 refs., 1 fig., 1 tab.

  16. Fixation and loss of hydrazine-induced premutational damage in Haemophilus influenzae

    Energy Technology Data Exchange (ETDEWEB)

    Kimball, R.F.; Hirsch, B.F.

    1976-01-01

    Premutational damage induced in Haemophilus influenzae by hydrazine appears to be fixed as final mutation only at replication as judged by the transformation assay. Fixation at replication is independent of the rec 1 gene, unlike the case with nitrosocarbaryl. Prior to replication premutational damage induced by hydrazine disappears by an unknown process that is not dependent on the presence of a pyrimidine dimer excision system nor on the rec 1 gene. Hydrazine does not produce detectable single-strand breaks or alkali-labile sites in the treated DNA nor gaps in DNA newly synthesized after treatment. In these respects it also differs from nitroso compounds. It is concluded that hydrazine acts to produce an altered base, possibly N(4)-aminocytosine, that produces mutations by mispairing at replication rather than by error-prone repair.

  17. Expression of Nav1.1 and its significance in brain tissues of FMR1 knockout mice%FMR1基因敲除小鼠脑组织中Nav1.1的改变及其意义

    Institute of Scientific and Technical Information of China (English)

    邸伟; 吕桦; 刘军; 廖卫平; 易咏红

    2015-01-01

    目的 探讨Nav1.1在脆性X综合征(FXS)癫痫易感性增加中的可能作用.方法 选用2周龄、4周龄的FVB品系FMR1基因敲除型小鼠(KO2周和KO4周)及同龄野生型小鼠(WT2周和WT4周)为实验对象,应用免疫组化染色方法检测小鼠大脑纹状皮质、颞听皮质、梨状皮质、海马CA1区、CA3区及齿状回中Nav1.1的表达;应用Western blotting检测小鼠大脑皮层和海马组织Nav1.1蛋白含量.结果 免疫组化染色结果显示:KO2周和KO4周小鼠大脑纹状皮质、颞听皮质、梨状皮质、海马CA1区及齿状回区Nav1.1表达的平均吸光度值(2周:0.058±0.006、0.054±0.006、0.130±0.015、0.090±0.009、0.142±0.010;4周:0.066±0.007、0.060±0.007、0.159±0.018、0.102±0.015、0.192±0.025)分别较WT2周和WT4周小鼠(2周:0.049±0.007、0.046±0.007、0.118±0.012、0.080±0.009、0.133±0.010;4周:0.051±0.007、0.048±0.005、0.127±0.012、0.089±0.012、0.175±0.024)明显增多,差异均有统计学意义(P<0.05).Western b1otting检测结果显示:KO2周和KO4周小鼠大脑皮层、海马组织Nav1.1蛋白含量(2周:0.635±0.082、0.954±0.111;4周:0.819±0.064、1.145±0.159)分别较WT2周和WT4周小鼠(2周:0.382±0.025、0.555±0.056;4周:0.550±0.040、0.847±0.127)明显增多,差异均有统计学意义(P<0.05).结论 Nav1.1表达增多可能是引起FXS模型小鼠癫痫易感性增加的原因之一.%Objective To explore the possible role of Nav 1.1 in the pathogenesis of increased susceptibility to epileptic seizures in FMR1 knockout (FMR1 KO) mice.Methods FVB strain FMR1 KO mice and wild type (WT) controls at ages of 2 and 4 weeks old were chosen;immunohistochemistry was used to determine the expression of Nav 1.1 in different brain regions (striate cortex,temporal cortex,piriform cortex,hippocampus CA1,CA3 and dentate gyrus),and Western blotting was used to determine the Nav1.1 level in the cerebral acustici cortex and hippocampus.Results The mean optical density

  18. MicroRNA-134在FMR1基因敲除鼠脑组织中的表达及意义%Expression and significance of microRNA-134 in mouse brain tissue with FMR1 gene knockout

    Institute of Scientific and Technical Information of China (English)

    曾志涌; 邸伟; 肖都; 孙逊沙; 王玉良; 欧阳梅; 易咏红

    2010-01-01

    Objective To observe the expression ofmicroRNA-134 (miR-134) in the mouse brain tissue with FMR1 gene knockout during the different development periods and its expression characteristic, and explore whether the deficiency of fragile X mental retardation protein (FMRP) can induce the changes of miR-134 transcription. Methods FVB strain male mice, including FMR1 gene knockout (KO, n=15) and their wild type (WT, n=15) counterparts were chosen in the experiment. The expressions of miR-134 in the brain tissues of these KO mice that were 0 d, 4 and 6 w old and the age-matched WT mice were detected by qRT-PCR. Results The transcriptional level of miR-134 in the brain tissue of KO mice had no significant difference as compared with that of age-matched WT mice (P>0.05). The transcriptional levels of miR-134 in 6-w-old KO and WT mice were significantly decreased as compared with the newbom and 4-w-old same genotype mice (P<0.05). Conclusion The absence of FMRP does not influence the transcription of miR-134 and the transcriptional level of miR-134 in the brain tissues maintains a high level during the developmental stage of the nervous system and gradually decreases to a low level after grow-up, demonstrating its important role in regulating the development of nervous system.%目的 观察脆性X综合征(FXS)模型小鼠不同发育时期脑组织中microRNA-134(miR-134)的表达,明确miR-134的表达特点及脆性X智力低下蛋白(FMRP)缺失是否导致miR-134转录的改变. 方法 应用荧光实时定量PCR检测FVB近交系雄性0 d、4、6周(W)龄FMR1基因敲除型(KO)(KO0d、KO4w、KO6w)和同龄野生型(WT)(WT0d、WT4w、WT6w)小鼠脑组织中miR-134的表达(n=5). 结果同龄KO与WT小鼠miR-134的转录表达量差异无统计学意义(P>0.05);KO6w小鼠脑组织miR-134的转录表达量低于KO0d和KO2w小鼠,WT6w小鼠脑组织miR-134的转录表达量也低于WT0d和WT2w小鼠,差异均有统计学意义(P<0.05). 结论 FMRp

  19. Estrategia de genotipado del gen FMR1: Método de diagnóstico alternativo para el Síndrome X Frágil y otras enfermedades por expansión de trinucleotidos

    OpenAIRE

    Lindo-Samanamud, Saúl; Servicio de Neurogenética, Instituto Nacional de Ciencias Neurológicas, Lima. Escuela de Genética y Biotecnología y Facultad de Medicina, Universidad Nacional Mayor de San Marcos. Lima.; Cornejo-Olivas, Mario; Servicio de Neurogenética, Instituto Nacional de Ciencias Neurológicas. Lima, Perú. Washington Universtity International Fogarty Scholar´s Program. Lima, Perú. Médico neurólogo.; Ortega, Olimpio; Servicio de Neurogenética, Instituto Nacional de Ciencias Neurológicas. Lima, Perú. Biólogo, genetista.; Marca, Victoria; Servicio de Neurogenética, Instituto Nacional de Ciencias Neurológicas, Lima; Espinoza-Huertas, Keren; Servicio de Neurogenética, Instituto Nacional de Ciencias Neurológicas, Lima. Escuela de Genética y Biotecnología y Facultad de Medicina, Universidad Nacional Mayor de San Marcos. Lima.; Mazzetti, Pilar; Servicio de Neurogenética, Instituto Nacional de Ciencias Neurológicas. Lima, Perú. Facultad de Medicina Humana, Universidad Nacional Mayor de San Marcos. Lima, Perú. Médico neurólogo, Magíster en Gestión Pública.

    2013-01-01

    Objetivos: Diseñar una estrategia alternativa por PCR para el genotipado de secuencias ricas en citosinas, basada en modificación nucleotídica. Material y métodos: Se modificó el gen FMR1 nativo de ocho individuos clínicamente no afectados por el Síndrome X frágil, cambiando las citosinas por uracilos, empleando bisulfito de sodio. El ADN modificado fue purificado y cuantificado por espectrofotometría. Las estructuras alternativas y potenciales islas CpG que adopta el microsatélite inestable ...

  20. Estrategia de genotipado del gen FMR1: Método de diagnóstico alternativo para el Síndrome X Frágil y otras enfermedades por expansión de trinucleotidos

    OpenAIRE

    Saúl Lindo-Samanamud; Mario Cornejo-Olivas; Olimpio Ortega; Victoria Marca; Keren Espinoza-Huertas; Pilar Mazzetti

    2013-01-01

    Objetivos: Diseñar una estrategia alternativa por PCR para el genotipado de secuencias ricas en citosinas, basada en modificación nucleotídica. Material y métodos: Se modificó el gen FMR1 nativo de ocho individuos clínicamente no afectados por el Síndrome X frágil, cambiando las citosinas por uracilos, empleando bisulfito de sodio. El ADN modificado fue purificado y cuantificado por espectrofotometría. Las estructuras alternativas y potenciales islas CpG que adopta el microsatélite inestable ...

  1. 华南地区不明原因智力低下患者FMR1和FMR2基因突变分析%Analysis of fragilex mental retardation 1 and fragilex mental retardation 2 gene mutations in intellectually disabled population of unknown causes in Southern China

    Institute of Scientific and Technical Information of China (English)

    段现来; 刘超; 李啬夫; 石奕武; 易咏红; 廖卫平

    2015-01-01

    Objective To screen the fragilex mental retardation 1 (FMR1) gene mutations and explore the frequency of FMR1 gene mutation in the population with mental retardation in South China.Methods Seventy-two patients (65 males and 7 females) with suspected fragile X syndrome (FXS) in South China were enrolled in our hospitals from October 2009 to April 2014.The CGG trinucleotide repeats in 5'UTR of FMR1 gene and CCG trinucleotide repeats in FMR2 gene were screened respectively by PCR.Southern blotting and capillary electrophoresis sequencing were performed in male patients without normal target bands and suspected female patients;patients with normal CGG alleles were,then,performed exons and 3'-UTR ofFMR1 gene amplification and sequencing.The frequency of FMR1 gene mutation in patients with mental retardation in different countries and regions was compared with statistical analysis.Results Six pedigrees with full mutation (one female and five males being the probands),one pedigree (mother and son) with FMR1 gene deletion and one pedigree (mother and son) with mutation in the transition region were identified in 72 patients with mental retardation.The prevalence of total mutation was 9.7% (7/72) and that in male patients was 9.2% (6/65).These results showed significant differences in prevalence as compared with the results from different countries and areas (P<0.05);there were no variations in 3'UTR ofFMR1 gene and FMR2 gene mutation in the patients with FXS-like phenotype.Conclusions FMR1 mutation frequency may be higher in mental retardation population in southem China as compared with that in developed countries or areas.Targeted screening on the unexplained mental retardation pedigrees (family history) can improve the diagnosis of FXS.Importantly,deletion mutations screening should also be performed in suspected FXS subjects with normal CGG repeats.%目的 探讨华南地区不明原因智力低下患者中脆性X智力低下基因FMR1和FMR2

  2. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study--preliminary data.

    Science.gov (United States)

    Allingham-Hawkins, D J; Babul-Hirji, R; Chitayat, D; Holden, J J; Yang, K T; Lee, C; Hudson, R; Gorwill, H; Nolin, S L; Glicksman, A; Jenkins, E C; Brown, W T; Howard-Peebles, P N; Becchi, C; Cummings, E; Fallon, L; Seitz, S; Black, S H; Vianna-Morgante, A M; Costa, S S; Otto, P A; Mingroni-Netto, R C; Murray, A; Webb, J; Vieri, F

    1999-04-01

    The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.

  3. Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Lara eCosta

    2015-03-01

    Full Text Available Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD in wild-type (wt and in Fmr1 KO mice, a mouse model of Fragile X syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices.Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions.The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of

  4. Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome.

    Science.gov (United States)

    Costa, Lara; Sardone, Lara M; Lacivita, Enza; Leopoldo, Marcello; Ciranna, Lucia

    2015-01-01

    Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome.

  5. Mouse models of the fragile x premutation and the fragile X associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hunsaker, Michael R; Arque, Gloria; Berman, Robert F; Willemsen, Rob; Hukema, Renate K

    2012-01-01

    The use of mutant mouse models of neurodevelopmental and neurodegenerative disease is essential in order to understand the pathogenesis of many genetic diseases such as fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). The choice of which animal model is most suitable to mimic a particular disease depends on a range of factors, including anatomical, physiological, and pathological similarities; presence of orthologs of genes of interest; and conservation of basic cell biological and metabolic processes. In this chapter, we will discuss two mouse models of the fragile X premutation which have been generated to study the pathogenesis of FXTAS and the effects of potential therapeutic interventions. Behavioral, molecular, neuropathological, and endocrine features of the mouse models and their relation to human FXTAS are discussed.

  6. Expressions of Drebrins and lcam-5 in mouse cerebral cortex with Fmr-1 gene knockout and their significance in fragile X syndrome%Drebrins和Icam-5在Fmr-1基因敲除鼠大脑皮层的表达和意义

    Institute of Scientific and Technical Information of China (English)

    徐琴; 竺智伟; 赵正言

    2012-01-01

    [Objective]To investigate and compare the changes of Drebrin A,Drebrin E and lcam-5 mRNA levels in the cerebral cortex of Frr-1 gene knockout mouse during brain development periods.[Methods]Fmr-1 gene knockout (KO) male mice and their wild type (WT) counterparts were chosen in our experiment (4≤n≤ 10);the levels of target mRNAs were detected by real time quantitative PCR;check points were set on the 7th,14th,21th and 28rh postnatal d.[Results] The mRNA level of Drebrin A in the KO group was significantly lower than that in the WT group on the 14th postnatal d,while that of Drebrin E was significantly higher than that in the WT group (P<0.05).The mRNA level of lcam-5 in the KO group was significantly higher than that in the WT group on the 14th and 21th postnatal d (P<0.05).[Conclusion] The delayed shift of Drebrin A to Drebrin E and transitional over-expression of lcam-5 in developmental cerebral cortex are the reasons for mental retardation in Fragile X Syndrome.%目的 观察脆性X综合征(FXS)模型小鼠不同发育时期大脑皮层中Drebrin A、Drebrin E及Icam-5 mRNA水平变化情况及意义.方法 应用荧光实时定量PCR(RT-PCR)法检测FmrJ基因敲除KO小鼠及野生健康对照小鼠H出生后第7天、第14天、第21天和第28天大脑皮层Drebrin A、Drebrin E及Icam-5 mRNA的表达(4≤n≤10).结果 KO组小鼠出生后第14天Drebrin A mRNA水平较健康对照组小鼠明显降低,而同时间Drebrin E mRNA水平较健康对照组小鼠明显增高,差异均有统计学意义(P<0.05);KO组小鼠Icam-5 mRNA水平在出生后第14和21天均明显高于健康对照组,差异均有统计学意义(P<0.05).结论 Drebrin A和Drebrin E在大脑皮层发育期的表达交替延迟及Icam-5的一过性过度表达是FXS智力低下的原因之一.

  7. The fragile X-associated tremor ataxia syndrome (FXTAS) in Indonesia

    NARCIS (Netherlands)

    Winarni, T.I.; Mundhofir, F.E.P.; Ediati, A.; Belladona, M.; Nillesen, W.M.; Yntema, H.G.; Hamel, B.C.J.; Faradz, S.M.H.; Hagerman, R.J.

    2013-01-01

    Fragile X-associated disorders caused by the premutation of the FMR1 gene, includes the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects more than 40% of premutation males over the age of 50 and 75% over the age of 80. FMR1 molecular analysis was done using PCR and confirmed by Sou

  8. Estrategia de genotipado del gen FMR1: Método de diagnóstico alternativo para el Síndrome X Frágil y otras enfermedades por expansión de trinucleotidos

    Directory of Open Access Journals (Sweden)

    Saúl Lindo-Samanamud

    2013-10-01

    Full Text Available Objetivos: Diseñar una estrategia alternativa por PCR para el genotipado de secuencias ricas en citosinas, basada en modificación nucleotídica. Material y métodos: Se modificó el gen FMR1 nativo de ocho individuos clínicamente no afectados por el Síndrome X frágil, cambiando las citosinas por uracilos, empleando bisulfito de sodio. El ADN modificado fue purificado y cuantificado por espectrofotometría. Las estructuras alternativas y potenciales islas CpG que adopta el microsatélite inestable fueron simuladas con los programas MFOLD y CpGplot. Se generaron cebadores específicos que hibriden tanto con el microsatélite modificado (Primer T y con una secuencia modificada de las islas CpG (Primer M, utilizando el programa MethPrimer. Finalmente, ambas secuencias fueron amplificadas por PCR y los amplicones fueron separados por electroforesis en gel de poliacrilamida (PAGE por sus siglas en inglés al 6% y visualizados con tinción de nitrato de plata. Resultados: La modificación del ADN fue evidenciada por espectrofotometría al uracilo. Las estructuras observadas en la simulación fueron las horquillas encontrándose dos potenciales islas CpG. La amplificación con los cebadores T, confirmó el diseño in silico desarrollado para abordar la estructura en horquillas. La amplificación con los cebadores M permitió detectar metilación de la primera isla CpG del gen FMR1.Conclusión: Se propone un diseño alternativo para amplificación de secuencias de microsatélite que contengan citosinas metiladas y no metiladas. Se requieren estudios posteriores con muestras de ADN que contengan microsatélites muy expandidos para validar su aplicación para diagnóstico molecular.

  9. Axonal neuropathy in female carriers of the fragile X premutation with fragile x-associated tremor ataxia syndrome.

    Science.gov (United States)

    Ram, Suresh; Devapriya, Inoka A; Fenton, Grace; Mcvay, Lindsey; Nguyen, Danh V; Tassone, Flora; Maselli, Ricardo A; Hagerman, Randi J

    2015-08-01

    In this study we examined whether females with the fragile X-associated tremor ataxia syndrome (FXTAS) and non-FXTAS premutation carriers have electrophysiological signs of underlying peripheral neuropathy. Nerve conduction studies (NCS) were performed on 19 women with FXTAS, 20 non-FXTAS carriers, and 26 age-matched controls. The results were compared with existing data on corresponding male carriers. Women with FXTAS and non-FXTAS carriers had reduced sensory nerve action potential amplitudes. Also, there was a strong trend for reduced compound muscle action potential amplitudes in women with FXTAS, but not in non-FXTAS carriers. No significant slowing of nerve conduction velocities, prolongation of F-wave latencies, or associations with molecular measures was observed. This study suggests an underlying axonal neuropathy in women with FXTAS. However, in comparison to men with FXTAS, the NCS abnormalities in women were less severe, possibly due to the effect of a normal X chromosome. © 2014 Wiley Periodicals, Inc.

  10. Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data.

    Science.gov (United States)

    Uzielli, M L; Guarducci, S; Lapi, E; Cecconi, A; Ricci, U; Ricotti, G; Biondi, C; Scarselli, B; Vieri, F; Scarnato, P; Gori, F; Sereni, A

    1999-05-28

    Early menopause in the fragile X carriers has been well documented in several reports. All surveys demonstrated that 13-25% of fragile X carriers experienced premature ovarian failure (POF), defined as menopause before the age of 40 years. In 1995 we started screening two groups of subjects as a part of a Fragile X Research Program: 1) women previously diagnosed as fragile X carriers from the register of our center and 2) women with POF and without a family history of fragile X or other forms of mental retardation. In this study we report the preliminary data collected from 75 fragile X families; in 30 of them, POF was present in one or several subjects, all of whom had a fragile X premutation. None of the women with a full mutation experienced POF in our series of patients. We also identified 89 families without a family history of fragile X or mental retardation, and there were 108 subjects who experienced POF, of which 6.5% had a fragile X premutation. This is 70-fold higher than the background prevalence of fragile X premutation in the Italian population and suggests an association with POF. These data confirm the results of other surveys.

  11. Emerging topics in FXTAS

    DEFF Research Database (Denmark)

    Hall, Deborah A; Birch, Rachael C; Anheim, Mathieu

    2014-01-01

    This paper summarizes key emerging issues in fragile X-associated tremor/ataxia syndrome (FXTAS) as presented at the First International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2013....

  12. Assessment of Premutation in Myotonic Dystrophy Type 1 Affected Family Members by TP-PCR and Genetic Counseling

    Directory of Open Access Journals (Sweden)

    Ashok Kumar

    2014-01-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is caused by the expansion of an unstable CTG repeat located in the 3′-UTR of (DMPK the DM protein kinase gene. Patients with DM1 have expansions of greater than 50 repeats and up to many thousands. In the present study we aimed to evaluate the utility of TP-PCR in diagnostics as well as the assessment of premutation carriers in proband families. Twenty-seven DM1 cases were enrolled (from twenty-six families and the 13 families of these cases came forward for family screening. The patient group constitute 22 males and 5 females and the average age of onset was 32.8 years (range 17 to 52. All clinically diagnosed DM1 cases and their family members DNA samples were analyzed by TP-PCR. All the cases were found to be positive for the CTG repeat expansion. Among those five families, four had at least an asymptomatic carrier. In the remaining one family other than the proband none was found to be neither affected nor asymptomatic. We reconfirmed the utility of PCR based screening for DM1 as being reliable and rapid molecular test and it should be used as an initial screening test for all patients with DM and their family members for initial screening purpose.

  13. Molecular analysis of 53 fragile X families with the probe StB12.3

    Energy Technology Data Exchange (ETDEWEB)

    Puissant, H.; Malinge, M.C.; Larget-Piet, A.; Larget-Piet, L. [Unite de Genetique CHU d`Angers (France); Martin, D. [Genetique Medicale CHR Le Mans (France); Chauveau, P. [Genetique Medicale CHR Le Havre (France); Odent, S.; Lemarec, B. [Genetique Medicale CHU Rennes (France); Plessis, G. [Genetique Medicale CHU de Caen (France); Parent, Ph. [Genetique Medicale CHU de Brest (France)

    1994-12-01

    Fifty-three pedigrees with the fragile X syndrome have been studied for amplification of the CGG repeat sequence adjacent to the CpG island in the FMR1 gene. Probe StB12.3 allowed direct detection of affected males, carrier females, normal transmitting males, as well as prenatal diagnosis. Comparison of our molecular data with our previous linkage data from 38 families indicates the effectiveness of direct DNA analysis. A total of 325 individuals were studied and no new mutation was found. All daughters of males with a premutation had a premutation. When the mother had a full mutation no children had a premutation. In premutated mothers, the size of the premutation seems to be a determining factor for the transition to the full mutation. All affected males had a full mutation or mosaicism and only 42% of the females with a full mutation were mentally impaired. Analysis of large families over 3 generations illustrated clearly the Sherman paradox. Furthermore, the analysis of these families is in reasonable agreement with the multiallelic model of Morton and Macpherson. Mosaic cases in the offspring of the mothers with a full mutation suggest a maternal germinal mosaicism. Then an abnormal methylation and a somatic heterogeneity established in very early steps of embryogenesis could explain these cases. 17 refs.

  14. Expression of calcium/calAulin kinaseⅡα in fragile X mental retardation 1 gene knockout brain tissues in mice%CaMKⅡα在FMR1基因敲除小鼠脑组织中的表达

    Institute of Scientific and Technical Information of China (English)

    韦朝霞; 陈盛强; 陈希; 戴丽军

    2013-01-01

    目的 观察FMRI基因敲除型(KO)小鼠脑组织中钙/钙调素依赖蛋白激酶Ⅱα(CaMKⅡα)表达的改变,探讨CaMKⅡα是否为脆性X综合征相关蛋白(FMRP)的下调蛋白. 方法 PCR鉴定FVB近交系小鼠的基因型,按基因型的不同分为KO组和野生型(WT)组,每组10只.免疫组化染色检测KO及WT小鼠脑组织CaMKⅡα的表达与分布,用图像分析仪分别采集不同脑区免疫信号的吸光度(A)值进行比较. 结果 免疫组化染色检测显示KO与WT小鼠各个脑区普遍存在阳性信号;神经元胞浆尤其是靠近胞体的近端突起上信号呈强阳性,树突中亦有阳性信号,轴突上信号较弱;KO小鼠各脑区CaMKⅡα阳性信号的A值均较WT小鼠显著增高,差异有统计学意义(P<0.05). 结论 CaMKⅡα在成年KO小鼠各脑区的表达均显著增多,提示FMRP负性调节CaMKⅡα的表达.%Objective To observe the expression of calcium/calAulin kinaseⅡα (CaMKⅡα) in the brain tissues of fragile X mental retardation 1 (FMR1) gene knockout (KO) mice to investigate whether CaMKⅡα is regulated by fragile X mental retardation protein (FMRP).Methods According to the gene types of the FVB inbred mice identified by PCR,20 mice were divided into KO group and WT (wide type) group (n=10).The subcellular distribution and expression of CaMKⅡα were observed by immunohistochemical staining; the mean optical density (A) values of immunostaining signal of CaMKⅡα in various brain regions,including the motor cortex,temporal cortex,amygdala,hypothalamus and hippocampus,were determined by IBAS 2.0 image-analyzed system.Results CaMKⅡα immunoreactive cells were abundantly found in all brain subregions of KO and WT mice; especial positive signal was noted in the proximal processes of neurons,so as to those in the dendrite; week signcal was observed in the axon.No distributional difference was found between KO and WT mice.As compared with those in the WT mice,the A values were

  15. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.

    Directory of Open Access Journals (Sweden)

    Peter K Todd

    Full Text Available Fragile X Tremor Ataxia Syndrome (FXTAS is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11 suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.

  16. The fragile X syndrome.

    Science.gov (United States)

    de Vries, B B; Halley, D J; Oostra, B A; Niermeijer, M F

    1998-01-01

    The fragile X syndrome is characterised by mental retardation, behavioural features, and physical features, such as a long face with large protruding ears and macro-orchidism. In 1991, after identification of the fragile X mental retardation (FMR1) gene, the cytogenetic marker (a fragile site at Xq27.3) became replaced by molecular diagnosis. The fragile X syndrome was one of the first examples of a "novel" class of disorders caused by a trinucleotide repeat expansion. In the normal population, the CGG repeat varies from six to 54 units. Affected subjects have expanded CGG repeats (>200) in the first exon of the FMR1 gene (the full mutation). Phenotypically normal carriers of the fragile X syndrome have a repeat in the 43 to 200 range (the premutation). The cloning of the FMR1 gene led to the characterisation of its protein product FMRP, encouraged further clinical studies, and opened up the possibility of more accurate family studies and fragile X screening programmes. Images PMID:9678703

  17. Psychosis and catatonia in fragile X: Case report and literature review.

    Science.gov (United States)

    Winarni, Tri Indah; Schneider, Andrea; Ghaziuddin, Neera; Seritan, Andreea; Hagerman, Randi J

    2015-08-01

    Fragile X mental retardation 1 (FMR1) premutation associated phenotypes have been explored extensively since the molecular mechanism emerged involving elevated FMR1 messenger ribonucleic acid (mRNA) levels. Lowered fragile X mental retardation protein (FMRP) can also occur which may have an additive effect to the high levels of mRNA leading to neurodevelopmental problems and psychopathology. This paper was aimed to review psychosis and catatonia in premutation carriers, express the role of elevated FMR1 mRNA and lowered FMRP in the phenotype of carriers and present a case of psychosis and catatonia in a carrier. This case also demonstrates additional genetic and environmental factors which may also affect the phenotype. We review the literature and report an exemplary case of a 25 year old male premutation carrier with elevated FMR1 mRNA, low FMRP, a cytochrome P450 family 2 subfamily D polypeptide 6 (CYP2D6)*2xN mutation and a perinatal insult. This patient developed an autism spectrum disorder, psychosis, catatonia with subsequent cognitive decline after electro-convulsive therapy (ECT) for his catatonia. He had a premutation of 72 CGG repeat in FMR1, FMR1 mRNA level that was over 2.4 times normal and FMRP level at 18% of normal, and additionally, a CYP2D6 allelic variant which leads to ultrarapid metabolism (UM) of medication. There is an overlapping pathophysiological mechanism of catatonia and fragile X-associated premutation phenotypes including autism and psychosis. This case demonstrates the shared phenotype and the overlap of the pathophysiological mechanisms that can influence the intervention. Multiple genetic and environmental hits can lead to more significant involvement in premutation carriers.

  18. Analysis of unstable DNA sequence in FRM1 gene in Polish families with fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Milewski, Michal; Bal, Jerzy; Obersztyn, Ewa; Bocian, Ewa; Mazurczak, Tadeusz [Instytut Matki i Dziecka, Warsaw (Poland); Zygulska, Marta; Horst, Juergen [Institute of Human Genetics, Muenster (Germany); Deelen, Wout H.; Halley, Dicky J.J. [Erasmus Univ., Rotterdam (Netherlands)

    1996-12-31

    The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGC repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted. (author). 19 refs., 4 figs, 1 tab.

  19. Reverse mutations in the fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Brown, W.T.; Houck, G.E. Jr.; Ding, Xiaohua [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)

    1996-08-09

    Three females were identified who have apparent reversal of fragile X premutations. Based on haplotype analysis of nearby markers, they were found to have inherited a fragile X chromosome from their premutation carrier mothers, and yet had normal size FMR1 repeat alleles. The changes in repeat sizes from mother to daughter was 95 to 35 in the first, 145 to 43 in the second, and 82 to 33 in the third. In the first family, mutations of the nearby microsatellites FRAXAC2 and DXS548 were also observed. In the other two, only mutations involving the FMR1 repeats were found. We suggest differing mutational mechanisms such as gene conversion versus DNA replication slippage may underlie such reversions. We estimate that such revertants may occur among 1% or less of premutation carrier offspring. Our results indicate that women identified to be carriers by linkage should be retested by direct DNA analysis. 35 refs., 5 figs.

  20. Patologías asociadas a la premutación del gen FMR1

    OpenAIRE

    2016-01-01

    Históricamente, los individuos portadores de alelos premutados se consideraban asintomáticos dado que no manifestaban discapacidad intelectual. Sin embargo, desde el año 2000 se han descrito dos patologías de aparición tardía asociadas específicamente a estos individuos: la insuficiencia ovárica primaria (FXPOI; OMIM#311360, ORPHA619) y el síndrome de temblor/ataxia asociado al X-Frágil (FXTAS; OMIM#300623, ORPHA93256). No obstante, cada vez es más evidente que existe un amplio espectro de ma...

  1. Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development

    NARCIS (Netherlands)

    K.E. Slegtenhorst-Eegdeman; D.G. de Rooij; M. Verhoef-Post (Miriam); H.J.G. van de Kant (Henk); C.E. Bakker (Cathy); B.A. Oostra (Ben); J.A. Grootegoed (Anton); A.P.N. Themmen (Axel)

    1998-01-01

    textabstractThe fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5'-untranslated region of the gene involved, the fragile

  2. Mosaicism for the FMR1 gene influences adaptive skills development in fragile X-affected males

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, I.L.; Sudhalter, V.; Nolin, S.L. [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)

    1996-08-09

    Fragile X syndrome is one of the most common forms of inherited mental retardation, and the first of a new class of genetic disorders associated with expanded trinucleotide repeats. Previously, we found that about 41% of affected males are mosaic for this mutation in that some of their blood cells have an active fragile X gene and others do not. It has been hypothesized that these mosaic cases should show higher levels of functioning than those who have only the inactive full mutation gene, but previous studies have provided negative or equivocal results. In the present study, the cross-sectional development of communication, self-care, socialization, and motor skills was studied in 46 males with fragile X syndrome under age 20 years as a function of two variables: age and the presence or absence of mosaicism. The rate of adaptive skills development was 2-4 times as great in mosaic cases as in full mutation cases. There was also a trend for cases with autism to be more prevalent in the full-mutation group. These results have implications for prognosis, for the utility of gene or protein replacement therapies for this disorder, and for understanding the association between mental retardation, developmental disorders, and fragile X syndrome. 21 refs., 3 figs.

  3. Craniofacial characteristics of fragile X syndrome in mouse and man

    OpenAIRE

    2012-01-01

    For a disorder as common as fragile X syndrome, the most common hereditary form of cognitive impairment, the facial features are relatively ill defined. An elongated face and prominent ears are the most commonly accepted dysmorphic hallmarks. We analysed 3D facial photographs of 51 males and 15 females with full FMR1 mutations and 9 females with a premutation using dense-surface modelling techniques and a new technique that forms a directed graph with normalized face shapes as nodes and edges...

  4. Reverse mutation in fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Antinolo, G.; Borrego, S.; Cabeza, J.C. [Hospital Universitario, Sevilla (Spain)] [and others

    1996-01-01

    The fragile X syndrome is the most common cause of familial mental retardation, with an incidence of {approximately}1/1,500 in males and 1/2,500 in females. The clinical expression includes moderate to severe mental retardation, macroorchidism, dysmorphic facial features and behavior disturbances. In 1991, the FMR-1 gene was isolated from the region of the fragile X site. The fragile X phenotype has been found, in most cases, to be characterized at the molecular level by expansion of a (CGG){sub n} repeat and hypermethylation of a CpG island identified in the 5{prime}-UTR of the FMR-1 gene. It has been proposed, and some evidence has been shown, that germ cells carry only premutation alleles and that expansion occurs at a postzygotic stage. A few cases of reduction of the (CGG){sub n} repeat in fragile X syndrome have been reported. These reductions were from a larger premutation to a smaller premutation, in female-to-male transmission, from full mutation to a mosaic pattern, reduction from mosaic full-mutation/premutation females or regression from premutation to normal. We present here the novel observation of a phenotypically normal female carrying a nonmosaic full-mutation allele in somatic cells who transmits a premutation allele to her daughter. This daughter has three mosaic offspring with the full mutation and the premutation. Two of them are monozygotic (MZ) twins sharing a concordant mutation pattern. They are monoamniotic monochorionic, which indicates a late form of twinning. 20 refs., 1 fig.

  5. Neurological and endocrine phenotypes of fragile X carrier women.

    Science.gov (United States)

    Hall, D; Todorova-Koteva, K; Pandya, S; Bernard, B; Ouyang, B; Walsh, M; Pounardjian, T; Deburghraeve, C; Zhou, L; Losh, M; Leehey, M; Berry-Kravis, E

    2016-01-01

    Women who carry fragile X mental retardation 1 (FMR1)gene premutation expansions frequently report neurological or endocrine symptoms and prior studies have predominantly focused on questionnaire report of medical issues. Premutation carrier (PMC) women (n = 33) and non-carrier controls (n = 13) were recruited and evaluated by a neurologist, neuropsychologist, and endocrinologist. Blood and skin biopsies were collected for molecular measures. Scales for movement disorders, neuropathy, cognitive function, psychiatric symptoms, sleep, and quality of life were completed. The average age of the women was 51 years (n = 46) and average CGG repeat size was 91 ± 24.9 in the FMR1 PMC women. Seventy percent of the PMC women had an abnormal neurological examination. PMC women had significantly higher scores on the Fragile X-Associated Tremor Ataxia Syndrome (FXTAS) rating scale, more neuropathy, and difficulty with tandem gait compared to controls. Central sensitivity syndromes, a neuroticism profile on the NEO Personality Profile, and sleep disorders were also prevalent. Discrepancies between subject report and examination findings were also seen. This pilot study suggests that women with the FMR1 premutation may have a phenotype that overlaps with that seen in FXTAS. Additional research with larger sample sizes is warranted to better delineate the clinical features.

  6. [Triplet expansion cytosine-guanine-guanine: Three cases of OMIM syndrome in the same family].

    Science.gov (United States)

    González-Pérez, Jesús; Izquierdo-Álvarez, Silvia; Fuertes-Rodrigo, Cristina; Monge-Galindo, Lorena; Peña-Segura, José Luis; López-Pisón, Francisco Javier

    2016-04-01

    The dynamic increase in the number of triplet repeats of cytosine-guanine-guanine (CGG) in the FMR1 gene mutation is responsible for three OMIM syndromes with a distinct clinical phenotype: Fragile X syndrome (FXS) and two pathologies in adult carriers of the premutation (55-200 CGG repeats): Primary ovarian insufficiency (FXPOI) and tremor-ataxia syndrome (FXTAS) associated with FXS. CGG mutation dynamics of the FMR1 gene were studied in DNA samples from peripheral blood from the index case and other relatives of first, second and third degree by TP-PCR, and the percentage methylation. Diagnosis of FXS was confirmed in three patients (21.4%), eight patients (57.1%) were confirmed in the premutation range transmitters, one male patient with full mutation/permutation mosaicism (7.1%) and two patients (14.3%) with normal study. Of the eight permutated patients, three had FXPOI and one male patient had FXTAS. Our study suggests the importance of making an early diagnosis of SXF in order to carry out a family study and genetic counselling, which allow the identification of new cases or premutated patients with FMR1 gene- associated syndromes (FXTAS, FXPOI). Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  7. Fragile X and autism: Intertwined at the molecular level leading to targeted treatments.

    Science.gov (United States)

    Hagerman, Randi; Hoem, Gry; Hagerman, Paul

    2010-09-21

    Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

  8. Fragile X and autism: Intertwined at the molecular level leading to targeted treatments

    Directory of Open Access Journals (Sweden)

    Hagerman Randi

    2010-09-01

    Full Text Available Abstract Fragile X syndrome (FXS is caused by an expanded CGG repeat (> 200 repeats in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1, leading to deficiency or absence of the FMR1 protein (FMRP. FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats may also give rise to autism spectrum disorders (ASD, including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS, in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR1/5 pathway and γ aminobutyric acid (GABAA pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

  9. Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    McConkie-Rosell, A.; Lachiewicz, A.M.; Spiridigliozzi, G.A.; Shoenwald, S. (Duke Univ., Durham, NC (United States)); Tarleton, J.; Phelan, M.C. (Greenwood Genetics Center, Greenwood, SC (United States)); Goonewardena, P. (Kaiser Permanente, San Jose, CA (United States)); Ding, X.; Brown, W.T. (Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States))

    1993-10-01

    DNA at the FMR-1 locus was analyzed by Southern blot using probe StB12.3 in an unusual fragile X family with six brothers, three of whom are affected with fragile X to varying degrees, two of whom are nonpenetrant carriers, and one of whom is unaffected. Fragile X chromosome studies, detailed physical examinations, and psychological testing were completed on all six. Two of the affected brothers and the two nonpenetrant brothers were found to be methylation mosaics. The three affected males spanned the phenotypic and cognitive spectrum of the fragile X syndrome. A correlation was seen between the degree of methylation and the phenotypic expression identified in the three affected males. The two males initially classified as nonpenetrant were found to have mild phenotypic expression which consisted of minor cognitive deficits and a partial physical phenotype. These two, who were negative on fragile X chromosome studies, were found on DNA analysis to have large broad smears, with approximately 97% of the DNA unmethylated. The results described here indicate that some [open quotes]nonpenetrant[close quotes] carrier males may have varying amounts of methylation of the FMR-1 region, which can result in mild expression of the fragile X syndrome. The apparently mild phenotypic and cognitive expression of the fragile X syndrome in the two males, initially classified as nonpenetrant, who are mosaic for hypermethylation of an expansion of the CGG repeat in the premutation range, indicates that expression of the syndrome is not confined to males with large, hypermethylated expansions (full mutation) but has instead a gradient effect with a threshold for the full expression of the phenotype. 41 refs., 2 tabs.

  10. Extreme variation between blood and fibroblast DNA patterns in mosaic fragile X males

    Energy Technology Data Exchange (ETDEWEB)

    Dobkin, C.; Ding, S.; Nolin, S. [New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)] [and others

    1994-09-01

    The fragile X mutation is the expansion of a CGG repeat in the 5{prime} untranslated region of the FMR-1 gene to > 200 repeats. This expansion to the {open_quotes}full mutation{close_quotes} probably occurs during early embryogenesis in individuals who inherit a {open_quotes}premutation{close_quotes} allele containing >50 and <200 repeats. Analysis of blood samples from a series of 148 fragile X males showed that 40% were {open_quotes}mosaics{close_quotes} who carried a mixture of premutation and full mutation alleles. The proportion of the premutation allele varied widely which suggested that there may have been differences in the way the repeat expanded during development. We examined a subset of these affected {open_quotes}mosaic{close_quotes} males who exhibited very different mosaic DNA patterns. Southern blot analysis showed that these males had a range of approximately 10 to 80% premutation allele in their blood DNA. In fibroblast DNA, however, the premutation allele was present at less than 10% in all of these affected males. Since erythrocyte stem cell precursors appear to be established from a yolk sac lineage,earlier in development compared to skin fibroblasts, we hypothesize that this difference in the extent of mosaicism may reflect variation in the progression of the CGG expansion during development. The differences in the proportion of mosaic alleles in different tissues may also help explain the weak correlation between the mosaic DNA patterns of blood samples from mosaic males and their degree of mental retardation.

  11. A Patient with Fragile X-Associated Tremor/Ataxia Syndrome Presenting with Executive Cognitive Deficits and Cerebral White Matter Lesions

    Directory of Open Access Journals (Sweden)

    Kensaku Kasuga

    2011-05-01

    Full Text Available Fragile X-associated tremor/ataxia syndrome (FXTAS is a late-onset neurodegenerative disorder that primarily affects males who are carriers of a premutation of a CGG expansion in the FMR1 gene. In Asian populations, FXTAS has rarely been reported. Here, we report the case of a Japanese FXTAS patient who showed predominant executive cognitive deficits as the main feature of his disease. In contrast, the patient exhibited only very mild symptoms of intention tremor and ataxia, which did not interfere with daily activities. A gene analysis revealed that the patient carried a premutation of a CGG expansion (111 CGG repeats in the FMR1 gene. The mRNA expression level of FMR1 in the patient was 1.5-fold higher than in controls. On brain MRI scans, fluid-attenuated inversion recovery images showed high-intensity lesions in the middle cerebellar peduncles and the cerebral white matter, with a frontal predominance. The present case extends previous notions regarding the cognitive impairment in FXTAS patients. Recognizing FXTAS patients with predominant cognitive impairment from various ethnic backgrounds would contribute to our understanding of the phenotypic variation of this disease.

  12. A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12. 3: The first 2,253 cases

    Energy Technology Data Exchange (ETDEWEB)

    Rousseau, F. (Unite de Recherche en Genetique Humaine et Moleculaire, Quebec (Canada)); Heitz, D. (CNRS-LGME, Strasbourg (France)); Tarleton, J. (Greenwood Genetic Center, SC (United States)); MacPherson, J. (Wessex Regional Genetics Lab., Salisbury (United Kingdom)); Malmgren, H.; Dahl, N.; Barnicoat, A.; Mathew, C.; Mornet, E.; Tejada, I. (and others)

    1994-08-01

    The authors report the results of a 14-center collaborative study of genotype-phenotype correlations in 318 fragile X families; these families comprised 2,253 individuals, 1,344 of whom carried a fragile X mutation and 693 of whom had a typical full fragile X mutation. This study demonstrates that direct DNA diagnosis establishes the genotype at the FRAXA-FMR-1 locus. There was a significantly higher prevalence of [open quotes]mosaic[close quotes] cases among males who carry a full mutation (12%) than among females who carry a full mutation (6%); the mosaic males had a larger expansion than did the mosaic females. Mental status of premutated individuals did not differ from that of those with a normal genotype. Both the abnormal methylation of the FMR-1-EagI site and the size of the expansion were highly correlated with cytogenetics, facial dysmorphism, macroorchidism, and mental retardation (MR). Among female carriers of a full mutation, those with MR had significantly larger expansion than did those without MR. Among 164 independent couples, 3 unrelated husbands carried a premutation that suggests that the prevalence of fragile X premutations in the general population is [approximately] 0.9% of the X chromosomes. The data validate the use of direct DNA testing for fragile X diagnosis as well as for carrier identification and support and complete the established relationships among the DNA results and the cytogenetic, physical, and psychological aspects of the disease. 38 refs., 1 fig., 9 tabs.

  13. Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia.

    Science.gov (United States)

    Kalus, Sarah; King, John; Lui, Elaine; Gaillard, Frank

    2016-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X "premutation", defined as 55-200 CGG repeats in the 5'-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The "MCP sign", referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations.

  14. Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism

    NARCIS (Netherlands)

    Haberl, M.G.; Zerbi, V.; Veltien, A.A.; Ginger, M.; Heerschap, A.; Frick, A.

    2015-01-01

    Fragile X syndrome (FXS), the most common inherited form of intellectual disability disorder and a frequent cause of autism spectrum disorder (ASD), is characterized by a high prevalence of sensory symptoms. Perturbations in the anatomical connectivity of neocortical circuits resulting in their

  15. GENERAL OVERGROWTH IN THE FRAGILE-X SYNDROME - VARIABILITY IN THE PHENOTYPIC-EXPRESSION OF THE FMR1 GENE MUTATION

    NARCIS (Netherlands)

    DEVRIES, BBA; ROBINSON, H; STOLTEDIJKSTRA, [No Value; GI, CVTP; DIJKSTRA, PF; VANDOOM, J; HALLEY, DJJ; OOSTRA, BA; TURNER, G; NIERMEIJER, MF

    1995-01-01

    The fragile X syndrome, which often presents in childhood with overgrowth, may in some cases show some diagnostic overlap with classical Sotos syndrome. We describe four fragile X patients with general overgrowth, all of whom are from families with other affected relatives who show the classic Marti

  16. Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism

    NARCIS (Netherlands)

    Haberl, M.G.; Zerbi, V.; Veltien, A.A.; Ginger, M.; Heerschap, A.; Frick, A.

    2015-01-01

    Fragile X syndrome (FXS), the most common inherited form of intellectual disability disorder and a frequent cause of autism spectrum disorder (ASD), is characterized by a high prevalence of sensory symptoms. Perturbations in the anatomical connectivity of neocortical circuits resulting in their func

  17. Large deviations

    CERN Document Server

    Varadhan, S R S

    2016-01-01

    The theory of large deviations deals with rates at which probabilities of certain events decay as a natural parameter in the problem varies. This book, which is based on a graduate course on large deviations at the Courant Institute, focuses on three concrete sets of examples: (i) diffusions with small noise and the exit problem, (ii) large time behavior of Markov processes and their connection to the Feynman-Kac formula and the related large deviation behavior of the number of distinct sites visited by a random walk, and (iii) interacting particle systems, their scaling limits, and large deviations from their expected limits. For the most part the examples are worked out in detail, and in the process the subject of large deviations is developed. The book will give the reader a flavor of how large deviation theory can help in problems that are not posed directly in terms of large deviations. The reader is assumed to have some familiarity with probability, Markov processes, and interacting particle systems.

  18. Large deviations

    CERN Document Server

    Hollander, Frank den

    2008-01-01

    This book is an introduction to the theory and applications of large deviations, a branch of probability theory that describes the probability of rare events in terms of variational problems. By focusing the theory, in Part A of the book, on random sequences, the author succeeds in conveying the main ideas behind large deviations without a need for technicalities, thus providing a concise and accessible entry to this challenging and captivating subject. The selection of modern applications, described in Part B of the book, offers a good sample of what large deviation theory is able to achieve

  19. The Stage- and Cell Type-Specific Localization of Fragile X Mental Retardation Protein in Rat Ovaries.

    Science.gov (United States)

    Takahashi, Noriyuki; Tarumi, Wataru; Itoh, Masanori T; Ishizuka, Bunpei

    2015-12-01

    Premutations of the fragile X mental retardation 1 (FMR1) gene are associated with increased risk of primary ovarian insufficiency. Here we examined the localization of the Fmr1 gene protein product, fragile X mental retardation protein (FMRP), in rat ovaries at different stages, including fetus, neonate, and old age. In ovaries dissected from 19 days postcoitum embryos, the germ cells were divided into 2 types: one with decondensed chromatin in the nucleus was FMRP positive in the cytoplasm, but the other with strongly condensed chromatin in the nucleus was FMRP negative in the cytoplasm. The FMRP was predominantly localized to the cytoplasm of oocytes in growing ovarian follicles. Levels of FMRP in oocytes from elderly (9 or 14 months of age) ovaries were lower than in those from younger ovaries. These results suggest that FMRP is associated with the activation of oogenesis and oocyte function. Especially, FMRP is likely to be implicated in germline development during oogenesis.

  20. Programming social behavior by the maternal fragile X protein.

    Science.gov (United States)

    Zupan, B; Sharma, A; Frazier, A; Klein, S; Toth, M

    2016-07-01

    The developing fetus and neonate are highly sensitive to maternal environment. Besides the well-documented effects of maternal stress, nutrition and infections, maternal mutations, by altering the fetal, perinatal and/or early postnatal environment, can impact the behavior of genetically normal offspring. Mutation/premutation in the X-linked FMR1 (encoding the translational regulator FMRP) in females, although primarily responsible for causing fragile X syndrome (FXS) in their children, may also elicit such maternal effects. We showed that a deficit in maternal FMRP in mice results in hyperactivity in the genetically normal offspring. To test if maternal FMRP has a broader intergenerational effect, we measured social behavior, a core dimension of neurodevelopmental disorders, in offspring of FMRP-deficient dams. We found that male offspring of Fmr1(+/-) mothers, independent of their own Fmr1 genotype, exhibit increased approach and reduced avoidance toward conspecific strangers, reminiscent of 'indiscriminate friendliness' or the lack of stranger anxiety, diagnosed in neglected children and in patients with Asperger's and Williams syndrome. Furthermore, social interaction failed to activate mesolimbic/amygdala regions, encoding social aversion, in these mice, providing a neurobiological basis for the behavioral abnormality. This work identifies a novel role for FMRP that extends its function beyond the well-established genetic function into intergenerational non-genetic inheritance/programming of social behavior and the corresponding neuronal circuit. As FXS premutation and some psychiatric conditions that can be associated with reduced FMRP expression are more prevalent in mothers than full FMR1 mutation, our findings potentially broaden the significance of FMRP-dependent programming of social behavior beyond the FXS population.

  1. DNA methylation and triplet repeat stability: New proposals addressing actual questions on the CGG repeat of fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Woehrle, D.; Schwemmle, S.; Steinbach, P. [Univ. of Ulm (Germany)

    1996-08-09

    Methylation of expanded CGG repeats in the FMR1 gene may well have different consequences. One is that methylation, extending into upstream regulatory elements, could lead to gene inactivation. Another effect of methylation, which we have obtained evidence for, could be stabilization of the repeat sequence and even prevention of premutations from expansion to full mutation. The full mutation of the fragile X syndrome probably occurs in an early transitional stage of embryonic development. The substrate is a maternally inherited premutation. The product usually is a mosaic pattern of full mutations detectable in early fetal life. These full mutation patterns are mitotically stable as, for instance, different somatic tissues of full mutation fetuses show identical mutation patterns. This raised the following questions: What triggers repeat expansion in that particular stage of development and what causes subsequent mitotic stability of expanded repeats? 21 refs., 1 fig.

  2. Large N

    CERN Document Server

    Hooft, G

    2002-01-01

    In the first part of this lecture, the 1/N expansion technique is illustrated for the case of the large-N sigma model. In large-N gauge theories, the 1/N expansion is tantamount to sorting the Feynman diagrams according to their degree of planarity, that is, the minimal genus of the plane onto which the diagram can be mapped without any crossings. This holds both for the usual perturbative expansion with respect to powers of {tilde g}^2=g^2 N, as well as for the expansion of lattice theories in positive powers of 1/{tilde g}^2. If there were no renormalization effects, the tilde g expansion would have a finite radius of convergence. The zero-dimensional theory can be used for counting planar diagrams. It can be solved explicitly, so that the generating function for the number of diagrams with given 3-vertices and 4-vertices, can be derived exactly. This can be done for various kinds of Feynman diagrams. We end with some remarks about planar renormalization.

  3. Tissue differences in fragile X mosaics: Mosaicism in blood cells may differ greatly from skin

    Energy Technology Data Exchange (ETDEWEB)

    Dobkin, C.S.; Nolin, S.L.; Cohen, I. [NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)] [and others

    1996-08-09

    The fragile X mutation is diagnosed from the structure of the FMR1 gene in blood cell DNA. An estimated 12 to 41% of affected males are mosaics who carry both a {open_quotes}full mutation{close_quotes} allele from which there is no gene expression and a {open_quotes}premutation{close_quotes} allele which has normal gene expression. We compared the DNA in blood cells and skin fibroblasts from four mosaic fragile X males to see if there was a difference in the relative amounts of premutation and full mutation alleles within the tissues of these individuals. Two of these males showed striking differences in the ratio of premutation to full mutation in different tissues while the other two showed only slight differences. These observations conform with the widely accepted hypothesis that the fragile X CGG repeat is unstable in somatic tissue during early embryogenesis. Accordingly, the mosaicism in brain and skin, which are both ectodermal in origin, may be similar to each other but different from blood which is not ectodermal in origin. Thus, the ratio of full mutation to premutation allele in skin fibroblasts might be a better indicator of psychological impairment than the ratio in blood cells. 24 refs., 4 figs., 1 tab.

  4. Fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hagerman, Paul J; Hagerman, Randi J

    2015-03-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some but not all carriers of small, noncoding CGG-repeat expansions (55-200 repeats; premutation) within the fragile X gene (FMR1). Principal features of FXTAS include intention tremor, cerebellar ataxia, Parkinsonism, memory and executive function deficits, autonomic dysfunction, brain atrophy with white matter disease, and cognitive decline. Although FXTAS was originally considered to be confined to the premutation range, rare individuals with a gray zone (45-54 repeats) or an unmethylated full mutation (>200 repeats) allele have now been described, the constant feature of the disorder remaining the requirement for FMR1 expression, in contradistinction to the gene silencing mechanism of fragile X syndrome. Although transcriptional activity is required for FXTAS pathogenesis, the specific trigger(s) for FXTAS pathogenesis remains elusive, highlighting the need for more research in this area. This need is underscored by recent neuroimaging findings of changes in the central nervous system that consistently appear well before the onset of clinical symptoms, thus creating an opportunity to delay or prevent the appearance of FXTAS. © 2015 New York Academy of Sciences.

  5. Dementia in Fragile X-associated Tremor/Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

    Full Text Available Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

  6. Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia

    Directory of Open Access Journals (Sweden)

    Yun Tae Hwang

    2016-09-01

    Full Text Available Mosaicism for FMR1 premutation (PM: 55–199 CGG/full mutation (FM: >200 CGG alleles or the presence of unmethylated FM (UFM have been associated with a less severe fragile X syndrome (FXS phenotype and fragile X associated tremor/ataxia syndrome (FXTAS—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB, which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.

  7. Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia

    Science.gov (United States)

    Hwang, Yun Tae; Dudding, Tracy; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; du Sart, Desirée; Heard, Robert; Godler, David Eugeny

    2016-01-01

    Mosaicism for FMR1 premutation (PM: 55–199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen. PMID:27657133

  8. Stable DNA methylation boundaries and expanded trinucleotide repeats: role of DNA insertions.

    Science.gov (United States)

    Naumann, Anja; Kraus, Cornelia; Hoogeveen, André; Ramirez, Christina M; Doerfler, Walter

    2014-07-15

    The human genome segment upstream of the FMR1 (fragile X mental retardation 1) gene (Xq27.3) contains several genetic signals, among them is a DNA methylation boundary that is located 65-70 CpGs upstream of the CGG repeat. In fragile X syndrome (FXS), the boundary is lost, and the promoter is inactivated by methylation spreading. Here we document boundary stability in spite of critical expansions of the CGG trinucleotide repeat in male or female premutation carriers and in high functioning males (HFMs). HFMs carry a full CGG repeat expansion but exhibit an unmethylated promoter and lack the FXS phenotype. The boundary is also stable in Turner (45, X) females. A CTCF-binding site is located slightly upstream of the methylation boundary and carries a unique G-to-A polymorphism (single nucleotide polymorphism), which occurs 3.6 times more frequently in genomes with CGG expansions. The increased frequency of this single nucleotide polymorphism might have functional significance. In CGG expansions, the CTCF region does not harbor additional mutations. In FXS individuals and often in cells transgenomic for EBV (Epstein Barr Virus) DNA or for the telomerase gene, the large number of normally methylated CpGs in the far-upstream region of the boundary is decreased about 4-fold. A methylation boundary is also present in the human genome segment upstream of the HTT (huntingtin) promoter (4p16.3) and is stable both in normal and Huntington disease chromosomes. Hence, the vicinity of an expanded repeat does not per se compromise methylation boundaries. Methylation boundaries exert an important function as promoter safeguards. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Fragile X gene instability: Anchoring AGGs and linked microsatellites

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Nan; Yang, Weihong; Dobkin, C. [Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States)] [and others

    1995-08-01

    Interspersed AGGs within the FMR1 gene CGG repeat region may anchor the sequence and prevent slippage during replication. In order to detect the AGG position variations, we developed a method employing partial MnlI restriction analysis and analyzed X chromosomes from 187 males, including 133 normal controls (17 with 20-34 and 16 with 35-52 repeats), plus 54 fragile X premutations with 56-180 repeats. Among controls, the interspersed AGG positions were highly polymorphic, with heterozygosity of 91%. Among the control samples, 1.5% had no AGG positions, 25% had one, 71% had two, and 3% had three. Among the fragile X premutation samples, 63% had no AGG, while 37% had only one AGG. Analysis of premutation samples within fragile X families showed that variation occurred only within the 3{prime} end of the region. Thus, the instability was polar. Controls with {ge}15 pure CGG repeats were associated with the longest alleles of two nearby microsatellites, FRAXAC1 with 20-21 repeats and DXS548 with 202-206 bp and with increased microsatellite heterzygosity. The association of long pure CGG regions, as with fragile X chromosomes, with the longer and more heterozygous microsatellite alleles suggests they may be related mechanistically. Further, our results do not support a recent suggestion that the frequency of fragile X alleles may be increasing. Finally, analysis of a set of nonhuman primate samples showed that long pure CGG tracks are variable in size and are located within the 3{prime} region, which suggests that polar instability within FMR1 is evolutionarily quite old. 55 refs., 3 figs., 4 tabs.

  10. Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse.

    Science.gov (United States)

    Pacey, Laura K K; Doss, Lilian; Cifelli, Carlo; van der Kooy, Derek; Heximer, Scott P; Hampson, David R

    2011-03-01

    Fragile X syndrome (FXS), the most common cause of inherited mental retardation, is caused by the loss of the mRNA binding protein, FMRP. Persons with FXS also display epileptic seizures, social anxiety, hyperactivity, and autistic behaviors. The metabotropic glutamate receptor theory of FXS postulates that in the absence of FMRP, enhanced signaling though G-protein coupled group I metabotropic glutamate receptors in the brain contributes to many of the abnormalities observed in the disorder. However, recent evidence suggests that alterations in cellular signaling through additional G-protein coupled receptors may also be involved in the pathogenesis of FXS, thus providing impetus for examining downstream molecules. One group of signaling molecules situated downstream of the receptors is the regulator of G-protein signaling (RGS) proteins. Notably, RGS4 is highly expressed in brain and has been shown to negatively regulate signaling through Group I mGluRs and GABA(B) receptors. To examine the potential role for RGS4 in the pathogenesis of FXS, we generated FXS/RGS4 double knockout mice. Characterization of these mice revealed that a subset of FXS related phenotypes, including increased body weight, altered synaptic protein expression, and abnormal social behaviors, were rescued in the double knockout mice. Other phenotypes, such as hyperactivity and macroorchidism, were not affected by the loss of RGS4. These findings suggest that tissue and cell-type specific differences in GPCR signaling and RGS function may contribute to the spectrum of phenotypic differences observed in FXS.

  11. The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice

    NARCIS (Netherlands)

    M.F. Vinueza Veloz (Maria); R.A.M. Buijsen (Ronald); R. Willemsen (Rob); A. Cupido (Alexander); L.W.J. Bosman (Laurens); S.K.E. Koekkoek (Bas); J.W. Potters (Jan Willem); B.A. Oostra (Ben); C.I. de Zeeuw (Chris)

    2012-01-01

    textabstractFragile X syndrome (FXS) is the most common inherited form of intellectual disability. Patients with FXS do not only suffer from cognitive problems, but also from abnormalities/deficits in procedural memory formation. It has been proposed that a lack of fragile X mental retardation prote

  12. Large Neighborhood Search

    DEFF Research Database (Denmark)

    Pisinger, David; Røpke, Stefan

    2010-01-01

    Heuristics based on large neighborhood search have recently shown outstanding results in solving various transportation and scheduling problems. Large neighborhood search methods explore a complex neighborhood by use of heuristics. Using large neighborhoods makes it possible to find better...... candidate solutions in each iteration and hence traverse a more promising search path. Starting from the large neighborhood search method,we give an overview of very large scale neighborhood search methods and discuss recent variants and extensions like variable depth search and adaptive large neighborhood...... search....

  13. Large Pelagics Intercept Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Intercept Survey (LPIS) is a dockside survey of private and charterboat captains who have just completed fishing trips directed at large pelagic...

  14. LARGE BUILDING RADON MANUAL

    Science.gov (United States)

    The report summarizes information on how bilding systems -- especially the heating, ventilating, and air-conditioning (HVAC) system -- inclurence radon entry into large buildings and can be used to mitigate radon problems. It addresses the fundamentals of large building HVAC syst...

  15. LARGE BUILDING RADON MANUAL

    Science.gov (United States)

    The report summarizes information on how bilding systems -- especially the heating, ventilating, and air-conditioning (HVAC) system -- inclurence radon entry into large buildings and can be used to mitigate radon problems. It addresses the fundamentals of large building HVAC syst...

  16. Large N Scalars

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2016-01-01

    We construct effective Lagrangians, and corresponding counting schemes, valid to describe the dynamics of the lowest lying large N stable massive composite state emerging in strongly coupled theories. The large N counting rules can now be employed when computing quantum corrections via an effective...... at the electroweak scale. To illustrate the formalism we consider the possibility that the Higgs emerges as: the lightest glueball of a new composite theory; the large N scalar meson in models of dynamical electroweak symmetry breaking; the large N pseudodilaton useful also for models of near-conformal dynamics....... For each of these realisations we determine the leading N corrections to the electroweak precision parameters. The results nicely elucidate the underlying large N dynamics and can be used to confront first principle lattice results featuring composite scalars with a systematic effective approach....

  17. Adaptive Large Neighbourhood Search

    DEFF Research Database (Denmark)

    Røpke, Stefan

    Large neighborhood search is a metaheuristic that has gained popularity in recent years. The heuristic repeatedly moves from solution to solution by first partially destroying the solution and then repairing it. The best solution observed during this search is presented as the final solution....... This tutorial introduces the large neighborhood search metaheuristic and the variant adaptive large neighborhood search that dynamically tunes parameters of the heuristic while it is running. Both heuristics belong to a broader class of heuristics that are searching a solution space using very large...... neighborhoods. The tutorial also present applications of the adaptive large neighborhood search, mostly related to vehicle routing problems for which the heuristic has been extremely successful. We discuss how the heuristic can be parallelized and thereby take advantage of modern desktop computers...

  18. Large N Scalars

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2016-01-01

    We construct effective Lagrangians, and corresponding counting schemes, valid to describe the dynamics of the lowest lying large N stable massive composite state emerging in strongly coupled theories. The large N counting rules can now be employed when computing quantum corrections via an effective...... at the electroweak scale. To illustrate the formalism we consider the possibility that the Higgs emerges as: the lightest glueball of a new composite theory; the large N scalar meson in models of dynamical electroweak symmetry breaking; the large N pseudodilaton useful also for models of near-conformal dynamics....... For each of these realisations we determine the leading N corrections to the electroweak precision parameters. The results nicely elucidate the underlying large N dynamics and can be used to confront first principle lattice results featuring composite scalars with a systematic effective approach....

  19. Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Ariza, Jeanelle; Steward, Craig; Rueckert, Flora; Widdison, Matt; Coffman, Robert; Afjei, Atiyeh; Noctor, Stephen C; Hagerman, Randi; Hagerman, Paul; Martínez-Cerdeño, Verónica

    2015-02-19

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.

  20. ERP inside Large Organizations

    Directory of Open Access Journals (Sweden)

    Constantin Daniel AVRAM

    2010-01-01

    Full Text Available Many large companies in Romania are still functioning without an ERP system. Instead they are using traditional application systems built around the strong boundaries of specific functions: finance, selling, HR, production. An ERP will offer lots of advantages among which the integration of functionalities and support for top management decisions. Although the total cost of ownership is not small and there are some risks when implementing an ERP inside large and very large organizations, having such a system is mandatory. Choosing the right product and vendor and using a correct risk management strategy, will ensure a successful implementation.

  1. Large Customers (DR Sellers)

    Energy Technology Data Exchange (ETDEWEB)

    Kiliccot, Sila [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2011-10-25

    State of the large customers for demand response integration of solar and wind into electric grid; openADR; CAISO; DR as a pseudo generation; commercial and industrial DR strategies; California regulations

  2. Large bowel resection - discharge

    Science.gov (United States)

    ... large bowel). You may also have had a colostomy . This article describes what to expect after surgery ... have diarrhea. You may have problems with your colostomy. Self-care Follow your health care provider's instructions ...

  3. Large whale incident database

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Large whale stranding, death, ship strike and entanglement incidents are all recorded to monitor the health of each population and track anthropogenic factors that...

  4. Large intestine (colon) (image)

    Science.gov (United States)

    ... portion of the digestive system most responsible for absorption of water from the indigestible residue of food. The ileocecal valve of the ileum (small intestine) passes material into the large intestine at the ...

  5. Large Rotor Test Apparatus

    Data.gov (United States)

    Federal Laboratory Consortium — This test apparatus, when combined with the National Full-Scale Aerodynamics Complex, produces a thorough, full-scale test capability. The Large Rotor Test Apparatus...

  6. Large Pelagics Telephone Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Telephone Survey (LPTS) collects fishing effort information directly from captains holding Highly Migratory Species (HMS) permits (required by...

  7. Large Pelagics Biological Survey

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Large Pelagics Biological Survey (LPBS) collects additional length and weight information and body parts such as otoliths, caudal vertebrae, dorsal spines, and...

  8. Sequence analysis of the fragile X trinucleotide repeat: Correlations with stability and haplotype and implications for the origin of fragile X alleles

    Energy Technology Data Exchange (ETDEWEB)

    Snow, K.; Tester, D.J.; Kruckeberg, K.E.; Thibodeau, S.N. [Mayo Clinic, Rochester, MN (United States)

    1994-09-01

    Fragile X (FX) syndrome is associated with amplification of a CGG trinucleotide repeat in the 5{prime} untranslated region of the gene FMR-1. To address mechanism of instability and concern related to overlap between sizes of normal stable alleles and FX unstable alleles, we have sequenced 165 alleles to analyze patterns of AGG interruptions within the CGG repeat, and have typed the (CA)n at DXS548 for 204 chromosomes. Overall, our data is consistent with the idea that the length of uninterrupted CGG repeats determines instability. For 17 stably transmitted alleles with total repeat lengths between 33 and 51, the longest stretch of uninterrupted CGGs was 41. In contrast, for 13 premutation alleles, the shortest stretch of uninterrupted CGGs was 48, suggesting a threshold for expansion between 41 and 48 pure CGGs. For expansion from a premutation to a full mutation, the threshold appears to be {ge}70 uninterrupted repeats. Interestingly, an AGG was detected in some carriers of a full mutation. Comparison of the number of {open_quote}shadow bands{close_quote} in PCR products from similar size alleles with different AGG interruption patterns supports replication slippage as a potential mechanism, i.e. replication slippage occurs more readily as the length of pure repeat increases. Alleles with high total repeat lengths but up to 3 AGGs may be relatively protected against expansion, whereas smaller alleles with pure CGG sequence could be at higher risk for instability. Comparison of sequence data and DXS548 (CA)n data revealed specific sequence trends for each of the DXS548 alleles, explaining the previously reported haplotype association with FX. Incorporating these observations into models for the origin of FX alleles, we consider replication slippage, unequal crossover within the CGG repeat region, recombination between FMR-1 and DXS548, and loss of AGGs by A to C transversion.

  9. Discrete large eddy simulation

    Institute of Scientific and Technical Information of China (English)

    L.TAO; K.R.RAJAGOPAL

    2001-01-01

    Despite the intense effort expended towards obtaining a model for describing the turbulent flows of fluid,there is no model at hand that can do an adequate job.This leads us to look for a non-traditional approach to turbulence modeling.In this work we conjoin the notion of large eddy simulation with those of fuzzy sets and neural networks to describe a class of turbulent flow.in previous works we had discussed several issues concerning large eddy simulation such as filtering and averaging,Here,we discuss the use of fuzzy sets to improve the filtering procedure.

  10. Developing Large Web Applications

    CERN Document Server

    Loudon, Kyle

    2010-01-01

    How do you create a mission-critical site that provides exceptional performance while remaining flexible, adaptable, and reliable 24/7? Written by the manager of a UI group at Yahoo!, Developing Large Web Applications offers practical steps for building rock-solid applications that remain effective even as you add features, functions, and users. You'll learn how to develop large web applications with the extreme precision required for other types of software. Avoid common coding and maintenance headaches as small websites add more pages, more code, and more programmersGet comprehensive soluti

  11. Large Deviations and Metastability

    Science.gov (United States)

    Olivieri, Enzo; Eulália Vares, Maria

    2005-02-01

    This self-contained account of the main results in large deviation theory includes recent developments and emphasizes the Freidlin-Wentzell results on small random perturbations. Metastability is described on physical grounds, followed by the development of more exacting approaches to its description. The first part of the book then develops such pertinent tools as the theory of large deviations which is used to provide a physically relevant dynamical description of metastability. Written for graduate students, this book affords an excellent route into contemporary research as well.

  12. Large litter sizes

    DEFF Research Database (Denmark)

    Sandøe, Peter; Rutherford, K.M.D.; Berg, Peer

    2012-01-01

    This paper presents some key results and conclusions from a review (Rutherford et al. 2011) undertaken regarding the ethical and welfare implications of breeding for large litter size in the domestic pig and about different ways of dealing with these implications. Focus is primarily on the direct...... adverse consequences for animal welfare of Danish breeding for large litter sizes due to increased piglet mortality and the subsequent attempts to reverse these consequences by breeding for number of live piglets at day five rather than number of piglets born. By this change of breeding goal it seems...

  13. Large electromagnetic pumps. [LMFBR

    Energy Technology Data Exchange (ETDEWEB)

    Kilman, G.B.

    1976-01-01

    The development of large electromagnetic pumps for the liquid metal heat transfer systems of fission reactors has progressed for a number of years. Such pumps are now planned for fusion reactors and solar plants as well. The Einstein-Szilard (annular) pump has been selected as the preferred configuration. Some of the reasons that electromagnetic pumps may be preferred over mechanical pumps and why the annular configuration was selected are discussed. A detailed electromagnetic analysis of the annular pump, based on slug flow, is presented. The analysis is then used to explore the implications of large size and power on considerations of electromagnetic skin effect, geometric skin effect and the cylindrical geometry.

  14. Fragile-X mental retardation: molecular diagnosis in Argentine patients.

    Science.gov (United States)

    Florencia, Giliberto; Irene, Szijan; Veronica, Ferreiro

    2006-11-30

    Fragile-X-syndrome (FXS) is the most common type of inherited cognitive impairment. The underlying molecular alteration consists of a CGG-repeat amplification within the FMR-1 gene. The phenotype is only apparent once a threshold in the number of repeats has been exceeded (full mutation). The aim of this study was to characterize the FMR-1 CGG-repeat status in Argentine patients exhibiting mental retardation. A total of 330 blood samples from patients were analyzed by PCR and Southern blot analysis. Initially, DNA from 78 affected individuals were studied by PCR. Since this method is unable to detect high molecular weight alleles, however, we undertook a second approach using the Southern blotting technique to analyze the CGG repeat number and methylation status. Southern blot analysis showed an altered pattern in 14 out of 240 (6%) unrelated patients, with half of them presenting a mosaic pattern. Eight out of 17 families (47%) showed a (suggest deleting highlight). The characteristic FXS pattern was identified in 8/17 families (47%), and in 4 of these families 25% of the individuals presented with a mosaic model. The expansion from pre-mutation to full mutation was shown to occur both at the pre and post zygotic levels. The detection of FXS mutations has allowed us to offer more informed genetic counseling, prenatal diagnosis and reliable patient follow-up.

  15. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice.

    Science.gov (United States)

    Foote, Molly; Arque, Gloria; Berman, Robert F; Santos, Mónica

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some carriers of the fragile X premutation (PM). In PM carriers, there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the fragile X mental retardation protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that causes PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically, we will discuss the construct, face, and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms, and potential treatments.

  16. Molecular/clinical correlations in females with fragile X

    Energy Technology Data Exchange (ETDEWEB)

    Sobesky, W.E.; Riddle, J.; Hagerman, R.J. [Children`s Hospital, Denver, CO (United States)] [and others

    1996-08-09

    Females who are affected by fragile X syndrome (FXS) can have significant physical, neuropsychological and emotional involvement. This study was designed to explore the relationships between these three domains and to learn how the degree of involvement in each of these phenotypic areas relates to molecular parameters including CGG repeat length and activation ratio (the proportion of normal FMR1 alleles on the active X chromosome). Three groups of females were studied: 35 women who grew up in a fragile X family but do not carry an FMR1 mutation, 92 women with a premutation, and 29 women with a full mutation. Correlations between neurocognitive, physical and emotional traits were calculated for each of the three groups. Within the full mutation group significant correlations were seen between schizotypal traits and full scale IQ. The Lie scale was significantly correlated with the physical findings index. The activation ratio correlated significantly with the measure of executive function (r = .50, P = .01). There was a trend toward correlations of activation ratio with the physical index score, outer ear prominence and IQ. CGG repeat number significantly correlated only with the physical index (r = .44, P = .0 1). Thus, activation ratio may be the more pertinent molecular parameter in full mutation women in determining the degree of cognitive and physical phenotypic involvement. 29 refs., 2 tabs.

  17. Recommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile X-associated disorders.

    Science.gov (United States)

    McConkie-Rosell, Allyn; Abrams, Liane; Finucane, Brenda; Cronister, Amy; Gane, Louise W; Coffey, Sarah M; Sherman, Stephanie; Nelson, Lawrence M; Berry-Kravis, Elizabeth; Hessl, David; Chiu, Sufen; Street, Natalie; Vatave, Ajay; Hagerman, Randi J

    2007-10-01

    The purpose of this paper is to report the outcome of a collaborative project between the Fragile X Research and Treatment Center at the Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute at the University of California at Davis, the National Fragile X Foundation (NFXF), and the Centers for Disease Control and Prevention (CDC). The objective of this collaboration was to develop and disseminate protocols for genetic counseling and cascade testing for the multiple disorders associated with the fragile X mental retardation 1 (FMR1) mutation. Over the last several years, there has been increasing insight into the phenotypic range associated with both the premutation and the full mutation of the FMR1 gene. To help develop recommendations related to screening for fragile X-associated disorders, four, two day advisory focus group meetings were conducted, each with a different theme. The four themes were: (1) fragile X-associated tremor/ataxia syndrome (FXTAS); (2) premature ovarian failure (POF) and reproductive endocrinology; (3) psychiatric, behavioral and psychological issues; and (4) population screening and related ethical issues.

  18. [Citogenetic and molecular genetic studies in infertility in eastern Hungary].

    Science.gov (United States)

    Mokánszki, Attila; Ujfalusi, Anikó; Balogh, Erzsébet; Molnár, Zsuzsanna; Sápy, Tamás; Jakab, Attila; Varga, Attila; Oláh, Eva

    2013-01-13

    In developed countries 10-15% of the couples are affected by infertility. In half of them genetic factors can be identified. We studied genetic alterations in infertility in Hungarian patients. Cyogenetic analyses were performed in 195 females and 305 males. In 17 females FMR1 mutations, in 150 males Y microdeletions, and aneuploidy were studied in the sperm of 28 males. In a carrier male sperm meiotic segregation was studied. The most common aberrations in females were X chromosome aneuploidia and inversion (3.6%), while the same in males Klinefelter-syndrome (3.3%) and autosomal translocations (2%). In two females FMR1 premutation was found. While Y microdeletions were identified only in azoospermic and severe oligozoospermic men, partial microdeletions could also be detected in normozoospermic males. A higher aberration rate was found in cases with abnormality in both the number and motility of sperm. In a male patient with 46,XY,t(3;6)(q21;q23) karyotype, 53.2% of spem carried unbalanced chromosome assortment. Knowledge of abnormalities may help in genetic counseling and choosing the most effective reproduction technique.

  19. 脆性X相关震颤和(或)共济失调综合征%Fragile X-associated tremor/ataxia syndrome

    Institute of Scientific and Technical Information of China (English)

    韩威威; 张琳; 江泓; 唐北沙

    2011-01-01

    脆性X相关震颤和(或)共济失调综合征(fragile X-associated tremor/ataxia syndrome,FXTAS)是由FMR1基因的前突变(premutation,PM)所导致的一种神经退行性疾病,其临床表现主要为意向性震颤和(或)共济失调,其发病机制与RNA毒性获得机制有关.本文就FXTAS的临床表现、病理特征、流行病学及分子机制等的研究进展做一综述.%Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by FMR1 gene permutation (PM). The main clinical manifestations are intention tremor and/or ataxia, and the pathogenesis was related to RNA toxicity. In this paper, the research progress of clinical manifestations, pathological characteristics, epidemiology and molecular mechanisms will be reviewed.

  20. Risks of Large Portfolios.

    Science.gov (United States)

    Fan, Jianqing; Liao, Yuan; Shi, Xiaofeng

    2015-06-01

    The risk of a large portfolio is often estimated by substituting a good estimator of the volatility matrix. However, the accuracy of such a risk estimator is largely unknown. We study factor-based risk estimators under a large amount of assets, and introduce a high-confidence level upper bound (H-CLUB) to assess the estimation. The H-CLUB is constructed using the confidence interval of risk estimators with either known or unknown factors. We derive the limiting distribution of the estimated risks in high dimensionality. We find that when the dimension is large, the factor-based risk estimators have the same asymptotic variance no matter whether the factors are known or not, which is slightly smaller than that of the sample covariance-based estimator. Numerically, H-CLUB outperforms the traditional crude bounds, and provides an insightful risk assessment. In addition, our simulated results quantify the relative error in the risk estimation, which is usually negligible using 3-month daily data.

  1. Estimating Large Numbers

    Science.gov (United States)

    Landy, David; Silbert, Noah; Goldin, Aleah

    2013-01-01

    Despite their importance in public discourse, numbers in the range of 1 million to 1 trillion are notoriously difficult to understand. We examine magnitude estimation by adult Americans when placing large numbers on a number line and when qualitatively evaluating descriptions of imaginary geopolitical scenarios. Prior theoretical conceptions…

  2. Death Writ Large

    Science.gov (United States)

    Kastenbaum, Robert

    2004-01-01

    Mainstream thanatology has devoted its efforts to improving the understanding, care, and social integration of people who are confronted with life-threatening illness or bereavement. This article suggests that it might now be time to expand the scope and mission to include large-scale death and death that occurs through complex and multi-domain…

  3. Large, Easily Deployable Structures

    Science.gov (United States)

    Agan, W. E.

    1983-01-01

    Study of concepts for large space structures will interest those designing scaffolding, radio towers, rescue equipment, and prefabricated shelters. Double-fold, double-cell module was selected for further design and for zero gravity testing. Concept is viable for deployment by humans outside space vehicle as well as by remotely operated manipulator.

  4. LARGE SCALE GLAZED

    DEFF Research Database (Denmark)

    Bache, Anja Margrethe

    2010-01-01

    WORLD FAMOUS ARCHITECTS CHALLENGE TODAY THE EXPOSURE OF CONCRETE IN THEIR ARCHITECTURE. IT IS MY HOPE TO BE ABLE TO COMPLEMENT THESE. I TRY TO DEVELOP NEW AESTHETIC POTENTIALS FOR THE CONCRETE AND CERAMICS, IN LARGE SCALES THAT HAS NOT BEEN SEEN BEFORE IN THE CERAMIC AREA. IT IS EXPECTED TO RESULT...

  5. The Large Hadron Collider

    CERN Multimedia

    Wright, Alison

    2007-01-01

    "We are on the threshold of a new era in particle-physics research. In 2008, the Large Hadron Collider (LHC) - the hightest-energy accelerator ever built - will come into operation at CERN, the European labortory that straddles the French-Swiss border near Geneva." (1/2 page)

  6. The large hadron computer

    CERN Multimedia

    Hirstius, Andreas

    2008-01-01

    Plans for dealing with the torrent of data from the Large Hadron Collider's detectors have made the CERN particle-phycis lab, yet again, a pioneer in computing as well as physics. The author describes the challenges of processing and storing data in the age of petabyt science. (4 pages)

  7. Dimensioning large call centers

    NARCIS (Netherlands)

    S.C. Borst (Sem); A. Mandelbaum; M.I. Reiman

    2000-01-01

    textabstractWe develop a framework for asymptotic optimization of a queueing system. The motivation is the staffing problem of call centers with 100's of agents (or more). Such a call center is modeled as an M/M/N queue, where the number of agents~$N$ is large. Within our framework, we determine the

  8. Teaching Very Large Classes

    Science.gov (United States)

    DeRogatis, Amy; Honerkamp, Kenneth; McDaniel, Justin; Medine, Carolyn; Nyitray, Vivian-Lee; Pearson, Thomas

    2014-01-01

    The editor of "Teaching Theology and Religion" facilitated this reflective conversation with five teachers who have extensive experience and success teaching extremely large classes (150 students or more). In the course of the conversation these professors exchange and analyze the effectiveness of several active learning strategies they…

  9. Dengfeng Large Gnomon

    Science.gov (United States)

    Xu, Fengxian

    Dengfeng large gnomon is a Yuan Dynasty astronomical instrument used for observing the length of the sun's shadow in different seasons and determining the tropical year. Together with the Tang Dynasty stele lying to the south of it, witnessed the idea of the center of the world.

  10. Large litter sizes

    DEFF Research Database (Denmark)

    Sandøe, Peter; Rutherford, K.M.D.; Berg, Peer

    2012-01-01

    This paper presents some key results and conclusions from a review (Rutherford et al. 2011) undertaken regarding the ethical and welfare implications of breeding for large litter size in the domestic pig and about different ways of dealing with these implications. Focus is primarily on the direct...

  11. Large myelomeningocele repair

    Directory of Open Access Journals (Sweden)

    Farideh Nejat

    2011-01-01

    Full Text Available Background: Wound closure is accomplished in most cases of myelomeningocele (MMC by undermining of the skin edges surrounding the defect. However, large defects cannot be closed reliably by this simple technique. Due to the technical challenge associated with large MMC, surgeons have devised different methods for repairing large defects. In this paper, we report our experience of managing large defects, which we believe bears a direct relationship to decrease the incidence of wound complications. Materials and Methods: Forty children with large MMCs underwent surgical repair and represent our experience. We recommend using all hairy skin around the defect as a way to decrease the tension on the edges of the wound and the possible subsequent necrosis. It is our experience that vertical incision on one or two flanks parallel to the midline can decrease the tension of the wound. Moreover, ventriculo-peritoneal shunting for children who developed hydrocephalus was performed simultaneously, which constitutes another recommendation for preventing fluid collection and build up of pressure on the wound. Results: Patients in this study were in the age range of 2 days to 8 years. The most common location of MMC was in the thoracolumbar area. All but four patients had severe weakness in lower extremities. We used as much hairy skin around the MMC sac as possible in all cases. Vertical incisions on one or both flanks and simultaneous shunt procedure were performed in 36 patients. We treated children with large MMC defects with acceptable tension-free closure. Nonetheless, three patients developed superficial skin infection and partial wound dehiscence, and they were managed conservatively. Conclusions: We recommend using all hairy skin around the MMC defect for closure of large defects. In cases that were expected to be at a higher risk to develop dehiscence release incisions on one or two flanks towards the fascia were found to be useful. Simultaneous

  12. Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome.

    Science.gov (United States)

    O'Keefe, Joan A; Robertson-Dick, Erin E; Hall, Deborah A; Berry-Kravis, Elizabeth

    2016-08-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS.

  13. Large reservoirs: Chapter 17

    Science.gov (United States)

    Miranda, Leandro E.; Bettoli, Phillip William

    2010-01-01

    Large impoundments, defined as those with surface area of 200 ha or greater, are relatively new aquatic ecosystems in the global landscape. They represent important economic and environmental resources that provide benefits such as flood control, hydropower generation, navigation, water supply, commercial and recreational fisheries, and various other recreational and esthetic values. Construction of large impoundments was initially driven by economic needs, and ecological consequences received little consideration. However, in recent decades environmental issues have come to the forefront. In the closing decades of the 20th century societal values began to shift, especially in the developed world. Society is no longer willing to accept environmental damage as an inevitable consequence of human development, and it is now recognized that continued environmental degradation is unsustainable. Consequently, construction of large reservoirs has virtually stopped in North America. Nevertheless, in other parts of the world construction of large reservoirs continues. The emergence of systematic reservoir management in the early 20th century was guided by concepts developed for natural lakes (Miranda 1996). However, we now recognize that reservoirs are different and that reservoirs are not independent aquatic systems inasmuch as they are connected to upstream rivers and streams, the downstream river, other reservoirs in the basin, and the watershed. Reservoir systems exhibit longitudinal patterns both within and among reservoirs. Reservoirs are typically arranged sequentially as elements of an interacting network, filter water collected throughout their watersheds, and form a mosaic of predictable patterns. Traditional approaches to fisheries management such as stocking, regulating harvest, and in-lake habitat management do not always produce desired effects in reservoirs. As a result, managers may expend resources with little benefit to either fish or fishing. Some locally

  14. Large Eddy Simulation

    Directory of Open Access Journals (Sweden)

    Joseph Mathew

    2010-10-01

    Full Text Available Large eddy simulation (LES is an emerging technique for obtaining an approximation to turbulent flow fields. It is an improvement over the widely prevalent practice of obtaining means of turbulent flows when the flow has large scale, low frequency, unsteadiness. An introduction to the method, its general formulation, and the more common modelling for flows without reaction, is discussed. Some attempts at extension to flows with combustion have been made. Examples from present work for flows with and without combustion are given. The final example of the LES of the combustor of a helicopter engine illustrates the state-of-the-art in application of the technique.Defence Science Journal, 2010, 60(6, pp.598-605, DOI:http://dx.doi.org/10.14429/dsj.60.602

  15. Large area mass analyzer

    Energy Technology Data Exchange (ETDEWEB)

    Rachev, Mikhail [Max-Planck-Institut for Nuclear Physics, Heidelberg Saupfercheckweg 1, Heidelberg 69117 (Germany)]. E-mail: mikhail.rachev@mpi-hd.mpg.de; Srama, Ralf [Max-Planck-Institut for Nuclear Physics, Heidelberg Saupfercheckweg 1, Heidelberg 69117 (Germany); Srowig, Andre [Max-Planck-Institut for Nuclear Physics, Heidelberg Saupfercheckweg 1, Heidelberg 69117 (Germany); Gruen, Eberhard [Max-Planck-Institut for Nuclear Physics, Heidelberg Saupfercheckweg 1, Heidelberg 69117 (Germany)

    2004-12-11

    A new time-of-flight spectrometer for the chemical analysis of cosmic dust particles in space has been simulated by Simion 7.0. The instrument is based upon impact ionization. This method is a reliable method for in situ dust detection and is well established. Instruments using the impact ionization flew on board of Helios and Galileo and are still in operation on board of the Ulysses and Cassini-Huygens missions. The new instrument has a large sensitive area of 0.1m2 in order to achieve a significant number of measurements. The mass resolution M/{delta}M>100 and the mass range covers the most relevant elements expected in cosmic dust. The instrument has a reflectron configuration which increases the mass resolution. Most of the ions released during the impact are focused to the detector. The ion detector consists of a large area ion-to-electron converter, an electron reflectron and a microchannel plate detector.

  16. The Large Hadron Collider

    CERN Document Server

    Juettner Fernandes, Bonnie

    2014-01-01

    What really happened during the Big Bang? Why did matter form? Why do particles have mass? To answer these questions, scientists and engineers have worked together to build the largest and most powerful particle accelerator in the world: the Large Hadron Collider. Includes glossary, websites, and bibliography for further reading. Perfect for STEM connections. Aligns to the Common Core State Standards for Language Arts. Teachers' Notes available online.

  17. Large Curved Surface Measurement

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The measurement principle of large curved surface through theodolite industry survey system is introduced. Two methods are suggested with respect to the distribution range of curved surface error. The experiments show that the measurement precision can be up to 0.15mm with relative precision of 3×10-5. Finally, something needed paying attention to and the application aspects on theodolite industry survey system are given.

  18. Lymphomas of large cells.

    Science.gov (United States)

    Staples, W G; Gétaz, E P

    1977-09-03

    Historial aspects of the classification of large-cell lymphomas are described. Immunological characterization of the lymphomas has been made possible by identification of T and B lymphocytes according to their cell membrane surface characteristics. The pathogenesis of lymphomas has been clarified by the germinal (follicular) centre cell concepts of Lennert and Lukes and Collins. The various classifications are presented and compared. Whether these subdivisions will have any relevance in the clinical context remains to be seen.

  19. Large area LED package

    Science.gov (United States)

    Goullon, L.; Jordan, R.; Braun, T.; Bauer, J.; Becker, F.; Hutter, M.; Schneider-Ramelow, M.; Lang, K.-D.

    2015-03-01

    Solid state lighting using LED-dies is a rapidly growing market. LED-dies with the needed increasing luminous flux per chip area produce a lot of heat. Therefore an appropriate thermal management is required for general lighting with LEDdies. One way to avoid overheating and shorter lifetime is the use of many small LED-dies on a large area heat sink (down to 70 μm edge length), so that heat can spread into a large area while at the same time light also appears on a larger area. The handling with such small LED-dies is very difficult because they are too small to be picked with common equipment. Therefore a new concept called collective transfer bonding using a temporary carrier chip was developed. A further benefit of this new technology is the high precision assembly as well as the plane parallel assembly of the LED-dies which is necessary for wire bonding. It has been shown that hundred functional LED-dies were transferred and soldered at the same time. After the assembly a cost effective established PCB-technology was applied to produce a large-area light source consisting of many small LED-dies and electrically connected on a PCB-substrate. The top contacts of the LED-dies were realized by laminating an adhesive copper sheet followed by LDI structuring as known from PCB-via-technology. This assembly can be completed by adding converting and light forming optical elements. In summary two technologies based on standard SMD and PCB technology have been developed for panel level LED packaging up to 610x 457 mm2 area size.

  20. Large Optics Technology.

    Science.gov (United States)

    1986-05-22

    EEEEEEEEEEmhEE SENSEffl -2-5 12" 110111111 LLLo 111M1. 2 15 .1 111-= NATIONAL BUREAU OF S Mouopy *9sO9u TESI , C N LARGE OPTICS TECHNOLOGY FINAL...Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1981 !mw ’(’* 17 ABSTRACT The mirrors used in high energy laser systems...SCIENCES (GRADUATE) In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1982

  1. A large thumb mass.

    Science.gov (United States)

    Shah, Amit K; Macnair, Rory; Figus, Andrea

    2012-02-01

    A 31-year-old man presented with a 5-year history of a spontaneously occurring soft tissue mass on the palmar aspect of his left non dominant thumb. Over 5 months he was having progressive difficulty flexing at the interphalangeal joint. Magnetic resonance imaging demonstrated an heterogeneously enhancing soft tissue mass likely to be either a peripheral fibromatosis or giant cell tumour of the flexor tendon (Figure 1). Intraoperatively a large neuroma in continuity with the ulnar digital nerve was found and debulked (Figure 2). The diagnosis was confirmed histologically.

  2. The large hadron computer

    Science.gov (United States)

    Hirstius, Andreas

    2008-11-01

    In the mid-1990s, when CERN physicists made their first cautious estimates of the amount of data that experiments at the Large Hadron Collider (LHC) would produce, the microcomputer component manufacturer Intel had just released the Pentium Pro processor. Windows was the dominant operating system, although Linux was gaining momentum. CERN had recently made the World Wide Web public, but the system was still a long way from the all-encompassing network it is today. And a single gigabyte (109 bytes) of disk space cost several hundred dollars.

  3. Large Particle Titanate Sorbents

    Energy Technology Data Exchange (ETDEWEB)

    Taylor-Pashow, K. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2015-10-08

    This research project was aimed at developing a synthesis technique for producing large particle size monosodium titanate (MST) to benefit high level waste (HLW) processing at the Savannah River Site (SRS). Two applications were targeted, first increasing the size of the powdered MST used in batch contact processing to improve the filtration performance of the material, and second preparing a form of MST suitable for deployment in a column configuration. Increasing the particle size should lead to improvements in filtration flux, and decreased frequency of filter cleaning leading to improved throughput. Deployment of MST in a column configuration would allow for movement from a batch process to a more continuous process. Modifications to the typical MST synthesis led to an increase in the average particle size. Filtration testing on dead-end filters showed improved filtration rates with the larger particle material; however, no improvement in filtration rate was realized on a crossflow filter. In order to produce materials suitable for column deployment several approaches were examined. First, attempts were made to coat zirconium oxide microspheres (196 µm) with a layer of MST. This proved largely unsuccessful. An alternate approach was then taken synthesizing a porous monolith of MST which could be used as a column. Several parameters were tested, and conditions were found that were able to produce a continuous structure versus an agglomeration of particles. This monolith material showed Sr uptake comparable to that of previously evaluated samples of engineered MST in batch contact testing.

  4. Large deviations from freeness

    CERN Document Server

    Kargin, Vladislav

    2010-01-01

    Let H=A+UBU* where A and B are two N-by-N Hermitian matrices and U is a Haar-distributed random unitary matrix, and let \\mu_H, \\mu_A, and \\mu_B be empirical measures of eigenvalues of matrices H, A, and B, respectively. Then, it is known (see, for example, Pastur-Vasilchuk, CMP, 2000, v.214, pp.249-286) that for large N, measure \\mu_H is close to the free convolution of measures \\mu_A and \\mu_B, where the free convolution is a non-linear operation on probability measures. The large deviations of the cumulative distribution function of \\mu_H from its expectation have been studied by Chatterjee in JFA, 2007, v. 245, pp.379-389. In this paper we improve Chatterjee's estimate and show that P {\\sup_x |F_H (x) -F_+ (x)| > \\delta} < exp [-f(\\delta) N^2], where F_H (x) and F_+ (x) denote the cumulative distribution functions of \\mu_H and the free convolution of \\mu_A and \\mu_B, respectively, and where f(\\delta) is a specific function.

  5. Large Spectral Library Problem

    Energy Technology Data Exchange (ETDEWEB)

    Chilton, Lawrence K.; Walsh, Stephen J.

    2008-10-03

    Hyperspectral imaging produces a spectrum or vector at each image pixel. These spectra can be used to identify materials present in the image. In some cases, spectral libraries representing atmospheric chemicals or ground materials are available. The challenge is to determine if any of the library chemicals or materials exist in the hyperspectral image. The number of spectra in these libraries can be very large, far exceeding the number of spectral channels collected in the ¯eld. Suppose an image pixel contains a mixture of p spectra from the library. Is it possible to uniquely identify these p spectra? We address this question in this paper and refer to it as the Large Spectral Library (LSL) problem. We show how to determine if unique identi¯cation is possible for any given library. We also show that if p is small compared to the number of spectral channels, it is very likely that unique identi¯cation is possible. We show that unique identi¯cation becomes less likely as p increases.

  6. Large Spin Perturbation Theory

    CERN Document Server

    Alday, Luis F

    2016-01-01

    We consider conformal field theories around points of large twist degeneracy. Examples of this are theories with weakly broken higher spin symmetry and perturbations around generalised free fields. At the degenerate point we introduce twist conformal blocks. These are eigenfunctions of certain quartic operators and encode the contribution, to a given four-point correlator, of the whole tower of intermediate operators with a given twist. As we perturb around the degenerate point, the twist degeneracy is lifted. In many situations this breaking is controlled by inverse powers of the spin. In such cases the twist conformal blocks can be decomposed into a sequence of functions which we systematically construct. Decomposing the four-point correlator in this basis turns crossing symmetry into an algebraic problem. Our method can be applied to a wide spectrum of conformal field theories in any number of dimensions and at any order in the breaking parameter. As an example, we compute the spectrum of various theories ...

  7. Silicic Large Igneous Provinces

    Institute of Scientific and Technical Information of China (English)

    Scott Bryan

    2007-01-01

    @@ Large Igneous Provinces (LIPs) are the end-product of huge additions of magma to the continental crust both at the surface and at depth. Since the first categorisation of LIPs by Coffin & Eldholm (1994), it has been recognised that LIPs are more varied inform, age and character, and this includes the recognition of Silicic LIPs. Silicic LIPs are the largest accumulations of primary volcaniclastic rocks at the Earth's surface with areal extents >0.1 Mkm2 and extrusive and subvolcanic intrusive volumes >0.25 Mkm3. The Late Palaeozoic to Cenozoic Silicic LIP events are the best recognised and are similar in terms of their dimension, crustal setting, volcanic architecture and geochemistry.

  8. Large Superconducting Magnet Systems

    CERN Document Server

    Védrine, P.

    2014-07-17

    The increase of energy in accelerators over the past decades has led to the design of superconducting magnets for both accelerators and the associated detectors. The use of Nb−Ti superconducting materials allows an increase in the dipole field by up to 10 T compared with the maximum field of 2 T in a conventional magnet. The field bending of the particles in the detectors and generated by the magnets can also be increased. New materials, such as Nb3Sn and high temperature superconductor (HTS) conductors, can open the way to higher fields, in the range 13–20 T. The latest generations of fusion machines producing hot plasma also use large superconducting magnet systems.

  9. Large Scale Solar Heating

    DEFF Research Database (Denmark)

    Heller, Alfred

    2001-01-01

    The main objective of the research was to evaluate large-scale solar heating connected to district heating (CSDHP), to build up a simulation tool and to demonstrate the application of the simulation tool for design studies and on a local energy planning case. The evaluation was mainly carried out...... model is designed and validated on the Marstal case. Applying the Danish Reference Year, a design tool is presented. The simulation tool is used for proposals for application of alternative designs, including high-performance solar collector types (trough solar collectors, vaccum pipe collectors......). Simulation programs are proposed as control supporting tool for daily operation and performance prediction of central solar heating plants. Finaly the CSHP technolgy is put into persepctive with respect to alternatives and a short discussion on the barries and breakthrough of the technology are given....

  10. Large area plasma source

    Science.gov (United States)

    Foster, John (Inventor); Patterson, Michael (Inventor)

    2008-01-01

    An all permanent magnet Electron Cyclotron Resonance, large diameter (e.g., 40 cm) plasma source suitable for ion/plasma processing or electric propulsion, is capable of producing uniform ion current densities at its exit plane at very low power (e.g., below 200 W), and is electrodeless to avoid sputtering or contamination issues. Microwave input power is efficiently coupled with an ionizing gas without using a dielectric microwave window and without developing a throat plasma by providing a ferromagnetic cylindrical chamber wall with a conical end narrowing to an axial entrance hole for microwaves supplied on-axis from an open-ended waveguide. Permanent magnet rings are attached inside the wall with alternating polarities against the wall. An entrance magnet ring surrounding the entrance hole has a ferromagnetic pole piece that extends into the chamber from the entrance hole to a continuing second face that extends radially across an inner pole of the entrance magnet ring.

  11. Decrease in the CGG{sub n} trinucleotide repeat mutation of the fragile X syndrome to normal size range during paternal transmission

    Energy Technology Data Exchange (ETDEWEB)

    Vaeisaenen, M.L.; Haataja, R.; Leisti, J. [Oulu Univ. Hospital (Finland)

    1996-09-01

    The fragile X syndrome, the most common inherited form of mental retardation, is caused by the expansion of a CGG{sub n} trinucleotide repeat in the FMR-1 gene. Although the repeat number usually increases during transmission, few cases with reduction of an expanded CGG{sub n} repeat back to the normal size range have been reported. We describe for the first time a family in which such reduction has occurred in the paternal transmission. The paternal premutation ({Delta} = 300 hp) was not detected in one of the five daughters or in the son of this daughter, although he had the grandpaternal RFLP haplotype. Instead, fragments indicating the normal CGG{sub n} repeat size were seen on a Southern blot probed with StB12.3. PCR analysis of the CGG{sub n} repeat confirmed this; in addition to a maternal allele of 30 repeats, an allele of 34 repeats was detected in the daughter and, further, in her son. Sequencing of this new allele revealed a pure CGG{sub n} repeat configuration without AGG interruptions. No evidence for a somatic mosaicism of a premutation allele in the daughter or a normal allele in her father was detected when investigating DNA derived from blood lymphocytes and skin fibroblasts. Another unusual finding in this family was lack of the PCR product of the microsatellite marker RS46 (DXS548) in one of the grandmaternal X chromosomes, detected as incompatible inheritance of RS46 alleles. The results suggest an intergenerational reduction in the CGG{sub n} repeat from premutation size to the normal size range and stable transmission of the contracted repeat to the next generation. However, paternal germ-line mosaicism could not be excluded as an alternative explanation for the reverse mutation. 37 refs., 4 figs.

  12. THE LARGE MILLIMETER TELESCOPE

    Directory of Open Access Journals (Sweden)

    D. H. Hughes

    2009-01-01

    Full Text Available This paper, presented on behalf of the Large Millimeter Telescope (LMT project team, describes the status and near-term plans for the telescope and its initial instrumentation. The LMT is a bi-national collaboration between M xico and the USA, led by the Instituto Nacional de Astrof sica, ptica y Electr nica (INAOE and the University of Massachusetts at Amherst, to construct, commission and operate a 50 m diameter millimeterwave radio telescope. Construction activities are nearly complete at the LMT site, at an altitude of 4600 m on the summit of Sierra Negra, an extinct volcano in the Mexican state of Puebla. Full movement of the telescope, under computer control in both azimuth and elevation, has been achieved. First-light at centimeter wavelengths on astronomical sources was obtained in November 2006. Installation of precision surface segments for millimeter-wave operation is underway, with the inner 32 m diameter of the surface now complete and ready to be used to obtain rst-light at millimeter wavelengths in 2008. Installation of the remainder of the re ector will continue during the next year and be completed in 2009 for nal commissioning of the antenna. The full LMT antenna, out ted with its initial complement of scienti c instruments, will be a world-leading scienti c research facility for millimeter-wave astronomy.

  13. Large Databases in Astronomy

    Science.gov (United States)

    Szalay, Alexander S.; Gray, Jim; Kunszt, Peter; Thakar, Anirudha; Slutz, Don

    The next-generation astronomy digital archives will cover most of the sky at fine resolution in many wavelengths, from X-rays through ultraviolet, optical, and infrared. The archives will be stored at diverse geographical locations. The intensive use of advanced data archives will enable astronomers to explore their data interactively. Data access will be aided by multidimensional spatial and attribute indices. The data will be partitioned in many ways. Small tag indices consisting of the most popular attributes will accelerate frequent searches. Splitting the data among multiple servers will allow parallel, scalable I/O and parallel data analysis. Hashing techniques will allow efficient clustering, and pair-wise comparison algorithms that should parallelize nicely. Randomly sampled subsets will allow debugging otherwise large queries at the desktop. Central servers will operate a data pump to support sweep searches touching most of the data. The anticipated queries will require special operators related to angular distances and complex similarity tests of object properties, like shapes, colors, velocity vectors, or temporal behaviors. These issues pose interesting data management challenges.

  14. Large scale tracking algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, Ross L. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Love, Joshua Alan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Melgaard, David Kennett [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Karelitz, David B. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Pitts, Todd Alan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Zollweg, Joshua David [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Anderson, Dylan Z. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Nandy, Prabal [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Whitlow, Gary L. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Bender, Daniel A. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Byrne, Raymond Harry [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-01-01

    Low signal-to-noise data processing algorithms for improved detection, tracking, discrimination and situational threat assessment are a key research challenge. As sensor technologies progress, the number of pixels will increase signi cantly. This will result in increased resolution, which could improve object discrimination, but unfortunately, will also result in a significant increase in the number of potential targets to track. Many tracking techniques, like multi-hypothesis trackers, suffer from a combinatorial explosion as the number of potential targets increase. As the resolution increases, the phenomenology applied towards detection algorithms also changes. For low resolution sensors, "blob" tracking is the norm. For higher resolution data, additional information may be employed in the detection and classfication steps. The most challenging scenarios are those where the targets cannot be fully resolved, yet must be tracked and distinguished for neighboring closely spaced objects. Tracking vehicles in an urban environment is an example of such a challenging scenario. This report evaluates several potential tracking algorithms for large-scale tracking in an urban environment.

  15. Large Size Telescope Report

    CERN Document Server

    Mazin, D; Teshima, M

    2016-01-01

    The Cherenkov Telescope Array (CTA) observatory will be deployed over two sites in the two hemispheres. Both sites will be equipped with four Large Size Telescopes (LSTs), which are crucial to achieve the science goals of CTA in the 20-200 GeV energy range. Each LST is equipped with a primary tessellated mirror dish of 23 m diameter, supported by a structure made mainly of carbon fibre reinforced plastic tubes and aluminum joints. This solution guarantees light weight (around 100 tons), essential for fast repositioning to any position in the sky in <20 seconds. The camera is composed of 1855 photomultiplier tubes and embeds the control, readout and trigger electronics. The detailed design is now complete and production of the first LST, which will serve as a prototype for the remaining seven, is ongoing. The installation of the first LST at the Roque de los Muchachos Observatory on the Canary island of La Palma (Spain) started in July 2016. In this paper we will outline the technical solutions adopted to f...

  16. Large Crater Clustering tool

    Science.gov (United States)

    Laura, Jason; Skinner, James A.; Hunter, Marc A.

    2017-08-01

    In this paper we present the Large Crater Clustering (LCC) tool set, an ArcGIS plugin that supports the quantitative approximation of a primary impact location from user-identified locations of possible secondary impact craters or the long-axes of clustered secondary craters. The identification of primary impact craters directly supports planetary geologic mapping and topical science studies where the chronostratigraphic age of some geologic units may be known, but more distant features have questionable geologic ages. Previous works (e.g., McEwen et al., 2005; Dundas and McEwen, 2007) have shown that the source of secondary impact craters can be estimated from secondary impact craters. This work adapts those methods into a statistically robust tool set. We describe the four individual tools within the LCC tool set to support: (1) processing individually digitized point observations (craters), (2) estimating the directional distribution of a clustered set of craters, back projecting the potential flight paths (crater clusters or linearly approximated catenae or lineaments), (3) intersecting projected paths, and (4) intersecting back-projected trajectories to approximate the local of potential source primary craters. We present two case studies using secondary impact features mapped in two regions of Mars. We demonstrate that the tool is able to quantitatively identify primary impacts and supports the improved qualitative interpretation of potential secondary crater flight trajectories.

  17. Large size telescope report

    Science.gov (United States)

    Mazin, D.; Cortina, J.; Teshima, M.

    2017-01-01

    The Cherenkov Telescope Array (CTA) observatory will be deployed over two sites in the two hemispheres. Both sites will be equipped with four Large Size Telescopes (LSTs), which are crucial to achieve the science goals of CTA in the 20-200 GeV energy range. Each LST is equipped with a primary tessellated mirror dish of 23 m diameter, supported by a structure made mainly of carbon fibre reinforced plastic tubes and aluminum joints. This solution guarantees light weight (around 100 tons), essential for fast repositioning to any position in the sky in <20 seconds. The camera is composed of 1855 photomultiplier tubes and embeds the control, readout and trigger electronics. The detailed design is now complete and production of the first LST, which will serve as a prototype for the remaining seven, is ongoing. The installation of the first LST at the Roque de los Muchachos Observatory on the Canary island of La Palma (Spain) started in July 2016. In this paper we will outline the technical solutions adopted to fulfill the design requirements, present results of element prototyping and describe the installation and operation plans.

  18. Large scale tracking algorithms.

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, Ross L.; Love, Joshua Alan; Melgaard, David Kennett; Karelitz, David B.; Pitts, Todd Alan; Zollweg, Joshua David; Anderson, Dylan Z.; Nandy, Prabal; Whitlow, Gary L.; Bender, Daniel A.; Byrne, Raymond Harry

    2015-01-01

    Low signal-to-noise data processing algorithms for improved detection, tracking, discrimination and situational threat assessment are a key research challenge. As sensor technologies progress, the number of pixels will increase signi cantly. This will result in increased resolution, which could improve object discrimination, but unfortunately, will also result in a significant increase in the number of potential targets to track. Many tracking techniques, like multi-hypothesis trackers, suffer from a combinatorial explosion as the number of potential targets increase. As the resolution increases, the phenomenology applied towards detection algorithms also changes. For low resolution sensors, "blob" tracking is the norm. For higher resolution data, additional information may be employed in the detection and classfication steps. The most challenging scenarios are those where the targets cannot be fully resolved, yet must be tracked and distinguished for neighboring closely spaced objects. Tracking vehicles in an urban environment is an example of such a challenging scenario. This report evaluates several potential tracking algorithms for large-scale tracking in an urban environment.

  19. Applied large eddy simulation.

    Science.gov (United States)

    Tucker, Paul G; Lardeau, Sylvain

    2009-07-28

    Large eddy simulation (LES) is now seen more and more as a viable alternative to current industrial practice, usually based on problem-specific Reynolds-averaged Navier-Stokes (RANS) methods. Access to detailed flow physics is attractive to industry, especially in an environment in which computer modelling is bound to play an ever increasing role. However, the improvement in accuracy and flow detail has substantial cost. This has so far prevented wider industrial use of LES. The purpose of the applied LES discussion meeting was to address questions regarding what is achievable and what is not, given the current technology and knowledge, for an industrial practitioner who is interested in using LES. The use of LES was explored in an application-centred context between diverse fields. The general flow-governing equation form was explored along with various LES models. The errors occurring in LES were analysed. Also, the hybridization of RANS and LES was considered. The importance of modelling relative to boundary conditions, problem definition and other more mundane aspects were examined. It was to an extent concluded that for LES to make most rapid industrial impact, pragmatic hybrid use of LES, implicit LES and RANS elements will probably be needed. Added to this further, highly industrial sector model parametrizations will be required with clear thought on the key target design parameter(s). The combination of good numerical modelling expertise, a sound understanding of turbulence, along with artistry, pragmatism and the use of recent developments in computer science should dramatically add impetus to the industrial uptake of LES. In the light of the numerous technical challenges that remain it appears that for some time to come LES will have echoes of the high levels of technical knowledge required for safe use of RANS but with much greater fidelity.

  20. Large Binocular Telescope Project

    Science.gov (United States)

    Hill, John M.

    1997-03-01

    The large binocular telescope (LBT) project have evolved from concepts first proposed in 1985. The present partners involved in the design and construction of this 2 by 8.4 meter binocular telescope are the University of Arizona, Italy represented by the Osservatorio Astrofisico di Arcetri and the Research Corporation based in Tucson, Arizona. These three partners have committed sufficient funds to build the enclosure and the telescope populated with a single 8.4 meter optical train -- approximately 40 million dollars (1989). Based on this commitment, design and construction activities are now moving forward. Additional partners are being sought. The next mirror to be cast at the Steward Observatory Mirror Lab in the fall of 1996 will be the first borosilicate honeycomb primary for LBT. The baseline optical configuration of LBT includes wide field Cassegrain secondaries with optical foci above the primaries to provide a corrected one degree field at F/4. The infrared F/15 secondaries are a Gregorian design to allow maximum flexibility for adaptive optics. The F/15 secondaries are undersized to provide a low thermal background focal plane which is unvignetted over a 4 arcminute diameter field-of-view. The interferometric focus combining the light from the two 8.4 meter primaries will reimage two folded Gregorian focal planes to a central location. The telescope elevation structure accommodates swing arms which allow rapid interchange of the various secondary and tertiary mirrors. Maximum stiffness and minimal thermal disturbance continue to be important drivers for the detailed design of the telescope. The telescope structure accommodates installation of a vacuum bell jar for aluminizing the primary mirrors in-situ on the telescope. The detailed design of the telescope structure will be completed in 1996 by ADS Italia (Lecco) and European Industrial Engineering (Mestre). The final enclosure design is now in progress at M3 Engineering (Tucson), EIE and ADS Italia

  1. Laboratory for Large Data Research

    Data.gov (United States)

    Federal Laboratory Consortium — FUNCTION: The Laboratory for Large Data Research (LDR) addresses a critical need to rapidly prototype shared, unified access to large amounts of data across both the...

  2. Reduced activity-dependent protein levels in a mouse model of the fragile X premutation

    NARCIS (Netherlands)

    R.E. von Leden (Ramona); L.C. Curley (Lindsey); G.D. Greenberg (Gian); M.R. Hunsaker (Michael); R. Willemsen (Rob); R.F. Berman (Robert)

    2014-01-01

    textabstractEnvironmental enrichment results in increased levels of Fmrp in brain and increased dendritic complexity. The present experiment evaluated activity-dependent increases in Fmrp levels in the motor cortex in response to training on a skilled forelimb reaching task in the CGG KI mouse model

  3. Cerebral protein synthesis in a knockin mouse model of the fragile X premutation

    NARCIS (Netherlands)

    M. Qin (Mei); T. Huang (Tianjian); Z. Liu (Zhonghua); M. Kader (Michael); T. Burlin (Thomas); Z. Xia (Zengyan); Z. Zeidler (Zachary); R.K. Hukema (Renate); C.B. Smith (Carolyn B.)

    2014-01-01

    textabstractThe (CGG)n-repeat in the 5’-untransiated region of the fragile X mental retardation gene (FMRi) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMRi and absence of its prot

  4. Large deviations and idempotent probability

    CERN Document Server

    Puhalskii, Anatolii

    2001-01-01

    In the view of many probabilists, author Anatolii Puhalskii''s research results stand among the most significant achievements in the modern theory of large deviations. In fact, his work marked a turning point in the depth of our understanding of the connections between the large deviation principle (LDP) and well-known methods for establishing weak convergence results.Large Deviations and Idempotent Probability expounds upon the recent methodology of building large deviation theory along the lines of weak convergence theory. The author develops an idempotent (or maxitive) probability theory, introduces idempotent analogues of martingales (maxingales), Wiener and Poisson processes, and Ito differential equations, and studies their properties. The large deviation principle for stochastic processes is formulated as a certain type of convergence of stochastic processes to idempotent processes. The author calls this large deviation convergence.The approach to establishing large deviation convergence uses novel com...

  5. Large Representation Recurrences in Large N Random Unitary Matrix Models

    CERN Document Server

    Karczmarek, Joanna L

    2011-01-01

    In a random unitary matrix model at large N, we study the properties of the expectation value of the character of the unitary matrix in the rank k symmetric tensor representation. We address the problem of whether the standard semiclassical technique for solving the model in the large N limit can be applied when the representation is very large, with k of order N. We find that the eigenvalues do indeed localize on an extremum of the effective potential; however, for finite but sufficiently large k/N, it is not possible to replace the discrete eigenvalue density with a continuous one. Nonetheless, the expectation value of the character has a well-defined large N limit, and when the discreteness of the eigenvalues is properly accounted for, it shows an intriguing approximate periodicity as a function of k/N.

  6. Large-scale data analytics

    CERN Document Server

    Gkoulalas-Divanis, Aris

    2014-01-01

    Provides cutting-edge research in large-scale data analytics from diverse scientific areas Surveys varied subject areas and reports on individual results of research in the field Shares many tips and insights into large-scale data analytics from authors and editors with long-term experience and specialization in the field

  7. Team Learning in Large Classes.

    Science.gov (United States)

    Roueche, Suanne D., Ed.

    1984-01-01

    Information and suggestions are provided on the use of team learning in large college classes. Introductory material discusses the negative cycle of student-teacher interaction that may be provoked by large classes, and the use of permanent, heterogeneous, six- or seven-member student learning groups as the central focus of class activity as a…

  8. Large amplitude oscillatory elongation flow

    DEFF Research Database (Denmark)

    Rasmussen, Henrik K.; Laillé, Philippe; Yu, Kaijia

    2008-01-01

    A filament stretching rheometer (FSR) was used for measuring the elongation flow with a large amplitude oscillative elongation imposed upon the flow. The large amplitude oscillation imposed upon the elongational flow as a function of the time t was defined as epsilon(t) =(epsilon) over dot(0)t + ...

  9. Querying Large Biological Network Datasets

    Science.gov (United States)

    Gulsoy, Gunhan

    2013-01-01

    New experimental methods has resulted in increasing amount of genetic interaction data to be generated every day. Biological networks are used to store genetic interaction data gathered. Increasing amount of data available requires fast large scale analysis methods. Therefore, we address the problem of querying large biological network datasets.…

  10. Large shareholders and accounting research

    Institute of Scientific and Technical Information of China (English)

    Ole-Kristian; Hope

    2013-01-01

    Large shareholders are a potentially very important element of firms’ corporate governance system. Whereas analytical research is typically vague on who these large shareholders are, in practice there are important variations in the types of large owners(and the different types of large owners could play very different governance roles). After briefly reviewing the standard agency cost arguments, in this article I emphasize the heterogeneity of concentrated ownership and in particular focus on the roles of families, institutions, governments, and employee ownership. I also discuss the role of large shareholders in private(i.e., unlisted) firms, where ownership tends to be more concentrated than in publicly traded firms. Finally, I briefly discuss variations in ownership structures across selected countries.

  11. Measuring happiness in large population

    Science.gov (United States)

    Wenas, Annabelle; Sjahputri, Smita; Takwin, Bagus; Primaldhi, Alfindra; Muhamad, Roby

    2016-01-01

    The ability to know emotional states for large number of people is important, for example, to ensure the effectiveness of public policies. In this study, we propose a measure of happiness that can be used in large scale population that is based on the analysis of Indonesian language lexicons. Here, we incorporate human assessment of Indonesian words, then quantify happiness on large-scale of texts gathered from twitter conversations. We used two psychological constructs to measure happiness: valence and arousal. We found that Indonesian words have tendency towards positive emotions. We also identified several happiness patterns during days of the week, hours of the day, and selected conversation topics.

  12. Large for Gestational Age (LGA)

    Science.gov (United States)

    ... primarily results from an abundance of nutrients. In pregnant women with diabetes, a large amount of sugar (glucose) crosses the placenta (the organ that connects the fetus to the uterus and provides nourishment to the fetus) and results ...

  13. Large Hadron Collider nears completion

    CERN Multimedia

    2008-01-01

    Installation of the final component of the Large Hadron Collider particle accelerator is under way along the Franco-Swiss border near Geneva, Switzerland. When completed this summer, the LHC will be the world's largest and most complex scientific instrument.

  14. Analytic bootstrap at large spin

    CERN Document Server

    Kaviraj, Apratim; Sinha, Aninda

    2015-01-01

    We use analytic conformal bootstrap methods to determine the anomalous dimensions and OPE coefficients for large spin operators in general conformal field theories in four dimensions containing a scalar operator of conformal dimension $\\Delta_\\phi$. It is known that such theories will contain an infinite sequence of large spin operators with twists approaching $2\\Delta_\\phi+2n$ for each integer $n$. By considering the case where such operators are separated by a twist gap from other operators at large spin, we analytically determine the $n$, $\\Delta_\\phi$ dependence of the anomalous dimensions. We find that for all $n$, the anomalous dimensions are negative for $\\Delta_\\phi$ satisfying the unitarity bound, thus extending the Nachtmann theorem to non-zero $n$. In the limit when $n$ is large, we find agreement with the AdS/CFT prediction corresponding to the Eikonal limit of a 2-2 scattering with dominant graviton exchange.

  15. Flannery's Nursing Home, Chapel Road, Abbeyknockmoy, Tuam, Galway.

    LENUS (Irish Health Repository)

    Hallahan, Brian P

    2012-08-30

    AbstractPurposeThere is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX.MethodsWe used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals.ResultsThere was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls.ConclusionsThis is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.

  16. A designated centre for people with disabilities operated by Peter Bradley Foundation Limited, Dublin 24

    LENUS (Irish Health Repository)

    Hallahan, Brian P

    2012-08-30

    AbstractPurposeThere is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX.MethodsWe used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals.ResultsThere was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls.ConclusionsThis is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.

  17. Elmhurst Nursing Home, Hampstead Avenue, Glasnevin, Dublin 9.

    LENUS (Irish Health Repository)

    Hallahan, Brian P

    2012-08-30

    AbstractPurposeThere is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX.MethodsWe used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals.ResultsThere was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls.ConclusionsThis is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.

  18. Large N lattice gauge theory

    CERN Document Server

    Narayanan, Rajamani

    2008-01-01

    Wilson loops in large N gauge theory exhibit a weak to strong coupling transition as the loop is dilated. A multiplicative matrix model captures the universal behavior associated with this transition. A universal scaling function is obtained in a double scaling limit. Numerical studies show that both large N QCD in three dimensions and the SU(N) principal chiral model in two dimensions are in the same universality class.

  19. Intravascular large B cell lymphoma

    Directory of Open Access Journals (Sweden)

    Ricardo García-Muñoz

    2014-01-01

    Full Text Available Intravascular large B cell lymphoma (IVBCL is a rare type of extranodal large B cell lymphoma characterized by selective growth of lymphoma cells within the microvasculature. We present an illustrative case of intravascular B cell lymphoma suspected by the presence of a very small monoclonal B cell population identified by immunophenotype and polymerase chain reaction in bone marrow. The diagnosis was confirmed by skin biopsy.

  20. Large-scale solar heat

    Energy Technology Data Exchange (ETDEWEB)

    Tolonen, J.; Konttinen, P.; Lund, P. [Helsinki Univ. of Technology, Otaniemi (Finland). Dept. of Engineering Physics and Mathematics

    1998-12-31

    In this project a large domestic solar heating system was built and a solar district heating system was modelled and simulated. Objectives were to improve the performance and reduce costs of a large-scale solar heating system. As a result of the project the benefit/cost ratio can be increased by 40 % through dimensioning and optimising the system at the designing stage. (orig.)

  1. Optimization theory for large systems

    CERN Document Server

    Lasdon, Leon S

    2011-01-01

    Important text examines most significant algorithms for optimizing large systems and clarifying relations between optimization procedures. Much data appear as charts and graphs and will be highly valuable to readers in selecting a method and estimating computer time and cost in problem-solving. Initial chapter on linear and nonlinear programming presents all necessary background for subjects covered in rest of book. Second chapter illustrates how large-scale mathematical programs arise from real-world problems. Appendixes. List of Symbols.

  2. Can we save large carnivores without losing large carnivore science?

    Science.gov (United States)

    Allen, Benjamin L.; Allen, Lee R.; Andrén, Henrik; Ballard, Guy; Boitani, Luigi; Engeman, Richard M.; Fleming, Peter J.S.; Haswell, Peter M.; Ford, Adam T.; Kowalczyk, Rafał; Mech, L. David; Linnell, John D.C.; Parker, Daniel M.

    2017-01-01

    Large carnivores are depicted to shape entire ecosystems through top-down processes. Studies describing these processes are often used to support interventionist wildlife management practices, including carnivore reintroduction or lethal control programs. Unfortunately, there is an increasing tendency to ignore, disregard or devalue fundamental principles of the scientific method when communicating the reliability of current evidence for the ecological roles that large carnivores may play, eroding public confidence in large carnivore science and scientists. Here, we discuss six interrelated issues that currently undermine the reliability of the available literature on the ecological roles of large carnivores: (1) the overall paucity of available data, (2) reliability of carnivore population sampling techniques, (3) general disregard for alternative hypotheses to top-down forcing, (4) lack of applied science studies, (5) frequent use of logical fallacies, and (6) generalisation of results from relatively pristine systems to those substantially altered by humans. We first describe how widespread these issues are, and given this, show, for example, that evidence for the roles of wolves (Canis lupus) and dingoes (Canis lupus dingo) in initiating trophic cascades is not as strong as is often claimed. Managers and policy makers should exercise caution when relying on this literature to inform wildlife management decisions. We emphasise the value of manipulative experiments and discuss the role of scientific knowledge in the decision-making process. We hope that the issues we raise here prompt deeper consideration of actual evidence, leading towards an improvement in both the rigour and communication of large carnivore science.

  3. Universal anomalous dimensions at large spin and large twist

    CERN Document Server

    Kaviraj, Apratim; Sinha, Aninda

    2015-01-01

    In this paper we consider anomalous dimensions of double trace operators at large spin ($\\ell$) and large twist ($\\tau$) in CFTs in arbitrary dimensions ($d\\geq 3$). Using analytic conformal bootstrap methods, we show that the anomalous dimensions are universal in the limit $\\ell\\gg \\tau\\gg 1$. In the course of the derivation, we extract an approximate closed form expression for the conformal blocks arising in the four point function of identical scalars in any dimension. We compare our results with two different calculations in holography and find perfect agreement.

  4. Preparation of large monodisperse vesicles.

    Directory of Open Access Journals (Sweden)

    Ting F Zhu

    Full Text Available Preparation of monodisperse vesicles is important both for research purposes and for practical applications. While the extrusion of vesicles through small pores (approximately 100 nm in diameter results in relatively uniform populations of vesicles, extrusion to larger sizes results in very heterogeneous populations of vesicles. Here we report a simple method for preparing large monodisperse multilamellar vesicles through a combination of extrusion and large-pore dialysis. For example, extrusion of polydisperse vesicles through 5-microm-diameter pores eliminates vesicles larger than 5 microm in diameter. Dialysis of extruded vesicles against 3-microm-pore-size polycarbonate membranes eliminates vesicles smaller than 3 microm in diameter, leaving behind a population of monodisperse vesicles with a mean diameter of approximately 4 microm. The simplicity of this method makes it an effective tool for laboratory vesicle preparation with potential applications in preparing large monodisperse liposomes for drug delivery.

  5. Large Scale Dynamos in Stars

    Science.gov (United States)

    Vishniac, Ethan T.

    2015-01-01

    We show that a differentially rotating conducting fluid automatically creates a magnetic helicity flux with components along the rotation axis and in the direction of the local vorticity. This drives a rapid growth in the local density of current helicity, which in turn drives a large scale dynamo. The dynamo growth rate derived from this process is not constant, but depends inversely on the large scale magnetic field strength. This dynamo saturates when buoyant losses of magnetic flux compete with the large scale dynamo, providing a simple prediction for magnetic field strength as a function of Rossby number in stars. Increasing anisotropy in the turbulence produces a decreasing magnetic helicity flux, which explains the flattening of the B/Rossby number relation at low Rossby numbers. We also show that the kinetic helicity is always a subdominant effect. There is no kinematic dynamo in real stars.

  6. Building large structures in space

    Science.gov (United States)

    Hagler, T.

    1976-01-01

    The building of large structures in space would be required for the establishment of a variety of systems needed for different forms of space utilization. The problems involved in the building of such structures in space and the approaches which can be used to solve these problems are illustrated with the aid of an example involving a concept for packaging, transporting, and assembling two representative large space structures. The structure of a radio-astronomy telescope 200 m in diam was felt to be representative of the many medium-size structures of the Shuttle era. A typical very large structure is represented by the supporting structure for the transmission system of a 5000-Mw space solar power station.

  7. Large-scale circuit simulation

    Science.gov (United States)

    Wei, Y. P.

    1982-12-01

    The simulation of VLSI (Very Large Scale Integration) circuits falls beyond the capabilities of conventional circuit simulators like SPICE. On the other hand, conventional logic simulators can only give the results of logic levels 1 and 0 with the attendent loss of detail in the waveforms. The aim of developing large-scale circuit simulation is to bridge the gap between conventional circuit simulation and logic simulation. This research is to investigate new approaches for fast and relatively accurate time-domain simulation of MOS (Metal Oxide Semiconductors), LSI (Large Scale Integration) and VLSI circuits. New techniques and new algorithms are studied in the following areas: (1) analysis sequencing (2) nonlinear iteration (3) modified Gauss-Seidel method (4) latency criteria and timestep control scheme. The developed methods have been implemented into a simulation program PREMOS which could be used as a design verification tool for MOS circuits.

  8. Inflating with large effective fields

    Science.gov (United States)

    Burgess, C. P.; Cicoli, M.; Quevedo, F.; Williams, M.

    2014-11-01

    We re-examine large scalar fields within effective field theory, in particular focussing on the issues raised by their use in inflationary models (as suggested by BICEP2 to obtain primordial tensor modes). We argue that when the large-field and low-energy regimes coincide the scalar dynamics is most effectively described in terms of an asymptotic large-field expansion whose form can be dictated by approximate symmetries, which also help control the size of quantum corrections. We discuss several possible symmetries that can achieve this, including pseudo-Goldstone inflatons characterized by a coset G/H (based on abelian and non-abelian, compact and non-compact symmetries), as well as symmetries that are intrinsically higher dimensional. Besides the usual trigonometric potentials of Natural Inflation we also find in this way simple large-field power laws (like V propto phi2) and exponential potentials, V(phi) = ∑kVxe-kphi/M. Both of these can describe the data well and give slow-roll inflation for large fields without the need for a precise balancing of terms in the potential. The exponential potentials achieve large r through the limit |η| ll epsilon and so predict r simeq (8/3)(1-ns) consequently ns simeq 0.96 gives r simeq 0.11 but not much larger (and so could be ruled out as measurements on r and ns improve). We examine the naturalness issues for these models and give simple examples where symmetries protect these forms, using both pseudo-Goldstone inflatons (with non-abelian non-compact shift symmetries following familiar techniques from chiral perturbation theory) and extra-dimensional models.

  9. Inflating with large effective fields

    Energy Technology Data Exchange (ETDEWEB)

    Burgess, C.P. [PH-TH Division, CERN, CH-1211, Genève 23 (Switzerland); Cicoli, M. [Dipartimento di Fisica e Astronomia, Università di Bologna, Via Irnerio 46, 40126 Bologna (Italy); Quevedo, F. [Abdus Salam ICTP, Strada Costiera 11, Trieste 34014 (Italy); Williams, M., E-mail: cburgess@perimeterinstitute.ca, E-mail: mcicoli@ictp.it, E-mail: f.quevedo@damtp.cam.ac.uk, E-mail: mwilliams@perimeterinsititute.ca [Department of Physics and Astronomy, McMaster University, 1280 Main Street West, Hamilton ON (Canada)

    2014-11-01

    We re-examine large scalar fields within effective field theory, in particular focussing on the issues raised by their use in inflationary models (as suggested by BICEP2 to obtain primordial tensor modes). We argue that when the large-field and low-energy regimes coincide the scalar dynamics is most effectively described in terms of an asymptotic large-field expansion whose form can be dictated by approximate symmetries, which also help control the size of quantum corrections. We discuss several possible symmetries that can achieve this, including pseudo-Goldstone inflatons characterized by a coset G/H (based on abelian and non-abelian, compact and non-compact symmetries), as well as symmetries that are intrinsically higher dimensional. Besides the usual trigonometric potentials of Natural Inflation we also find in this way simple large-field power laws (like V ∝ φ{sup 2}) and exponential potentials, V(φ) = ∑{sub k}V{sub x}e{sup −kφ/M}. Both of these can describe the data well and give slow-roll inflation for large fields without the need for a precise balancing of terms in the potential. The exponential potentials achieve large r through the limit |η| || ε and so predict r ≅ (8/3)(1-n{sub s}); consequently n{sub s} ≅ 0.96 gives r ≅ 0.11 but not much larger (and so could be ruled out as measurements on r and n{sub s} improve). We examine the naturalness issues for these models and give simple examples where symmetries protect these forms, using both pseudo-Goldstone inflatons (with non-abelian non-compact shift symmetries following familiar techniques from chiral perturbation theory) and extra-dimensional models.

  10. Intracranial Large Artery Occlusive Disease

    Institute of Scientific and Technical Information of China (English)

    Wong KS; Li H; Kay R

    2000-01-01

    @@Intracranial large artery stenosis is the most commonly found vascular lesion in stroke patient of Chinese, Hispanic and African ancestry. There .have been few studies on the epidemiology, pathophysiology, treatment and prognosis of this important disease. Recent advances in technology provide safe and reliable investigation for studying large number of patients. Transcranial Doppler is an easily accessible, cheap and reliable method to diagnose intracranial stenosis. It is suitable for screening for and monitoring the progress of intracranial stenosis. Magnetic resonance angiography and CT angiography provide the morphology of lumenal stenosis but are less accessible.

  11. Management of large hepatocellular carcinoma.

    Science.gov (United States)

    Amarapurkar, D N

    2004-04-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. There is increasing incidence of HCC in India. More than 70% of HCC are not suitable for curative treatment. Majority of the HCCs are large when diagnosed all over the world. There is no standard treatment for large HCCs. Different palliative treatments like arterial embolization/chemoembolization, intraarterial lipoidol chemotherapy, hormonal compounds like tamoxifene, octerotide systemic chemotherapy, immuno therapy with interferon, internal radiation with 131I or 99Yttrium. Arterial chemoembolization is the treatment of choice with proved efficacy in selected group of patients. The newer modalities and strategies need to be tried in controlled randomized trials.

  12. Strings and large scale magnetohydrodynamics

    CERN Document Server

    Olesen, P

    1995-01-01

    From computer simulations of magnetohydrodynamics one knows that a turbulent plasma becomes very intermittent, with the magnetic fields concentrated in thin flux tubes. This situation looks very "string-like", so we investigate whether strings could be solutions of the magnetohydrodynamics equations in the limit of infinite conductivity. We find that the induction equation is satisfied, and we discuss the Navier-Stokes equation (without viscosity) with the Lorentz force included. We argue that the string equations (with non-universal maximum velocity) should describe the large scale motion of narrow magnetic flux tubes, because of a large reparametrization (gauge) invariance of the magnetic and electric string fields.

  13. Physics with large extra dimensions

    Indian Academy of Sciences (India)

    Ignatios Antoniadis

    2004-02-01

    The recent understanding of string theory opens the possibility that the string scale can be as low as a few TeV. The apparent weakness of gravitational interactions can then be accounted by the existence of large internal dimensions, in the sub-millimeter region. Furthermore, our world must be confined to live on a brane transverse to these large dimensions, with which it interacts only gravitationally. In my lecture, I describe briefly this scenario which gives a new theoretical framework for solving the gauge hierarchy problem and the unification of all interactions. I also discuss a minimal embedding of the standard model, gauge coupling unification and proton stability.

  14. Dijets at large rapidity intervals

    CERN Document Server

    Pope, B G

    2001-01-01

    Inclusive diet production at large pseudorapidity intervals ( Delta eta ) between the two jets has been suggested as a regime for observing BFKL dynamics. We have measured the dijet cross section for large Delta eta in pp collisions at square root s = 1800 and 630 GeV using the DOE detector. The partonic cross section increases strongly with the size of Delta eta . The observed growth is even stronger than expected on the basis of BFKL resummation in the leading logarithmic approximation. The growth of the partonic cross section can be accommodated with an effective BFKL intercept of alpha /sub BFKL/(20 GeV) = 1.65 +or- 0.07.

  15. The Limit of Large Vessels

    Institute of Scientific and Technical Information of China (English)

    Yang Peiju

    2011-01-01

    On Feb 21(st),the industry was shocked by the news that AP Moller-Maersk placed an order of 10 container ships of 18,000 TEU with the South Korean ship yards.The order brings the development of large vessels to a new climax and at the same time puts forward a series of research subjects to the industry,such as what is the limit for the development of large vessels,whether ship safety can be guaranteed,and etc.

  16. Large radii and string unification

    CERN Document Server

    Antoniadis, Ignatios

    1997-01-01

    We study strong coupling effects in four-dimensional heterotic string models where supersymmetry is spontaneously broken with large internal dimensions, consistently with perturbative unification of gauge couplings. These effects give rise to thresholds associated to the dual theories: type I superstring or M-theory. In the case of one large dimension, we find that these thresholds appear close to the field-theoretical unification scale $\\sim 10^{16}$ GeV, offering an appealing scenario for unification of gravitational and gauge interactions. We also identify the inverse size of the eleventh dimension of M-theory with the energy at which four-fermion effective operators become important.

  17. Large even order character sums

    CERN Document Server

    Goldmakher, Leo

    2012-01-01

    A classical theorem of Paley asserts the existence of an infinite family of quadratic characters whose character sums become exceptionally large. In this paper, we establish an analogous result for characters of any fixed even order. Previously our bounds were only known under the assumption of the Generalized Riemann Hypothesis.

  18. Large deviations and portfolio optimization

    Science.gov (United States)

    Sornette, Didier

    Risk control and optimal diversification constitute a major focus in the finance and insurance industries as well as, more or less consciously, in our everyday life. We present a discussion of the characterization of risks and of the optimization of portfolios that starts from a simple illustrative model and ends by a general functional integral formulation. A major item is that risk, usually thought of as one-dimensional in the conventional mean-variance approach, has to be addressed by the full distribution of losses. Furthermore, the time-horizon of the investment is shown to play a major role. We show the importance of accounting for large fluctuations and use the theory of Cramér for large deviations in this context. We first treat a simple model with a single risky asset that exemplifies the distinction between the average return and the typical return and the role of large deviations in multiplicative processes, and the different optimal strategies for the investors depending on their size. We then analyze the case of assets whose price variations are distributed according to exponential laws, a situation that is found to describe daily price variations reasonably well. Several portfolio optimization strategies are presented that aim at controlling large risks. We end by extending the standard mean-variance portfolio optimization theory, first within the quasi-Gaussian approximation and then using a general formulation for non-Gaussian correlated assets in terms of the formalism of functional integrals developed in the field theory of critical phenomena.

  19. Inconsistency in large pharmacogenomic studies

    DEFF Research Database (Denmark)

    Haibe-Kains, Benjamin; El-Hachem, Nehme; Birkbak, Nicolai Juul;

    2013-01-01

    Two large-scale pharmacogenomic studies were published recently in this journal. Genomic data are well correlated between studies; however, the measured drug response data are highly discordant. Although the source of inconsistencies remains uncertain, it has potential implications for using...

  20. Very Large Scale Integration (VLSI).

    Science.gov (United States)

    Yeaman, Andrew R. J.

    Very Large Scale Integration (VLSI), the state-of-the-art production techniques for computer chips, promises such powerful, inexpensive computing that, in the future, people will be able to communicate with computer devices in natural language or even speech. However, before full-scale VLSI implementation can occur, certain salient factors must be…

  1. Adding large EM stack support

    KAUST Repository

    Holst, Glendon

    2016-12-01

    Serial section electron microscopy (SSEM) image stacks generated using high throughput microscopy techniques are an integral tool for investigating brain connectivity and cell morphology. FIB or 3View scanning electron microscopes easily generate gigabytes of data. In order to produce analyzable 3D dataset from the imaged volumes, efficient and reliable image segmentation is crucial. Classical manual approaches to segmentation are time consuming and labour intensive. Semiautomatic seeded watershed segmentation algorithms, such as those implemented by ilastik image processing software, are a very powerful alternative, substantially speeding up segmentation times. We have used ilastik effectively for small EM stacks – on a laptop, no less; however, ilastik was unable to carve the large EM stacks we needed to segment because its memory requirements grew too large – even for the biggest workstations we had available. For this reason, we refactored the carving module of ilastik to scale it up to large EM stacks on large workstations, and tested its efficiency. We modified the carving module, building on existing blockwise processing functionality to process data in manageable chunks that can fit within RAM (main memory). We review this refactoring work, highlighting the software architecture, design choices, modifications, and issues encountered.

  2. Ideas for Managing Large Classes.

    Science.gov (United States)

    Kabel, Robert L.

    1983-01-01

    Describes management strategies used in a large kinetics/industrial chemistry course. Strategies are designed to make instruction in such classes more efficient and effective. Areas addressed include homework assignment, quizzes, final examination, grading and feedback, and rewards for conducting the class in the manner described. (JN)

  3. Large deviations in Taylor dispersion

    Science.gov (United States)

    Kahlen, Marcel; Engel, Andreas; Van den Broeck, Christian

    2017-01-01

    We establish a link between the phenomenon of Taylor dispersion and the theory of empirical distributions. Using this connection, we derive, upon applying the theory of large deviations, an alternative and much more precise description of the long-time regime for Taylor dispersion.

  4. COOPERATIVE LEARNING IN LARGE CLASSES

    Institute of Scientific and Technical Information of China (English)

    GuoXiangju

    2004-01-01

    Teaching college English in large classes is a new challenge to teachers. To meet this challenge, the strategy of cooperative learning is practicable. This paper introduces cooperative learning and describes the experiment results, which prove the advantages of cooperative learning over competitive learning or individualistic learning.

  5. Making Large Classes More Interactive.

    Science.gov (United States)

    Brenner, John

    2000-01-01

    Describes the method of using prompts to allow students to have more "voice" in a large class. The prompt assignment requires students to respond anonymously to a statement that concerns the chapter being discussed in the class. Discusses how the Internet has allowed more freedom with the prompts. Puts forth some student responses to the…

  6. Inflating with Large Effective Fields

    CERN Document Server

    Burgess, C P; Quevedo, F; Williams, M

    2014-01-01

    We re-examine large scalar fields within effective field theory, in particular focussing on the issues raised by their use in inflationary models (as suggested by BICEP2 to obtain primordial tensor modes). We argue that when the large-field and low-energy regimes coincide the scalar dynamics is most effectively described in terms of an asymptotic large-field expansion whose form can be dictated by approximate symmetries, which also help control the size of quantum corrections. We discuss several possible symmetries that can achieve this, including pseudo-Goldstone inflatons characterized by a coset $G/H$ (based on abelian and non-abelian, compact and non-compact symmetries), as well as symmetries that are intrinsically higher dimensional. Besides the usual trigonometric potentials of Natural Inflation we also find in this way simple {\\em large-field} power laws (like $V \\propto \\phi^2$) and exponential potentials, $V(\\phi) = \\sum_{k} V_k \\; e^{-k \\phi/M}$. Both of these can describe the data well and give slo...

  7. Large area CMOS image sensors

    Science.gov (United States)

    Turchetta, R.; Guerrini, N.; Sedgwick, I.

    2011-01-01

    CMOS image sensors, also known as CMOS Active Pixel Sensors (APS) or Monolithic Active Pixel Sensors (MAPS), are today the dominant imaging devices. They are omnipresent in our daily life, as image sensors in cellular phones, web cams, digital cameras, ... In these applications, the pixels can be very small, in the micron range, and the sensors themselves tend to be limited in size. However, many scientific applications, like particle or X-ray detection, require large format, often with large pixels, as well as other specific performance, like low noise, radiation hardness or very fast readout. The sensors are also required to be sensitive to a broad spectrum of radiation: photons from the silicon cut-off in the IR down to UV and X- and gamma-rays through the visible spectrum as well as charged particles. This requirement calls for modifications to the substrate to be introduced to provide optimized sensitivity. This paper will review existing CMOS image sensors, whose size can be as large as a single CMOS wafer, and analyse the technical requirements and specific challenges of large format CMOS image sensors.

  8. Large-scale pool fires

    Directory of Open Access Journals (Sweden)

    Steinhaus Thomas

    2007-01-01

    Full Text Available A review of research into the burning behavior of large pool fires and fuel spill fires is presented. The features which distinguish such fires from smaller pool fires are mainly associated with the fire dynamics at low source Froude numbers and the radiative interaction with the fire source. In hydrocarbon fires, higher soot levels at increased diameters result in radiation blockage effects around the perimeter of large fire plumes; this yields lower emissive powers and a drastic reduction in the radiative loss fraction; whilst there are simplifying factors with these phenomena, arising from the fact that soot yield can saturate, there are other complications deriving from the intermittency of the behavior, with luminous regions of efficient combustion appearing randomly in the outer surface of the fire according the turbulent fluctuations in the fire plume. Knowledge of the fluid flow instabilities, which lead to the formation of large eddies, is also key to understanding the behavior of large-scale fires. Here modeling tools can be effectively exploited in order to investigate the fluid flow phenomena, including RANS- and LES-based computational fluid dynamics codes. The latter are well-suited to representation of the turbulent motions, but a number of challenges remain with their practical application. Massively-parallel computational resources are likely to be necessary in order to be able to adequately address the complex coupled phenomena to the level of detail that is necessary.

  9. Strategic Management of Large Projects

    Institute of Scientific and Technical Information of China (English)

    WangYingluo; LiuYi; LiYuan

    2004-01-01

    The strategic management of large projects is both theoretically and practically important. Some scholars have advanced flexible strategy theory in China. The difference of strategic flexibility and flexible strategy is pointed out. The supporting system and characteristics of flexible strategy are analyzed. The changes of flexible strategy and integration of strategic management are discussed.

  10. Large Unifying Hybrid Supernetwork Model

    Institute of Scientific and Technical Information of China (English)

    LIU; Qiang; FANG; Jin-qing; LI; Yong

    2015-01-01

    For depicting multi-hybrid process,large unifying hybrid network model(so called LUHNM)has two sub-hybrid ratios except dr.They are deterministic hybrid ratio(so called fd)and random hybrid ratio(so called gr),respectively.

  11. Large N Expansion. Vector Models

    CERN Document Server

    Nissimov, E; Nissimov, Emil; Pacheva, Svetlana

    2006-01-01

    Preliminary version of a contribution to the "Quantum Field Theory. Non-Perturbative QFT" topical area of "Modern Encyclopedia of Mathematical Physics" (SELECTA), eds. Aref'eva I, and Sternheimer D, Springer (2007). Consists of two parts - "main article" (Large N Expansion. Vector Models) and a "brief article" (BPHZL Renormalization).

  12. Chunking of Large Multidimensional Arrays

    Energy Technology Data Exchange (ETDEWEB)

    Rotem, Doron; Otoo, Ekow J.; Seshadri, Sridhar

    2007-02-28

    Data intensive scientific computations as well on-lineanalytical processing applications as are done on very large datasetsthat are modeled as k-dimensional arrays. The storage organization ofsuch arrays on disks is done by partitioning the large global array intofixed size hyper-rectangular sub-arrays called chunks or tiles that formthe units of data transfer between disk and memory. Typical queriesinvolve the retrieval of sub-arrays in a manner that accesses all chunksthat overlap the query results. An important metric of the storageefficiency is the expected number of chunks retrieved over all suchqueries. The question that immediately arises is "what shapes of arraychunks give the minimum expected number of chunks over a query workload?"In this paper we develop two probabilistic mathematical models of theproblem and provide exact solutions using steepest descent and geometricprogramming methods. Experimental results, using synthetic workloads onreal life data sets, show that our chunking is much more efficient thanthe existing approximate solutions.

  13. Large Extremity Peripheral Nerve Repair

    Science.gov (United States)

    2015-10-01

    IL, Kochevar IE, Redmond RW. Large extremity peripheral nerve repair. Military Health System Research Symposium (MHSRS) Fort Lauderdale, FL. August...some notable discoveries that may impact military health care in the near future. There is a clear need in military medicine to improve outcomes in...membranes or “caul” intact was considered extremely lucky. Children were gifted with life-long happiness , the ability to see spirits, and protection

  14. Large Extremity Peripheral Nerve Repair

    Science.gov (United States)

    2015-10-01

    MB, Roberts AB, Wakersfield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of trans- forming growth factor-beta. J Cell Biol...animal facility and had access to food and water as required. 59 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction...s): F1 Art : PRS182917 Input-nlm 69 Manuscript 3: Large Gap Nerve Reconstruction Using Acellular Nerve Allografts And Photochemical Tissue

  15. Community Detection for Large Graphs

    KAUST Repository

    Peng, Chengbin

    2014-05-04

    Many real world networks have inherent community structures, including social networks, transportation networks, biological networks, etc. For large scale networks with millions or billions of nodes in real-world applications, accelerating current community detection algorithms is in demand, and we present two approaches to tackle this issue -A K-core based framework that can accelerate existing community detection algorithms significantly; -A parallel inference algorithm via stochastic block models that can distribute the workload.

  16. Testing gravity on Large Scales

    OpenAIRE

    Raccanelli Alvise

    2013-01-01

    We show how it is possible to test general relativity and different models of gravity via Redshift-Space Distortions using forthcoming cosmological galaxy surveys. However, the theoretical models currently used to interpret the data often rely on simplifications that make them not accurate enough for precise measurements. We will discuss improvements to the theoretical modeling at very large scales, including wide-angle and general relativistic corrections; we then show that for wide and deep...

  17. Structure functions at large x

    CERN Document Server

    Zhang, Z

    2002-01-01

    Structure function data together with other measurements from fixed-target deep inelastic scattering and hadron-hadron collider experiments which contribute to our knowledge of the parton density functions are reviewed. The inclusive cross-section measurements of neutral and charged current interactions at HERA are presented and their impact on the parton density functions is discussed. Future prospects for an improved knowledge of the parton density functions at large x are briefly mentioned.

  18. Large floating structures technological advances

    CERN Document Server

    Wang, BT

    2015-01-01

    This book surveys key projects that have seen the construction of large floating structures or have attained detailed conceptual designs. This compilation of key floating structures in a single volume captures the innovative features that mark the technological advances made in this field of engineering, and will provide a useful reference for ideas, analysis, design, and construction of these unique and emerging urban projects to offshore and marine engineers, urban planners, architects and students.

  19. The next large helical devices

    Science.gov (United States)

    Iiyoshi, Atsuo; Yamazaki, Kozo

    1995-06-01

    Helical systems have the strong advantage of inherent steady-state operation for fusion reactors. Two large helical devices with fully superconducting coil systems are presently under design and construction. One is the LHD (Large Helical Device) [Fusion Technol. 17, 169 (1990)] with major radius=3.9 m and magnetic field=3-4 T, that is under construction during 1990-1997 at NIFS (National Institute for Fusion Science), Nagoya/Toki, Japan; it features continuous helical coils and a clean helical divertor focusing on edge configuration optimization. The other one in the W7-X (Wendelstein 7-X) [in Plasma Physics and Controlled Fusion Nuclear Research, 1990, (International Atomic Energy Agency, Vienna, 1991), Vol. 3, p. 525] with major radius=5.5 m and magnetic field=3 T, that is under review at IPP (Max-Planck Institute for Plasma Physics), Garching, Germany; it has adopted a modular coil system after elaborate optimization studies. These two programs are complementary in promoting world helical fusion research and in extending the understanding of toroidal plasmas through comparisons with large tokamaks.

  20. Models of large scale structure

    Energy Technology Data Exchange (ETDEWEB)

    Frenk, C.S. (Physics Dept., Univ. of Durham (UK))

    1991-01-01

    The ingredients required to construct models of the cosmic large scale structure are discussed. Input from particle physics leads to a considerable simplification by offering concrete proposals for the geometry of the universe, the nature of the dark matter and the primordial fluctuations that seed the growth of structure. The remaining ingredient is the physical interaction that governs dynamical evolution. Empirical evidence provided by an analysis of a redshift survey of IRAS galaxies suggests that gravity is the main agent shaping the large-scale structure. In addition, this survey implies large values of the mean cosmic density, {Omega}> or approx.0.5, and is consistent with a flat geometry if IRAS galaxies are somewhat more clustered than the underlying mass. Together with current limits on the density of baryons from Big Bang nucleosynthesis, this lends support to the idea of a universe dominated by non-baryonic dark matter. Results from cosmological N-body simulations evolved from a variety of initial conditions are reviewed. In particular, neutrino dominated and cold dark matter dominated universes are discussed in detail. Finally, it is shown that apparent periodicities in the redshift distributions in pencil-beam surveys arise frequently from distributions which have no intrinsic periodicity but are clustered on small scales. (orig.).

  1. Large wood recruitment and transport during large floods: A review

    Science.gov (United States)

    Comiti, F.; Lucía, A.; Rickenmann, D.

    2016-09-01

    Large wood (LW) elements transported during large floods are long known to have the capacity to induce dangerous obstructions along the channel network, mostly at bridges and at hydraulic structures such as weirs. However, our current knowledge of wood transport dynamics during high-magnitude flood events is still very scarce, mostly because these are (locally) rare and thus unlikely to be directly monitored. Therefore, post-event surveys are invaluable ways to get insights (although indirectly) on LW recruitment processes, transport distance, and factors inducing LW deposition - all aspects that are crucial for the proper management of river basins related to flood hazard mitigation. This paper presents a review of the (quite limited) literature available on LW transport during large floods, drawing extensively on the authors' own experience in mountain and piedmont rivers, published and unpublished. The overall picture emerging from these studies points to a high, catchment-specific variability in all the different processes affecting LW dynamics during floods. Specifically, in the LW recruitment phase, the relative floodplain (bank erosion) vs. hillslope (landslide and debris flows) contribution in mountain rivers varies substantially, as it relates to the extent of channel widening (which depends on many variables itself) but also to the hillslope-channel connectivity of LW mobilized on the slopes. As to the LW transport phase within the channel network, it appears to be widely characterized by supply-limited conditions; whereby LW transport rates (and thus volumes) are ultimately constrained by the amount of LW that is made available to the flow. Indeed, LW deposition during floods was mostly (in terms of volume) observed at artificial structures (bridges) in all the documented events. This implies that the estimation of LW recruitment and the assessment of clogging probabilities for each structure (for a flood event of given magnitude) are the most important

  2. Large-bore pipe decontamination

    Energy Technology Data Exchange (ETDEWEB)

    Ebadian, M.A.

    1998-01-01

    The decontamination and decommissioning (D and D) of 1200 buildings within the US Department of Energy-Office of Environmental Management (DOE-EM) Complex will require the disposition of miles of pipe. The disposition of large-bore pipe, in particular, presents difficulties in the area of decontamination and characterization. The pipe is potentially contaminated internally as well as externally. This situation requires a system capable of decontaminating and characterizing both the inside and outside of the pipe. Current decontamination and characterization systems are not designed for application to this geometry, making the direct disposal of piping systems necessary in many cases. The pipe often creates voids in the disposal cell, which requires the pipe to be cut in half or filled with a grout material. These methods are labor intensive and costly to perform on large volumes of pipe. Direct disposal does not take advantage of recycling, which could provide monetary dividends. To facilitate the decontamination and characterization of large-bore piping and thereby reduce the volume of piping required for disposal, a detailed analysis will be conducted to document the pipe remediation problem set; determine potential technologies to solve this remediation problem set; design and laboratory test potential decontamination and characterization technologies; fabricate a prototype system; provide a cost-benefit analysis of the proposed system; and transfer the technology to industry. This report summarizes the activities performed during fiscal year 1997 and describes the planned activities for fiscal year 1998. Accomplishments for FY97 include the development of the applicable and relevant and appropriate regulations, the screening of decontamination and characterization technologies, and the selection and initial design of the decontamination system.

  3. Large volume cryogenic silicon detectors

    Energy Technology Data Exchange (ETDEWEB)

    Braggio, C. [Dipartimento di Fisica, Universita di Padova, via Marzolo 8, 35131 Padova (Italy); Boscardin, M. [Fondazione Bruno Kessler (FBK), via Sommarive 18, I-38100 Povo (Italy); Bressi, G. [INFN sez. di Pavia, via Bassi 6, 27100 Pavia (Italy); Carugno, G.; Corti, D. [INFN sez. di Padova, via Marzolo 8, 35131 Padova (Italy); Galeazzi, G. [INFN lab. naz. Legnaro, viale dell' Universita 2, 35020 Legnaro (Italy); Zorzi, N. [Fondazione Bruno Kessler (FBK), via Sommarive 18, I-38100 Povo (Italy)

    2009-12-15

    We present preliminary measurements for the development of a large volume silicon detector to detect low energy and low rate energy depositions. The tested detector is a one cm-thick silicon PIN diode with an active volume of 31 cm{sup 3}, cooled to the liquid helium temperature to obtain depletion from thermally-generated free carriers. A thorough study has been done to show that effects of charge trapping during drift disappears at a bias field value of the order of 100V/cm.

  4. Teaching Reading in Large Classes

    Directory of Open Access Journals (Sweden)

    Rojas B Leyla María

    2001-08-01

    Full Text Available This article deals with the problem of overcrowded classes. Ideas from research findings are given in an attempt to approach the teaching of reading at tertiary and secondary levels. This study is mainly based on the analysis of five pedagogical principles that emerged from the Lancaster-Leeds Language Learning in Large Classes Research Project in the United Kingdom (1986- 1999. Emphasis is also made on two important general principles emerging from the project: being realistic and giving more responsibility to the learner. Practical suggestions from research on reading are made based on the principles stated.

  5. Large area and flexible electronics

    CERN Document Server

    Caironi, Mario

    2015-01-01

    From materials to applications, this ready reference covers the entire value chain from fundamentals via processing right up to devices, presenting different approaches to large-area electronics, thus enabling readers to compare materials, properties and performance.Divided into two parts, the first focuses on the materials used for the electronic functionality, covering organic and inorganic semiconductors, including vacuum and solution-processed metal-oxide semiconductors, nanomembranes and nanocrystals, as well as conductors and insulators. The second part reviews the devices and applicatio

  6. Japanese large-scale interferometers

    CERN Document Server

    Kuroda, K; Miyoki, S; Ishizuka, H; Taylor, C T; Yamamoto, K; Miyakawa, O; Fujimoto, M K; Kawamura, S; Takahashi, R; Yamazaki, T; Arai, K; Tatsumi, D; Ueda, A; Fukushima, M; Sato, S; Shintomi, T; Yamamoto, A; Suzuki, T; Saitô, Y; Haruyama, T; Sato, N; Higashi, Y; Uchiyama, T; Tomaru, T; Tsubono, K; Ando, M; Takamori, A; Numata, K; Ueda, K I; Yoneda, H; Nakagawa, K; Musha, M; Mio, N; Moriwaki, S; Somiya, K; Araya, A; Kanda, N; Telada, S; Sasaki, M; Tagoshi, H; Nakamura, T; Tanaka, T; Ohara, K

    2002-01-01

    The objective of the TAMA 300 interferometer was to develop advanced technologies for kilometre scale interferometers and to observe gravitational wave events in nearby galaxies. It was designed as a power-recycled Fabry-Perot-Michelson interferometer and was intended as a step towards a final interferometer in Japan. The present successful status of TAMA is presented. TAMA forms a basis for LCGT (large-scale cryogenic gravitational wave telescope), a 3 km scale cryogenic interferometer to be built in the Kamioka mine in Japan, implementing cryogenic mirror techniques. The plan of LCGT is schematically described along with its associated R and D.

  7. Large Brillouin Amplification in Silicon

    CERN Document Server

    Kittlaus, Eric A; Rakich, Peter T

    2015-01-01

    Strong Brillouin coupling has only recently been realized in silicon using a new class of optomechanical waveguides that yield both optical and phononic confinement. Despite these major advances, appreciable Brillouin amplification has yet to be observed in silicon. Using a new membrane-suspended silicon waveguide we report large Brillouin amplification for the first time, reaching levels greater than 5 dB for modest pump powers, and demonstrate a record low (5 mW) threshold for net amplification. This work represents a crucial advance necessary to realize high-performance Brillouin lasers and amplifiers in silicon.

  8. Quick Mining of Isomorphic Exact Large Patterns from Large Graphs

    KAUST Repository

    Almasri, Islam

    2014-12-01

    The applications of the sub graph isomorphism search are growing with the growing number of areas that model their systems using graphs or networks. Specifically, many biological systems, such as protein interaction networks, molecular structures and protein contact maps, are modeled as graphs. The sub graph isomorphism search is concerned with finding all sub graphs that are isomorphic to a relevant query graph, the existence of such sub graphs can reflect on the characteristics of the modeled system. The most computationally expensive step in the search for isomorphic sub graphs is the backtracking algorithm that traverses the nodes of the target graph. In this paper, we propose a pruning approach that is inspired by the minimum remaining value heuristic that achieves greater scalability over large query and target graphs. Our testing on various biological networks shows that performance enhancement of our approach over existing state-of-the-art approaches varies between 6x and 53x. © 2014 IEEE.

  9. Large data centers interconnect bottlenecks.

    Science.gov (United States)

    Ghiasi, Ali

    2015-02-09

    Large data centers interconnect bottlenecks are dominated by the switch I/O BW and the front panel BW as a result of pluggable modules. To overcome the front panel BW and the switch ASIC BW limitation one approach is to either move the optics onto the mid-plan or integrate the optics into the switch ASIC. Over the last 4 years, VCSEL based optical engines have been integrated into the packages of large-scale HPC routers, moderate size Ethernet switches, and even FPGA's. Competing solutions based on Silicon Photonics (SiP) have also been proposed for integration into HPC and Ethernet switch packages but with better integration path through the use of TSV (Through Silicon Via) stack dies. Integrating either VCSEL or SiP based optical engines into complex ASIC package that operates at high temperatures, where the required reliability is not trivial, one should ask what is the technical or the economic advantage before embarking on such a complex integration. High density Ethernet switches addressing data centers currently in development are based on 25G NRZ signaling and QSFP28 optical module that can support up to 3.6 Tb of front panel bandwidth.

  10. Large scale cluster computing workshop

    Energy Technology Data Exchange (ETDEWEB)

    Dane Skow; Alan Silverman

    2002-12-23

    Recent revolutions in computer hardware and software technologies have paved the way for the large-scale deployment of clusters of commodity computers to address problems heretofore the domain of tightly coupled SMP processors. Near term projects within High Energy Physics and other computing communities will deploy clusters of scale 1000s of processors and be used by 100s to 1000s of independent users. This will expand the reach in both dimensions by an order of magnitude from the current successful production facilities. The goals of this workshop were: (1) to determine what tools exist which can scale up to the cluster sizes foreseen for the next generation of HENP experiments (several thousand nodes) and by implication to identify areas where some investment of money or effort is likely to be needed. (2) To compare and record experimences gained with such tools. (3) To produce a practical guide to all stages of planning, installing, building and operating a large computing cluster in HENP. (4) To identify and connect groups with similar interest within HENP and the larger clustering community.

  11. Mesoscale Ocean Large Eddy Simulations

    Science.gov (United States)

    Pearson, Brodie; Fox-Kemper, Baylor; Bachman, Scott; Bryan, Frank

    2015-11-01

    The highest resolution global climate models (GCMs) can now resolve the largest scales of mesoscale dynamics in the ocean. This has the potential to increase the fidelity of GCMs. However, the effects of the smallest, unresolved, scales of mesoscale dynamics must still be parametrized. One such family of parametrizations are mesoscale ocean large eddy simulations (MOLES), but the effects of including MOLES in a GCM are not well understood. In this presentation, several MOLES schemes are implemented in a mesoscale-resolving GCM (CESM), and the resulting flow is compared with that produced by more traditional sub-grid parametrizations. Large eddy simulation (LES) is used to simulate flows where the largest scales of turbulent motion are resolved, but the smallest scales are not resolved. LES has traditionally been used to study 3D turbulence, but recently it has also been applied to idealized 2D and quasi-geostrophic (QG) turbulence. The MOLES presented here are based on 2D and QG LES schemes.

  12. Large phased-array radars

    Science.gov (United States)

    Brookner, Eli, Dr.

    1988-12-01

    Large phased-array radars can play a very important part in arms control. They can be used to determine the number of RVs being deployed, the type of targeting of the RVs (the same or different targets), the shape of the deployed objects, and possibly the weight and yields of the deployed RVs. They can provide this information at night as well as during the day and during rain and cloud covered conditions. The radar can be on the ground, on a ship, in an airplane, or space-borne. Airborne and space-borne radars can provide high resolution map images of the ground for reconnaissance, of anti-ballistic missile (ABM) ground radar installations, missile launch sites, and tactical targets such as trucks and tanks. The large ground based radars can have microwave carrier frequencies or be at HF (high frequency). For a ground-based HF radar the signal is reflected off the ionosphere so as to provide over-the-horizon (OTH) viewing of targets. OTH radars can potentially be used to monitor stealth targets and missile traffic.

  13. Crystallization in large wireless networks

    CERN Document Server

    Morgenshtern, Veniamin I

    2007-01-01

    We analyze fading interference relay networks where M single-antenna source-destination terminal pairs communicate concurrently and in the same frequency band through a set of K single-antenna relays using half-duplex two-hop relaying. Assuming that the relays have channel state information (CSI), it is shown that in the large-M limit, provided K grows fast enough as a function of M, the network "decouples" in the sense that the individual source-destination terminal pair capacities are strictly positive. The corresponding required rate of growth of K as a function of M is found to be sufficient to also make the individual source-destination fading links converge to nonfading links. We say that the network "crystallizes" as it breaks up into a set of effectively isolated "wires in the air". A large-deviations analysis is performed to characterize the "crystallization" rate, i.e., the rate (as a function of M,K) at which the decoupled links converge to nonfading links. In the course of this analysis, we develo...

  14. Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study.

    Science.gov (United States)

    Yang, Jin-Chen; Niu, Yu-Qiong; Simon, Christa; Seritan, Andreea L; Chen, Lawrence; Schneider, Andrea; Moghaddam, Shayan T; Hagerman, Paul J; Hagerman, Randi J; Olichney, John M

    2014-11-01

    Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.

  15. Large-scale solar heating

    Energy Technology Data Exchange (ETDEWEB)

    Tolonen, J.; Konttinen, P.; Lund, P. [Helsinki Univ. of Technology, Otaniemi (Finland). Advanced Energy Systems

    1998-10-01

    Solar heating market is growing in many European countries and annually installed collector area has exceeded one million square meters. There are dozens of collector manufacturers and hundreds of firms making solar heating installations in Europe. One tendency in solar heating is towards larger systems. These can be roof integrated, consisting of some tens or hundreds of square meters of collectors, or they can be larger centralized solar district heating plants consisting of a few thousand square meters of collectors. The increase of size can reduce the specific investments of solar heating systems, because e.g. the costs of some components (controllers, pumps, and pipes), planning and installation can be smaller in larger systems. The solar heat output can also be higher in large systems, because more advanced technique is economically viable

  16. Author Clustering on Large Bibliographies

    CERN Document Server

    Sterz, Christoph

    2014-01-01

    We analyze and design an algorithm for clustering large sets of authors in Bibliographies. Not considering a distance function for a mutual comparison, but transforming the data into a multidimensional metric space, the algorithm described is similar to locally sensitive hashing. The task lies in the field of Record-Linkage. The algorithm was designed and performed based on the data of the CERN Document Server, consisting out of more than 1.7 million metadata entries and is part of the digital assets-managing-software invenio. Meant as a prototype, the algorithm performs efficiently, clustering all authors on CDS in under 30 minutes. We will discuss extensions improving the recall rate, wich still remains inferior to the currently used clustering-approach.

  17. Adaptive Optics for Large Telescopes

    Energy Technology Data Exchange (ETDEWEB)

    Olivier, S

    2008-06-27

    The use of adaptive optics was originally conceived by astronomers seeking to correct the blurring of images made with large telescopes due to the effects of atmospheric turbulence. The basic idea is to use a device, a wave front corrector, to adjust the phase of light passing through an optical system, based on some measurement of the spatial variation of the phase transverse to the light propagation direction, using a wave front sensor. Although the original concept was intended for application to astronomical imaging, the technique can be more generally applied. For instance, adaptive optics systems have been used for several decades to correct for aberrations in high-power laser systems. At Lawrence Livermore National Laboratory (LLNL), the world's largest laser system, the National Ignition Facility, uses adaptive optics to correct for aberrations in each of the 192 beams, all of which must be precisely focused on a millimeter scale target in order to perform nuclear physics experiments.

  18. Large-Scale Galaxy Bias

    CERN Document Server

    Desjacques, Vincent; Schmidt, Fabian

    2016-01-01

    This review presents a comprehensive overview of galaxy bias, that is, the statistical relation between the distribution of galaxies and matter. We focus on large scales where cosmic density fields are quasi-linear. On these scales, the clustering of galaxies can be described by a perturbative bias expansion, and the complicated physics of galaxy formation is absorbed by a finite set of coefficients of the expansion, called bias parameters. The review begins with a pedagogical proof of this very important result, which forms the basis of the rigorous perturbative description of galaxy clustering, under the assumptions of General Relativity and Gaussian, adiabatic initial conditions. Key components of the bias expansion are all leading local gravitational observables, which includes the matter density but also tidal fields and their time derivatives. We hence expand the definition of local bias to encompass all these contributions. This derivation is followed by a presentation of the peak-background split in i...

  19. Robust large dimension terahertz cloaking

    CERN Document Server

    Liang, Dachuan; Han, Jiaguang; Yang, Yuanmu; Zhang, Shuang; Zhang, Weili

    2011-01-01

    Invisibility cloaking not only catches the human imagination, but also promises fascinating applications in optics and photonics. By manipulating electromagnetic waves with metamaterials, researchers have been able to realize electromagnetic cloaking in the microwave, terahertz and optical regimes. Nevertheless, the complex design and fabrication process, narrow bandwidth, and high intrinsic losses in the metamaterial-based cloaks have imposed intractable limitations on their realistic applications. Seeking new approaches to overcome these perceived disadvantages is in progress. Here by using uniform sapphire crystal, we demonstrate the first homogenous invisibility cloak functioning at terahertz frequencies. The terahertz invisibility device features a large concealed volume, low loss, and broad bandwidth. In particular, it is capable of hiding objects with a dimension nearly an order of magnitude larger than that of its lithographic counterpart, but without involving complex and time-consuming cleanroom pro...

  20. Large Eddy Simulations in Astrophysics

    CERN Document Server

    Schmidt, Wolfram

    2014-01-01

    In this review, the methodology of large eddy simulations (LES) is introduced and applications in astrophysics are discussed. As theoretical framework, the scale decomposition of the dynamical equations for neutral fluids by means of spatial filtering is explained. For cosmological applications, the filtered equations in comoving coordinates are also presented. To obtain a closed set of equations that can be evolved in LES, several subgrid scale models for the interactions between numerically resolved and unresolved scales are discussed, in particular the subgrid scale turbulence energy equation model. It is then shown how model coefficients can be calculated, either by dynamical procedures or, a priori, from high-resolution data. For astrophysical applications, adaptive mesh refinement is often indispensable. It is shown that the subgrid scale turbulence energy model allows for a particularly elegant and physically well motivated way of preserving momentum and energy conservation in AMR simulations. Moreover...

  1. Large scale biomimetic membrane arrays

    DEFF Research Database (Denmark)

    Hansen, Jesper Søndergaard; Perry, Mark; Vogel, Jörg

    2009-01-01

    To establish planar biomimetic membranes across large scale partition aperture arrays, we created a disposable single-use horizontal chamber design that supports combined optical-electrical measurements. Functional lipid bilayers could easily and efficiently be established across CO2 laser micro......-structured 8 x 8 aperture partition arrays with average aperture diameters of 301 +/- 5 mu m. We addressed the electro-physical properties of the lipid bilayers established across the micro-structured scaffold arrays by controllable reconstitution of biotechnological and physiological relevant membrane...... peptides and proteins. Next, we tested the scalability of the biomimetic membrane design by establishing lipid bilayers in rectangular 24 x 24 and hexagonal 24 x 27 aperture arrays, respectively. The results presented show that the design is suitable for further developments of sensitive biosensor assays...

  2. Large Scale Glazed Concrete Panels

    DEFF Research Database (Denmark)

    Bache, Anja Margrethe

    2010-01-01

    Today, there is a lot of focus on concrete surface’s aesthitic potential, both globally and locally. World famous architects such as Herzog De Meuron, Zaha Hadid, Richard Meyer and David Chippenfield challenge the exposure of concrete in their architecture. At home, this trend can be seen...... existing buildings in and around Copenhagen that are covered with mosaic tiles or glazed tiles; buildings such as Nanna Ditzel’s House in Klareboderne, Arne Jacobsen’s gas station, Erik Møller’s Industriens Hus, Bent Helweg Møller’s Berlingske Hus, Arne Jacobsen’s Stellings Hus and Toms Chocolate Factories...... and finally Lene Tranberg and Bøje Lungård’s Elsinore water purification plant. These buildings have qualities that I would like applied, perhaps transformed or most preferably, if possible, interpreted anew, for the large glazed concrete panels I shall develop. The article is ended and concluded...

  3. Testing gravity on Large Scales

    Directory of Open Access Journals (Sweden)

    Raccanelli Alvise

    2013-09-01

    Full Text Available We show how it is possible to test general relativity and different models of gravity via Redshift-Space Distortions using forthcoming cosmological galaxy surveys. However, the theoretical models currently used to interpret the data often rely on simplifications that make them not accurate enough for precise measurements. We will discuss improvements to the theoretical modeling at very large scales, including wide-angle and general relativistic corrections; we then show that for wide and deep surveys those corrections need to be taken into account if we want to measure the growth of structures at a few percent level, and so perform tests on gravity, without introducing systematic errors. Finally, we report the results of some recent cosmological model tests carried out using those precise models.

  4. OSIRIS Large Guaranteed Time Programs

    Science.gov (United States)

    Cepa, J.; Bongiovanni, A.; Ramón-Pérez, M.; Pérez García, A. M.; Alfaro, E. J.; Castaneda, H. O.; Cervino, M.; Gallego, J.; González, J. J.; González-Serrano, J. I.; Lara-López, M. A.; Pérez-Martínez, R.; Pintos-Castro, I.; Sánchez-Portal, M.; Bland-Hawthorn, J.; Jones, D. H.

    2017-03-01

    The status of OTELO and Lockman SpReSO surveys, the two large guaranteed time programs currently under way using OSIRIS at the 10.4m GTC is presented. The OTELO project, designed to detect the main optical emission lines from Hα to Lyα at redshifts from 0.4 through 7, is the deepest emission line survey to date, with unprecedented sensitivity in the detection of small equivalent widths. Lockman SpReSO is aimed to obtaining optical spectra, up to 24.5 AB magnitudes, in the central 24×24 square arcminutes of the Lockman Hole field, which has been observed with ROSAT and XMM–Newton at the highest depth. Lockman SpReSO mainly targets Far Infrared sources detected with the Herschel Space Observatory.

  5. Large errors and severe conditions

    CERN Document Server

    Smith, D L; Van Wormer, L A

    2002-01-01

    Physical parameters that can assume real-number values over a continuous range are generally represented by inherently positive random variables. However, if the uncertainties in these parameters are significant (large errors), conventional means of representing and manipulating the associated variables can lead to erroneous results. Instead, all analyses involving them must be conducted in a probabilistic framework. Several issues must be considered: First, non-linear functional relations between primary and derived variables may lead to significant 'error amplification' (severe conditions). Second, the commonly used normal (Gaussian) probability distribution must be replaced by a more appropriate function that avoids the occurrence of negative sampling results. Third, both primary random variables and those derived through well-defined functions must be dealt with entirely in terms of their probability distributions. Parameter 'values' and 'errors' should be interpreted as specific moments of these probabil...

  6. Conference on Large Scale Optimization

    CERN Document Server

    Hearn, D; Pardalos, P

    1994-01-01

    On February 15-17, 1993, a conference on Large Scale Optimization, hosted by the Center for Applied Optimization, was held at the University of Florida. The con­ ference was supported by the National Science Foundation, the U. S. Army Research Office, and the University of Florida, with endorsements from SIAM, MPS, ORSA and IMACS. Forty one invited speakers presented papers on mathematical program­ ming and optimal control topics with an emphasis on algorithm development, real world applications and numerical results. Participants from Canada, Japan, Sweden, The Netherlands, Germany, Belgium, Greece, and Denmark gave the meeting an important international component. At­ tendees also included representatives from IBM, American Airlines, US Air, United Parcel Serice, AT & T Bell Labs, Thinking Machines, Army High Performance Com­ puting Research Center, and Argonne National Laboratory. In addition, the NSF sponsored attendance of thirteen graduate students from universities in the United States and abro...

  7. Large Scale Correlation Clustering Optimization

    CERN Document Server

    Bagon, Shai

    2011-01-01

    Clustering is a fundamental task in unsupervised learning. The focus of this paper is the Correlation Clustering functional which combines positive and negative affinities between the data points. The contribution of this paper is two fold: (i) Provide a theoretic analysis of the functional. (ii) New optimization algorithms which can cope with large scale problems (>100K variables) that are infeasible using existing methods. Our theoretic analysis provides a probabilistic generative interpretation for the functional, and justifies its intrinsic "model-selection" capability. Furthermore, we draw an analogy between optimizing this functional and the well known Potts energy minimization. This analogy allows us to suggest several new optimization algorithms, which exploit the intrinsic "model-selection" capability of the functional to automatically recover the underlying number of clusters. We compare our algorithms to existing methods on both synthetic and real data. In addition we suggest two new applications t...

  8. Horner's syndrome in large animals.

    Science.gov (United States)

    Smith, J S; Mayhew, I G

    1977-10-01

    The sympathetic nervous innervation of the head was surgically transected in the horse, cow, sheep and goat. The site of transection was preganglionic in all 4 species and ganglionic-postganglionic in 2 additional horses. The Horner's syndrome, manifested as a result of the iatrogenic lesion, varied with the species. Ptosis was the most constant sign in all species. Unilateral sweating over the face and proximal neck, particularly at the base of the ear, was the most prominent feature in the horse. The cow revealed distension of vasculature and cutaneous heat of the pinna, and a reduced production of beads of sweat over the nostril on the affected side. The goat and sheep exhibited little more than slight ptosis of the upper eyelid of the affected side as the most prominent sign. The ophthalmologic manifestations of Horner's syndrome seen in these large animals were not readily apparent and could easily be overlooked upon clinical examination.

  9. Global large carnivore conservation and international law

    NARCIS (Netherlands)

    Trouwborst, A.

    2015-01-01

    International cooperation, including through international legal instruments, appears important for the conservation of large carnivores worldwide. This is due to, inter alia, the worrying conservation status and population trends of many large carnivore species; the importance of large carnivores f

  10. Global large carnivore conservation and international law

    NARCIS (Netherlands)

    Trouwborst, A.

    2015-01-01

    International cooperation, including through international legal instruments, appears important for the conservation of large carnivores worldwide. This is due to, inter alia, the worrying conservation status and population trends of many large carnivore species; the importance of large carnivores

  11. Large and small photovoltaic powerplants

    Science.gov (United States)

    Cormode, Daniel

    The installed base of photovoltaic power plants in the United States has roughly doubled every 1 to 2 years between 2008 and 2015. The primary economic drivers of this are government mandates for renewable power, falling prices for all PV system components, 3rd party ownership models, and a generous tariff scheme known as net-metering. Other drivers include a desire for decreasing the environmental impact of electricity generation and a desire for some degree of independence from the local electric utility. The result is that in coming years, PV power will move from being a minor niche to a mainstream source of energy. As additional PV power comes online this will create challenges for the electric grid operators. We examine some problems related to large scale adoption of PV power in the United States. We do this by first discussing questions of reliability and efficiency at the PV system level. We measure the output of a fleet of small PV systems installed at Tucson Electric Power, and we characterize the degradation of those PV systems over several years. We develop methods to predict energy output from PV systems and quantify the impact of negatives such as partial shading, inverter inefficiency and malfunction of bypass diodes. Later we characterize the variability from large PV systems, including fleets of geographically diverse utility scale power plants. We also consider the power and energy requirements needed to smooth those systems, both from the perspective of an individual system and as a fleet. Finally we report on experiments from a utility scale PV plus battery hybrid system deployed near Tucson, Arizona where we characterize the ability of this system to produce smoothly ramping power as well as production of ancillary energy services such as frequency response.

  12. Large-Scale Information Systems

    Energy Technology Data Exchange (ETDEWEB)

    D. M. Nicol; H. R. Ammerlahn; M. E. Goldsby; M. M. Johnson; D. E. Rhodes; A. S. Yoshimura

    2000-12-01

    Large enterprises are ever more dependent on their Large-Scale Information Systems (LSLS), computer systems that are distinguished architecturally by distributed components--data sources, networks, computing engines, simulations, human-in-the-loop control and remote access stations. These systems provide such capabilities as workflow, data fusion and distributed database access. The Nuclear Weapons Complex (NWC) contains many examples of LSIS components, a fact that motivates this research. However, most LSIS in use grew up from collections of separate subsystems that were not designed to be components of an integrated system. For this reason, they are often difficult to analyze and control. The problem is made more difficult by the size of a typical system, its diversity of information sources, and the institutional complexities associated with its geographic distribution across the enterprise. Moreover, there is no integrated approach for analyzing or managing such systems. Indeed, integrated development of LSIS is an active area of academic research. This work developed such an approach by simulating the various components of the LSIS and allowing the simulated components to interact with real LSIS subsystems. This research demonstrated two benefits. First, applying it to a particular LSIS provided a thorough understanding of the interfaces between the system's components. Second, it demonstrated how more rapid and detailed answers could be obtained to questions significant to the enterprise by interacting with the relevant LSIS subsystems through simulated components designed with those questions in mind. In a final, added phase of the project, investigations were made on extending this research to wireless communication networks in support of telemetry applications.

  13. Sweetwater, Texas Large N Experiment

    Science.gov (United States)

    Sumy, D. F.; Woodward, R.; Barklage, M.; Hollis, D.; Spriggs, N.; Gridley, J. M.; Parker, T.

    2015-12-01

    From 7 March to 30 April 2014, NodalSeismic, Nanometrics, and IRIS PASSCAL conducted a collaborative, spatially-dense seismic survey with several thousand nodal short-period geophones complemented by a backbone array of broadband sensors near Sweetwater, Texas. This pilot project demonstrates the efficacy of industry and academic partnerships, and leveraged a larger, commercial 3D survey to collect passive source seismic recordings to image the subsurface. This innovative deployment of a large-N mixed-mode array allows industry to explore array geometries and investigate the value of broadband recordings, while affording academics a dense wavefield imaging capability and an operational model for high volume instrument deployment. The broadband array consists of 25 continuously-recording stations from IRIS PASSCAL and Nanometrics, with an array design that maximized recording of horizontal-traveling seismic energy for surface wave analysis over the primary target area with sufficient offset for imaging objectives at depth. In addition, 2639 FairfieldNodal Zland nodes from NodalSeismic were deployed in three sub-arrays: the outlier, backbone, and active source arrays. The backbone array consisted of 292 nodes that covered the entire survey area, while the outlier array consisted of 25 continuously-recording nodes distributed at a ~3 km distance away from the survey perimeter. Both the backbone and outlier array provide valuable constraints for the passive source portion of the analysis. This project serves as a learning platform to develop best practices in the support of large-N arrays with joint industry and academic expertise. Here we investigate lessons learned from a facility perspective, and present examples of data from the various sensors and array geometries. We will explore first-order results from local and teleseismic earthquakes, and show visualizations of the data across the array. Data are archived at the IRIS DMC under stations codes XB and 1B.

  14. Simulating cosmic reionization: How large a volume is large enough?

    CERN Document Server

    Iliev, Ilian T; Ahn, Kyungjin; Shapiro, Paul R; Mao, Yi; Pen, Ue-Li

    2013-01-01

    We present the largest-volume (425 Mpc/h=607 Mpc on a side) full radiative transfer simulation of cosmic reionization to date. We show that there is significant additional power in density fluctuations at very large scales. We systematically investigate the effects this additional power has on the progress, duration and features of reionization, as well as on selected reionization observables. We find that comoving simulation volume of ~100 Mpc/h per side is sufficient for deriving a convergent mean reionization history, but that the reionization patchiness is significantly underestimated. We use jackknife splitting to quantify the convergence of reionization properties with simulation volume for both mean-density and variable-density sub-regions. We find that sub-volumes of ~100 Mpc/h per side or larger yield convergent reionization histories, except for the earliest times, but smaller volumes of ~50 Mpc/h or less are not well converged at any redshift. Reionization history milestones show significant scatte...

  15. Large optical field enhancement for nanotips with large opening angles

    Science.gov (United States)

    Thomas, Sebastian; Wachter, Georg; Lemell, Christoph; Burgdörfer, Joachim; Hommelhoff, Peter

    2015-06-01

    We theoretically investigate the dependence of the enhancement of optical near-fields at nanometric tips on the shape, size, and material of the tip. We confirm the strong dependence of the field enhancement factor on the radius of curvature. In addition, we find a surprisingly strong increase of field enhancement with increasing opening angle of the nanotips. For gold and tungsten nanotips in the experimentally relevant parameter range (radius of curvature ≥slant 5 nm at 800 nm laser wavelength), we obtain field enhancement factors of up to ∼ 35 for Au and ∼ 12 for W for large opening angles. We confirm this strong dependence on the opening angle for many other materials featuring a wide variety in their dielectric response. For dielectrics, the opening angle dependence is traced back to the electrostatic force of the induced surface charge at the tip shank. For metals, the plasmonic response strongly increases the field enhancement and shifts the maximum field enhancement to smaller opening angles.

  16. Fragile X founder effects and new mutations in Finland

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, N.; Smits, B.; Curley, D. [New York State Inst. for Basic Research in Developmental Disabilities, Staten Island, NY (United States)] [and others

    1996-07-12

    The apparent associations between fragile X mutations and nearby microsatellites may reflect both founder effects and microsatellite instability. To gain further insight into their relative contributions, we typed a sample of 56 unrelated control and 37 fragile X chromosomes from an eastern Finnish population for FMR1 CGG repeat lengths, AGG interspersion patterns, DXS548, FRAXAC1, FRAXE and a new polymorphic locus, Alu-L. In the controls, the most common FMR1 allele was 30 repeats with a range of 20 to 47 and a calculated heterozygosity of 88%. A strong founder effect was observed for locus DXS548 with 95% of fragile X chromosomes having the 21 CA repeat (196 bp) allele compared to 17% of controls, while none of the fragile X but 69% of controls had the 20 repeat allele. Analysis of the combined loci DXS548-FRAXAC1-FRAXE showed three founder haplotypes. Haplotype 21-19-16 was found on 27 (75%) of fragile X chromosomes but on none of controls. Three (8.4%) fragile X chromosomes had haplotypes 21-19-15, 21-19-20, and 21-19-25 differing from the common fragile X haplotype only in FRAXE. These could have arisen by recombination or from mutations of FRAXE. A second haplotype 21-18-17 was found in four (11.1%) fragile X chromosomes but only one (1.9%) control. This may represent a more recent founder mutation. A third haplotype 25-21-15, seen in two fragile X chromosomes (5.6%) and one (1.9%) control, was even less common and thus may represent an even more recent mutation or admixture of immigrant types. Analysis of the AGG interspersions within the FMR1 CGG repeat showed that 7/8 premutation chromosomes lacked an AGG whereas all controls had at least one AGG. This supports the hypothesis that the mutation of AGG to CGG leads to repeat instability and mutational expansion. 43 refs., 3 figs., 7 tabs.

  17. Gastric Large Cell Neuroendocrine Carcinoma

    Science.gov (United States)

    Rustagi, Tarun; Alekshun, Todd J.

    2010-01-01

    Case: A 63-year-old male presented with unintentional weight loss of 20 pounds over a 4-month duration. He reported loss of appetite, intermittent post-prandial nausea, bloating and early satiety. He also complained of dyspepsia and had been treated for reflux during the previous 2 years. He denied vomiting, dysphagia, odynophagia, abdominal pain, melena, hematochezia, or alterations in bowel habits. Additionally, he denied fevers, night sweats, cough, or dyspnea. He quit smoking 25 years ago, and denied alcohol use. His past medical history was significant for basal cell carcinoma treated with local curative therapy and he was without recurrence on surveillance. Pertinent family history included a paternal uncle with lung cancer at the age of 74. Physical examination was unremarkable except for occult heme-positive stools. Laboratory evaluation revealed elevated liver enzymes (ALT-112, AST-81, AlkPhos-364). CT scan of the chest, abdomen and pelvis showed diffuse heterogeneous liver with extensive nodularity, raising the concern for metastases. Serum tumor-markers: PSA, CEA, CA 19-9, and AFP were all within normal limits. Screening colonoscopy was normal, but esophagogastroduodenoscopy revealed a malignant-appearing ulcerative lesion involving the gastro-esophageal junction and gastric cardia. Pathology confirmed an invasive gastric large cell neuroendocrine carcinoma. Ultrasound-guided fine needle aspiration of a hepatic lesion revealed malignant cells with cytologic features consistent with large-cell type carcinoma and positive immunostaining for synaptophysin favoring neuroendocrine differentiation. A PET-CT demonstrated intense diffuse FDG uptake of the liver, suggesting diffuse hepatic parenchymal infiltration by tumor. There were multiple foci of intense osseous FDG uptake with corresponding osteolytic lesions seen on CT scan. The remaining intra-abdominal and intra-thoracic structures were unremarkable. The patient will receive palliative systemic therapy

  18. Large Block Test Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lin, W

    2001-12-01

    This report documents the Large-Block Test (LBT) conducted at Fran Ridge near Yucca Mountain, Nevada. The LBT was a thermal test conducted on an exposed block of middle non-lithophysal Topopah Spring tuff (Tptpmn) and was designed to assist in understanding the thermal-hydrological-mechanical-chemical (THMC) processes associated with heating and then cooling a partially saturated fractured rock mass. The LBT was unique in that it was a large (3 x 3 x 4.5 m) block with top and sides exposed. Because the block was exposed at the surface, boundary conditions on five of the six sides of the block were relatively well known and controlled, making this test both easier to model and easier to monitor. This report presents a detailed description of the test as well as analyses of the data and conclusions drawn from the test. The rock block that was tested during the LBT was exposed by excavation and removal of the surrounding rock. The block was characterized and instrumented, and the sides were sealed and insulated to inhibit moisture and heat loss. Temperature on the top of the block was also controlled. The block was heated for 13 months, during which time temperature, moisture distribution, and deformation were monitored. After the test was completed and the block cooled down, a series of boreholes were drilled, and one of the heater holes was over-cored to collect samples for post-test characterization of mineralogy and mechanical properties. Section 2 provides background on the test. Section 3 lists the test objectives and describes the block site, the site configuration, and measurements made during the test. Section 3 also presents a chronology of events associated with the LBT, characterization of the block, and the pre-heat analyses of the test. Section 4 describes the fracture network contained in the block. Section 5 describes the heating/cooling system used to control the temperature in the block and presents the thermal history of the block during the test

  19. The Large Millimeter Telescope (LMT)

    Science.gov (United States)

    Young, J. S.; Carrasco, L.; Schloerb, F. P.

    2002-05-01

    The Large Millimeter Telescope (LMT) project is a collaboration between the University of Massachusetts (UMass) in the USA and the Instituto Nacional de Astrofisica, Optica y Electronica (INAOE) in Mexico to build a 50m-diameter millimeter-wave antenna which will operate with good efficiency at wavelengths as short as 1 mm. The LMT is being built at an altitude of 4600 m atop Volcan Sierra Negra, an extinct volcanic peak in the state of Puebla, Mexico, approximately 100 km east of the city of Puebla. At 18 degrees 59' N latitude, the site offers an excellent view of the Galactic Center and good sky coverage of both hemispheres. Construction of the telescope is now well underway, and it is expected to be completed in late 2004. The LMT specifications call for an overall effective surface accuracy of 75 microns rms and a pointing accuracy of 1" rms. The strategy for meeting these performance goals supplements conventional antenna designs with various "active" systems to bring the final performance within the requirements. For surface accuracy, the LMT will rely on an open loop active surface which includes 180 moveable surface segments. For pointing accuracy, we will use traditional approaches supplemented by measurements to characterize the behavior of the structure, including inclinometers and temperature sensors which may be used with finite element models to determine structural deformations and predict pointing behavior. The initial complement of instruments will include a 32 element, heterodyne focal plane array at 3mm; a large format, focal plane bolometer array; a unique wide band receiver and spectrometer to determine the redshifts of primordial galaxies; and a 4 element receiver for the 1mm band. With its excellent sensitivity and angular resolution, the LMT will enable unique studies of the early universe and galaxy evolution, the interstellar medium and star formation in galaxies, and planetary science. In particular, with nearly 2000 m2 of collecting

  20. MALIGNANCY IN LARGE COLORECTAL LESIONS

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Oliveira dos SANTOS

    2014-09-01

    Full Text Available Context The size of colorectal lesions, besides a risk factor for malignancy, is a predictor for deeper invasion Objectives To evaluate the malignancy of colorectal lesions ≥20 mm. Methods Between 2007 and 2011, 76 neoplasms ≥20 mm in 70 patients were analyzed Results The mean age of the patients was 67.4 years, and 41 were women. Mean lesion size was 24.7 mm ± 6.2 mm (range: 20 to 50 mm. Half of the neoplasms were polypoid and the other half were non-polypoid. Forty-two (55.3% lesions were located in the left colon, and 34 in the right colon. There was a high prevalence of III L (39.5% and IV (53.9% pit patterns. There were 72 adenomas and 4 adenocarcinomas. Malignancy was observed in 5.3% of the lesions. Thirty-three lesions presented advanced histology (adenomas with high-grade dysplasia or early adenocarcinoma, with no difference in morphology and site. Only one lesion (1.3% invaded the submucosa. Lesions larger than 30 mm had advanced histology (P = 0.001. The primary treatment was endoscopic resection, and invasive carcinoma was referred to surgery. Recurrence rate was 10.6%. Conclusions Large colorectal neoplasms showed a low rate of malignancy. Endoscopic treatment is an effective therapy for these lesions.

  1. Large Scale Magnetostrictive Valve Actuator

    Science.gov (United States)

    Richard, James A.; Holleman, Elizabeth; Eddleman, David

    2008-01-01

    Marshall Space Flight Center's Valves, Actuators and Ducts Design and Development Branch developed a large scale magnetostrictive valve actuator. The potential advantages of this technology are faster, more efficient valve actuators that consume less power and provide precise position control and deliver higher flow rates than conventional solenoid valves. Magnetostrictive materials change dimensions when a magnetic field is applied; this property is referred to as magnetostriction. Magnetostriction is caused by the alignment of the magnetic domains in the material s crystalline structure and the applied magnetic field lines. Typically, the material changes shape by elongating in the axial direction and constricting in the radial direction, resulting in no net change in volume. All hardware and testing is complete. This paper will discuss: the potential applications of the technology; overview of the as built actuator design; discuss problems that were uncovered during the development testing; review test data and evaluate weaknesses of the design; and discuss areas for improvement for future work. This actuator holds promises of a low power, high load, proportionally controlled actuator for valves requiring 440 to 1500 newtons load.

  2. Mapping change in large networks.

    Directory of Open Access Journals (Sweden)

    Martin Rosvall

    Full Text Available Change is a fundamental ingredient of interaction patterns in biology, technology, the economy, and science itself: Interactions within and between organisms change; transportation patterns by air, land, and sea all change; the global financial flow changes; and the frontiers of scientific research change. Networks and clustering methods have become important tools to comprehend instances of these large-scale structures, but without methods to distinguish between real trends and noisy data, these approaches are not useful for studying how networks change. Only if we can assign significance to the partitioning of single networks can we distinguish meaningful structural changes from random fluctuations. Here we show that bootstrap resampling accompanied by significance clustering provides a solution to this problem. To connect changing structures with the changing function of networks, we highlight and summarize the significant structural changes with alluvial diagrams and realize de Solla Price's vision of mapping change in science: studying the citation pattern between about 7000 scientific journals over the past decade, we find that neuroscience has transformed from an interdisciplinary specialty to a mature and stand-alone discipline.

  3. Large Eddy Simulations in Astrophysics

    Science.gov (United States)

    Schmidt, Wolfram

    2015-12-01

    In this review, the methodology of large eddy simulations (LES) is introduced and applications in astrophysics are discussed. As theoretical framework, the scale decomposition of the dynamical equations for neutral fluids by means of spatial filtering is explained. For cosmological applications, the filtered equations in comoving coordinates are also presented. To obtain a closed set of equations that can be evolved in LES, several subgrid-scale models for the interactions between numerically resolved and unresolved scales are discussed, in particular the subgrid-scale turbulence energy equation model. It is then shown how model coefficients can be calculated, either by dynamic procedures or, a priori, from high-resolution data. For astrophysical applications, adaptive mesh refinement is often indispensable. It is shown that the subgrid-scale turbulence energy model allows for a particularly elegant and physically well-motivated way of preserving momentum and energy conservation in adaptive mesh refinement (AMR) simulations. Moreover, the notion of shear-improved models for in-homogeneous and non-stationary turbulence is introduced. Finally, applications of LES to turbulent combustion in thermonuclear supernovae, star formation and feedback in galaxies, and cosmological structure formation are reviewed.

  4. Anthropogenic triggering of large earthquakes.

    Science.gov (United States)

    Mulargia, Francesco; Bizzarri, Andrea

    2014-08-26

    The physical mechanism of the anthropogenic triggering of large earthquakes on active faults is studied on the basis of experimental phenomenology, i.e., that earthquakes occur on active tectonic faults, that crustal stress values are those measured in situ and, on active faults, comply to the values of the stress drop measured for real earthquakes, that the static friction coefficients are those inferred on faults, and that the effective triggering stresses are those inferred for real earthquakes. Deriving the conditions for earthquake nucleation as a time-dependent solution of the Tresca-Von Mises criterion applied in the framework of poroelasticity yields that active faults can be triggered by fluid overpressures oil and gas production and storage may trigger destructive earthquakes on active faults at a few tens of kilometers. Fluid pressure propagates as slow stress waves along geometric paths operating in a drained condition and can advance the natural occurrence of earthquakes by a substantial amount of time. Furthermore, it is illusory to control earthquake triggering by close monitoring of minor "foreshocks", since the induction may occur with a delay up to several years.

  5. Large cities are less green

    Science.gov (United States)

    Oliveira, Erneson A.; Andrade, José S.; Makse, Hernán A.

    2014-02-01

    We study how urban quality evolves as a result of carbon dioxide emissions as urban agglomerations grow. We employ a bottom-up approach combining two unprecedented microscopic data on population and carbon dioxide emissions in the continental US. We first aggregate settlements that are close to each other into cities using the City Clustering Algorithm (CCA) defining cities beyond the administrative boundaries. Then, we use data on CO2 emissions at a fine geographic scale to determine the total emissions of each city. We find a superlinear scaling behavior, expressed by a power-law, between CO2 emissions and city population with average allometric exponent β = 1.46 across all cities in the US. This result suggests that the high productivity of large cities is done at the expense of a proportionally larger amount of emissions compared to small cities. Furthermore, our results are substantially different from those obtained by the standard administrative definition of cities, i.e. Metropolitan Statistical Area (MSA). Specifically, MSAs display isometric scaling emissions and we argue that this discrepancy is due to the overestimation of MSA areas. The results suggest that allometric studies based on administrative boundaries to define cities may suffer from endogeneity bias.

  6. Large earthquakes and creeping faults

    Science.gov (United States)

    Harris, Ruth A.

    2017-01-01

    Faults are ubiquitous throughout the Earth's crust. The majority are silent for decades to centuries, until they suddenly rupture and produce earthquakes. With a focus on shallow continental active-tectonic regions, this paper reviews a subset of faults that have a different behavior. These unusual faults slowly creep for long periods of time and produce many small earthquakes. The presence of fault creep and the related microseismicity helps illuminate faults that might not otherwise be located in fine detail, but there is also the question of how creeping faults contribute to seismic hazard. It appears that well-recorded creeping fault earthquakes of up to magnitude 6.6 that have occurred in shallow continental regions produce similar fault-surface rupture areas and similar peak ground shaking as their locked fault counterparts of the same earthquake magnitude. The behavior of much larger earthquakes on shallow creeping continental faults is less well known, because there is a dearth of comprehensive observations. Computational simulations provide an opportunity to fill the gaps in our understanding, particularly of the dynamic processes that occur during large earthquake rupture and arrest.

  7. Large cities are less green

    CERN Document Server

    Oliveira, E A; Makse, H A

    2014-01-01

    We study how urban quality evolves as a result of carbon dioxide emissions as urban agglomerations grow. We employ a bottom-up approach combining two unprecedented microscopic data on population and carbon dioxide emissions in the continental US. We first aggregate settlements that are close to each other into cities using the City Clustering Algorithm (CCA) defining cities beyond the administrative boundaries. Then, we use data on $\\rm{CO}_2$ emissions at a fine geographic scale to determine the total emissions of each city. We find a superlinear scaling behavior, expressed by a power-law, between $\\rm{CO}_2$ emissions and city population with average allometric exponent $\\beta = 1.46$ across all cities in the US. This result suggests that the high productivity of large cities is done at the expense of a proportionally larger amount of emissions compared to small cities. Furthermore, our results are substantially different from those obtained by the standard administrative definition of cities, i.e. Metropol...

  8. How large should whales be?

    Directory of Open Access Journals (Sweden)

    Aaron Clauset

    Full Text Available The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2 g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000 g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000 g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.

  9. How large should whales be?

    Science.gov (United States)

    Clauset, Aaron

    2013-01-01

    The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2 g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000 g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000 g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.

  10. Large optics inspection, tilting, and washing stand

    Science.gov (United States)

    Ayers, Marion Jay; Ayers, Shannon Lee

    2010-08-24

    A large optics stand provides a risk free means of safely tilting large optics with ease and a method of safely tilting large optics with ease. The optics are supported in the horizontal position by pads. In the vertical plane the optics are supported by saddles that evenly distribute the optics weight over a large area.

  11. Temporal Large-Eddy Simulation

    Science.gov (United States)

    Pruett, C. D.; Thomas, B. C.

    2004-01-01

    In 1999, Stolz and Adams unveiled a subgrid-scale model for LES based upon approximately inverting (defiltering) the spatial grid-filter operator and termed .the approximate deconvolution model (ADM). Subsequently, the utility and accuracy of the ADM were demonstrated in a posteriori analyses of flows as diverse as incompressible plane-channel flow and supersonic compression-ramp flow. In a prelude to the current paper, a parameterized temporal ADM (TADM) was developed and demonstrated in both a priori and a posteriori analyses for forced, viscous Burger's flow. The development of a time-filtered variant of the ADM was motivated-primarily by the desire for a unifying theoretical and computational context to encompass direct numerical simulation (DNS), large-eddy simulation (LES), and Reynolds averaged Navier-Stokes simulation (RANS). The resultant methodology was termed temporal LES (TLES). To permit exploration of the parameter space, however, previous analyses of the TADM were restricted to Burger's flow, and it has remained to demonstrate the TADM and TLES methodology for three-dimensional flow. For several reasons, plane-channel flow presents an ideal test case for the TADM. Among these reasons, channel flow is anisotropic, yet it lends itself to highly efficient and accurate spectral numerical methods. Moreover, channel-flow has been investigated extensively by DNS, and a highly accurate data base of Moser et.al. exists. In the present paper, we develop a fully anisotropic TADM model and demonstrate its utility in simulating incompressible plane-channel flow at nominal values of Re(sub tau) = 180 and Re(sub tau) = 590 by the TLES method. The TADM model is shown to perform nearly as well as the ADM at equivalent resolution, thereby establishing TLES as a viable alternative to LES. Moreover, as the current model is suboptimal is some respects, there is considerable room to improve TLES.

  12. The Large Binocular Telescope Project

    Science.gov (United States)

    Hill, J. M.

    1995-05-01

    The Large Binocular Telescope (LBT) Project has evolved from concepts first proposed in 1985. The present partners involved in the design and construction of this 2 x 8.4 meter binocular telescope are the University of Arizona, Italy represented by the Osservatorio Astrofisico di Arcetri and the Research Corporation based in Tucson. These three partners have committed sufficient funds to build the enclosure and the telescope populated with a single 8.4 meter optical train --- approximately 40 million dollars (1989). Based on this commitment, design and construction activities are now moving forward. Additional partners are being sought. The next mirror to be cast at the Steward Observatory Mirror Lab in spring of 1996 will be the first borosilicate honeycomb primary for LBT. The baseline optical configuration of LBT includes wide field Cassegrain secondaries with optical foci above the primaries to provide a corrected one degree field at F/4. The infrared F/15 secondaries are a Gregorian design to allow maximicrons flexibility for adaptive optics. The F/15 secondaries are undersized to provide a low thermal background focal plane which is unvignetted over a 4 arcminute diameter field-of-view. The interferometric focus combining the light from the two 8.4 meter primaries will reimage two folded Gregorian focal planes to a central location. The telescope elevation structure accommodates swing arms which allow rapid interchange of the various secondary and tertiary mirrors. Maximicrons stiffness and minimal thermal disturbance continue to be important drivers for the detailed design of the telescope. The telescope structure accommodates installation of a vacuum bell jar for aluminizing the primary mirrors in-situ on the telescope. The detailed design of the telescope structure will be completed in 1995 by ADS Italia (Lecco) and European Industrial Engineering (Mestre). The final enclosure design is now in progress at M3 Engineering (Tucson) and ADS Italia

  13. Large springs of east Tennessee

    Science.gov (United States)

    Sun, Pao-chang P.; Criner, J.H.; Poole, J.L.

    1963-01-01

    Springs constitute an important source of water in east Tennessee, and many individual springs are capable of supplying the large quantities needed for municipal and industrial supplies. Most of the springs in east Tennessee issue from solution openings and fractured and faulted zones in limestone and dolomite of the Knox Group, Chickamauga Limestone, and Conasauga Group. The ability of these rocks to yield a sustained flow of water to springs is dependent on a system of interconnected openings through which water can infiltrate from the land surface and move to points of natural discharge. Ninety springs were selected for detailed study, and 84 of these are analyzed in terms of magnitude and variability of discharge. Of the 84 springs analyzed, 4 flow at an average rate of 10 to 100 cfs (cubic feet per second), 62 at an average rate of 1 to 10 cfs, and 18 at an average rate of 1 cfs or less. Of the 90 springs, 75 are variable in their discharge; that is, the ratio of their fluctuations to their average discharges exceeds 100 percent. Mathematical analysis of the flow recession curve of Mill Spring near Jefferson City shows that the hydrologic system contributing to the flow of the spring has an effective capacity of about 70 million cubic feet of water. The rate of depletion of this volume of water, in the absence of significant precipitation, averages 0.0056 cfs per day between the time when the hydrologic system is full and the time when the spring ceases to flow. From such a curve it is possible to determine at any time the residual volume of water remaining in the system and the expected rate of decrease in discharge from that time to cessation of flow. Correlation of discharge measurements of 22 springs with those of Mill Spring shows that rough approximations of discharge can be projected for springs for which few measurements are available. Seventeen of the springs analyzed in this manner show good correlation with Mill Spring: that is, their coefficients

  14. Handbook of Large-Scale Random Networks

    CERN Document Server

    Bollobas, Bela; Miklos, Dezso

    2008-01-01

    Covers various aspects of large-scale networks, including mathematical foundations and rigorous results of random graph theory, modeling and computational aspects of large-scale networks, as well as areas in physics, biology, neuroscience, sociology and technical areas

  15. Picky: oligo microarray design for large genomes

    National Research Council Canada - National Science Library

    Chou, Hui-Hsien; Hsia, An-Ping; Mooney, Denise L; Schnable, Patrick S

    2004-01-01

    Many large genomes are getting sequenced nowadays. Biologists are eager to start microarray analysis taking advantage of all known genes of a species, but existing microarray design tools were very inefficient for large genomes...

  16. 76 FR 17521 - Assessments, Large Bank Pricing

    Science.gov (United States)

    2011-03-30

    ... 327 RIN 3064-AD66 Assessments, Large Bank Pricing AGENCY: Federal Deposit Insurance Corporation (FDIC... Register of February 25, 2011 (76 FR 10672), regarding Assessments, Large Bank Pricing. This...

  17. Innovations in Large Classes in Pakistan.

    Science.gov (United States)

    Sarwar, Zakia

    2001-01-01

    Explains innovations taking place in large English-as-a-foreign-language classrooms in Pakistan. Describes a pilot project that investigated ways of bringing out effective learning in large classes. (Author/VWL)

  18. 27 CFR 19.915 - Large plants.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Large plants. 19.915... OF THE TREASURY LIQUORS DISTILLED SPIRITS PLANTS Distilled Spirits For Fuel Use Permits § 19.915 Large plants. Any person wishing to establish a large plant shall make application for and obtain...

  19. Forecasting distribution of numbers of large fires

    Science.gov (United States)

    Haiganoush K. Preisler; Jeff Eidenshink; Stephen Howard; Robert E. Burgan

    2015-01-01

    Systems to estimate forest fire potential commonly utilize one or more indexes that relate to expected fire behavior; however they indicate neither the chance that a large fire will occur, nor the expected number of large fires. That is, they do not quantify the probabilistic nature of fire danger. In this work we use large fire occurrence information from the...

  20. Large Devaluations and the Real Exchange Rate

    Science.gov (United States)

    Burstein, Ariel; Eichenbaum, Martin; Rebelo, Sergio

    2005-01-01

    In this paper we argue that the primary force behind the large drop in real exchange rates that occurs after large devaluations is the slow adjustment in the prices of nontradable goods and services. Our empirical analysis uses data from five large devaluation episodes: Argentina (2002), Brazil (1999), Korea (1997), Mexico (1994), and Thailand…

  1. Conundrum of the Large Scale Streaming

    CERN Document Server

    Malm, T M

    1999-01-01

    The etiology of the large scale peculiar velocity (large scale streaming motion) of clusters would increasingly seem more tenuous, within the context of the gravitational instability hypothesis. Are there any alternative testable models possibly accounting for such large scale streaming of clusters?

  2. Novel Blood Biomarkers Are Associated with White Matter Lesions in Fragile X- Associated Tremor/Ataxia Syndrome.

    Science.gov (United States)

    Loesch, Danuta Z; Annesley, Sarah J; Trost, Nicholas; Bui, Minh Q; Lay, Sui T; Storey, Elsdon; De Piazza, Shawn W; Sanislav, Oana; Francione, Lisa M; Hammersley, Eleanor M; Tassone, Flora; Francis, David; Fisher, Paul R

    2017-01-01

    The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles. To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions. Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XFe24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls. The regional white matter hyperintensity (WMH) scores were obtained from MRI. Mitochondrial respiratory activity was significantly elevated in lymphoblasts from PM carriers compared with controls, with a 2- to 3-fold increase in basal and maximum OCR attributable to complex I activity, and ATP synthesis, accompanied by unaltered mitochondrial mass and membrane potential. The changes, which were more advanced in FXTAS patients, were significantly associated with the WMH scores in the supratentorial regions. The dramatic increase in mitochondrial activity in lymphoblasts from PM carriers may represent either the early stages of disease (specific alterations in short-lived blood cells) or an activation of the lymphocytes under pathological situations. These changes may provide early, convenient blood biomarkers of clinical involvements. © 2016 S. Karger AG, Basel.

  3. Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

    Science.gov (United States)

    Tamás, Gertrúd; Kovács, Norbert; Varga, Noémi Ágnes; Barsi, Péter; Erőss, Loránd; Molnár, Mária Judit; Balás, István

    2016-01-01

    We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved.

  4. Hair root FMRP expression for screening of fragile X full mutation females

    Directory of Open Access Journals (Sweden)

    Lantip Rujito

    2016-02-01

    Full Text Available The fragile X syndrome is the most common form of inherited mental retardation in humans, caused by an expansion of the cytosine-guanine-guanine (CGG repeat in the fragile X mental retardation 1 (FMR1 gene located on the X chromosome. Antibody tests have been developed to identify fragile X patients, based on the presence or absence of fragile mental retardation protein (FMRP in both lymphocytes and hair roots. The objective of this study was to compare correlations of hair root and lymphocyte FMRP expression with cognitive functioning in female rural area probands carrying the full mutation. Thirty females (normal, premutation, or full mutation were selected from Indonesian fragile X families and were tested for FMRP expression in lymphocytes and hair roots using the FMRP antibody test. Subject genotype was determined by Southern blot analysis, and IQ equivalent by Raven’s Standard Progressive Matrices. Statistical analysis was by Pearson correlation. FMRP expression in blood lymphocytes was relatively higher than that in hair roots, but hair root FMRP expression was strongly correlated with cognitive functioning in female full mutation carriers (r=0.64, p=0.015, whereas no significant correlation between lymphocyte FMRP and cognitive functioning was found (r=0.31, p= 0.281. Around 14% of subjects had a normal and 7% a borderline IQ level, while 79% had mild mental impairment. In conclusion, hair root FMRP expression may be a useful marker for identification of fragile X full mutation females.

  5. Hair root FMRP expression for screening of fragile X full mutation females

    Directory of Open Access Journals (Sweden)

    Lantip Rujito

    2011-04-01

    Full Text Available The fragile X syndrome is the most common form of inherited mental retardation in humans, caused by an expansion of the cytosine-guanine-guanine (CGG repeat in the fragile X mental retardation 1 (FMR1 gene located on the X chromosome. Antibody tests have been developed to identify fragile X patients, based on the presence or absence of fragile mental retardation protein (FMRP in both lymphocytes and hair roots. The objective of this study was to compare correlations of hair root and lymphocyte FMRP expression with cognitive functioning in female rural area probands carrying the full mutation. Thirty females (normal, premutation, or full mutation were selected from Indonesian fragile X families and were tested for FMRP expression in lymphocytes and hair roots using the FMRP antibody test. Subject genotype was determined by Southern blot analysis, and IQ equivalent by Raven’s Standard Progressive Matrices. Statistical analysis was by Pearson correlation. FMRP expression in blood lymphocytes was relatively higher than that in hair roots, but hair root FMRP expression was strongly correlated with cognitive functioning in female full mutation carriers (r=0.64, p=0.015, whereas no significant correlation between lymphocyte FMRP and cognitive functioning was found (r=0.31, p= 0.281. Around 14% of subjects had a normal and 7% a borderline IQ level, while 79% had mild mental impairment. In conclusion, hair root FMRP expression may be a useful marker for identification of fragile X full mutation females.

  6. Craniofacial characteristics of fragile X syndrome in mouse and man.

    Science.gov (United States)

    Heulens, Inge; Suttie, Michael; Postnov, Andrei; De Clerck, Nora; Perrotta, Concetta S; Mattina, Teresa; Faravelli, Francesca; Forzano, Francesca; Kooy, R Frank; Hammond, Peter

    2013-08-01

    For a disorder as common as fragile X syndrome, the most common hereditary form of cognitive impairment, the facial features are relatively ill defined. An elongated face and prominent ears are the most commonly accepted dysmorphic hallmarks. We analysed 3D facial photographs of 51 males and 15 females with full FMR1 mutations and 9 females with a premutation using dense-surface modelling techniques and a new technique that forms a directed graph with normalized face shapes as nodes and edges linking those with closest dysmorphism. In addition to reconfirming known features, we confirmed the occurrence of some at an earlier age than previously recorded. We also identified as yet unrecorded facial characteristics such as reduced facial depth, hypoplasticity of the nasal bone-cartilage interface and narrow mid-facial width exaggerating ear prominence. As no consistent craniofacial abnormalities had been reported in animal models, we analysed micro-CT images of the fragile X mouse model. Results indicated altered dimensions in the mandible and both outer and inner skull, with the latter potentially reflecting differences in neuroanatomy. We extrapolated the mouse results to face shape differences of the human fragile X face.

  7. Large-group psychodynamics and massive violence

    Directory of Open Access Journals (Sweden)

    Vamik D. Volkan

    2006-06-01

    Full Text Available Beginning with Freud, psychoanalytic theories concerning large groups have mainly focused on individuals' perceptions of what their large groups psychologically mean to them. This chapter examines some aspects of large-group psychology in its own right and studies psychodynamics of ethnic, national, religious or ideological groups, the membership of which originates in childhood. I will compare the mourning process in individuals with the mourning process in large groups to illustrate why we need to study large-group psychology as a subject in itself. As part of this discussion I will also describe signs and symptoms of large-group regression. When there is a threat against a large-group's identity, massive violence may be initiated and this violence in turn, has an obvious impact on public health.

  8. Large-bandwidth planar photonic crystal waveguides

    DEFF Research Database (Denmark)

    Søndergaard, Thomas; Lavrinenko, Andrei

    2002-01-01

    A general design principle is presented for making finite-height photonic crystal waveguides that support leakage-free guidance of light over large frequency intervals. The large bandwidth waveguides are designed by introducing line defects in photonic crystal slabs, where the material in the lin......-free single-mode guidance is found for a large frequency interval covering 60% of the photonic band-gap.......A general design principle is presented for making finite-height photonic crystal waveguides that support leakage-free guidance of light over large frequency intervals. The large bandwidth waveguides are designed by introducing line defects in photonic crystal slabs, where the material in the line...... defect has appropriate dispersion properties relative to the photonic crystal slab material surrounding the line defect. A three-dimensional theoretical analysis is given for large-bandwidth waveguide designs based on a silicon-air photonic crystal slab suspended in air. In one example, the leakage...

  9. Trust Dynamics in a Large System Implementation

    DEFF Research Database (Denmark)

    Schlichter, Bjarne Rerup; Rose, Jeremy

    2013-01-01

    A large information systems implementation (such as ERP systems) relies on the trust of its stakeholders to suc-ceed. Such projects impact diverse groups of stakeholders, each with their legitimate interests and expectations. Levels of stakeholder trust can be expected to vary in large scale impl...... and restoration of trust, the role of the information system in restoring trust, and the emergent and reciprocal nature of trust and project outcomes......A large information systems implementation (such as ERP systems) relies on the trust of its stakeholders to suc-ceed. Such projects impact diverse groups of stakeholders, each with their legitimate interests and expectations. Levels of stakeholder trust can be expected to vary in large scale...... implementations (which can take several years), and cannot be taken for granted. Previous studies have largely focused on the taxonomic deconstruction of the trust construct, through point-in-time variance studies. They have identified the relationship between trust and project outcomes, but largely ignored...

  10. ELID Grinding of Large Aspheric Optics Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Large aperture aspheric optics are among the most susceptible optical surfaces to the accumulation of periodic surface artifacts during fabrication. Periodic...

  11. Reliability of large and complex systems

    CERN Document Server

    Kolowrocki, Krzysztof

    2014-01-01

    Reliability of Large and Complex Systems, previously titled Reliability of Large Systems, is an innovative guide to the current state and reliability of large and complex systems. In addition to revised and updated content on the complexity and safety of large and complex mechanisms, this new edition looks at the reliability of nanosystems, a key research topic in nanotechnology science. The author discusses the importance of safety investigation of critical infrastructures that have aged or have been exposed to varying operational conditions. This reference provides an asympt

  12. Large-Scale Damage Control Facility

    Data.gov (United States)

    Federal Laboratory Consortium — FUNCTION: Performs large‑scale fire protection experiments that simulate actual Navy platform conditions. Remote control firefighting systems are also tested....

  13. What is a large-scale dynamo?

    Science.gov (United States)

    Nigro, G.; Pongkitiwanichakul, P.; Cattaneo, F.; Tobias, S. M.

    2017-01-01

    We consider kinematic dynamo action in a sheared helical flow at moderate to high values of the magnetic Reynolds number (Rm). We find exponentially growing solutions which, for large enough shear, take the form of a coherent part embedded in incoherent fluctuations. We argue that at large Rm large-scale dynamo action should be identified by the presence of structures coherent in time, rather than those at large spatial scales. We further argue that although the growth rate is determined by small-scale processes, the period of the coherent structures is set by mean-field considerations.

  14. Large Format Uncooled Focal Plane Array Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Black Forest Engineering has identified innovative modifications in uncooled focal plane array (UFPA) architecture and processing that allows development of large...

  15. A large electrically excited synchronous generator

    DEFF Research Database (Denmark)

    2014-01-01

    adjacent neighbouring poles. In this way, a large electrically excited synchronous generator (EESG) is provided that readily enables a relatively large number of poles, compared to a traditional EESG, since the excitation coil in this design provides MMF for all the poles, whereas in a traditional EESG...

  16. Implementing Large Projects in Software Engineering Courses

    Science.gov (United States)

    Coppit, David

    2006-01-01

    In software engineering education, large projects are widely recognized as a useful way of exposing students to the real-world difficulties of team software development. But large projects are difficult to put into practice. First, educators rarely have additional time to manage software projects. Second, classrooms have inherent limitations that…

  17. Fast large-scale reionization simulations

    NARCIS (Netherlands)

    Thomas, Rajat M.; Zaroubi, Saleem; Ciardi, Benedetta; Pawlik, Andreas H.; Labropoulos, Panagiotis; Jelic, Vibor; Bernardi, Gianni; Brentjens, Michiel A.; de Bruyn, A. G.; Harker, Geraint J. A.; Koopmans, Leon V. E.; Pandey, V. N.; Schaye, Joop; Yatawatta, Sarod; Mellema, G.

    2009-01-01

    We present an efficient method to generate large simulations of the epoch of reionization without the need for a full three-dimensional radiative transfer code. Large dark-matter-only simulations are post-processed to produce maps of the redshifted 21-cm emission from neutral hydrogen. Dark matter h

  18. Hierarchies of Alarms for Large Distributed Systems

    CERN Document Server

    Boccioli, M; Martos, V; Holme, O

    2014-01-01

    The control systems of most of the infrastructure at CERN make use of the SCADA package WinCC Open Architecture by ETM*, including successful projects to control large scale systems such as the Large Hadron Collider (LHC) accelerator and associated experiments.).

  19. Evaluating Large-Scale Interactive Radio Programmes

    Science.gov (United States)

    Potter, Charles; Naidoo, Gordon

    2009-01-01

    This article focuses on the challenges involved in conducting evaluations of interactive radio programmes in South Africa with large numbers of schools, teachers, and learners. It focuses on the role such large-scale evaluation has played during the South African radio learning programme's development stage, as well as during its subsequent…

  20. Computing in Large-Scale Dynamic Systems

    NARCIS (Netherlands)

    Pruteanu, A.S.

    2013-01-01

    Software applications developed for large-scale systems have always been difficult to de- velop due to problems caused by the large number of computing devices involved. Above a certain network size (roughly one hundred), necessary services such as code updating, topol- ogy discovery and data dissem

  1. Large Scale Computations in Air Pollution Modelling

    DEFF Research Database (Denmark)

    Zlatev, Z.; Brandt, J.; Builtjes, P. J. H.

    Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998......Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998...

  2. Large-scale perspective as a challenge

    NARCIS (Netherlands)

    Plomp, M.G.A.

    2012-01-01

    1. Scale forms a challenge for chain researchers: when exactly is something ‘large-scale’? What are the underlying factors (e.g. number of parties, data, objects in the chain, complexity) that determine this? It appears to be a continuum between small- and large-scale, where positioning on that cont

  3. Gestures to Intuitively Control Large Displays

    NARCIS (Netherlands)

    Fikkert, F.W.; Vet, van der P.E.; Rauwerda, H.; Breit, T.; Nijholt, A.; Sales Dias, M.; Gibet, S.; Wanderley, M.W.; Bastos, R.

    2009-01-01

    Large displays are highly suited to support discussions in empirical science. Such displays can display project results on a large digital surface to feed the discussion. This paper describes our approach to closely involve multidisciplinary omics scientists in the design of an intuitive display con

  4. Large scale parallel document image processing

    NARCIS (Netherlands)

    van der Zant, Tijn; Schomaker, Lambert; Valentijn, Edwin; Yanikoglu, BA; Berkner, K

    2008-01-01

    Building a system which allows to search a very large database of document images. requires professionalization of hardware and software, e-science and web access. In astrophysics there is ample experience dealing with large data sets due to an increasing number of measurement instruments. The probl

  5. Fast large-scale reionization simulations

    NARCIS (Netherlands)

    Thomas, Rajat M.; Zaroubi, Saleem; Ciardi, Benedetta; Pawlik, Andreas H.; Labropoulos, Panagiotis; Jelic, Vibor; Bernardi, Gianni; Brentjens, Michiel A.; de Bruyn, A. G.; Harker, Geraint J. A.; Koopmans, Leon V. E.; Pandey, V. N.; Schaye, Joop; Yatawatta, Sarod; Mellema, G.

    2009-01-01

    We present an efficient method to generate large simulations of the epoch of reionization without the need for a full three-dimensional radiative transfer code. Large dark-matter-only simulations are post-processed to produce maps of the redshifted 21-cm emission from neutral hydrogen. Dark matter

  6. Implementing Large Projects in Software Engineering Courses

    Science.gov (United States)

    Coppit, David

    2006-01-01

    In software engineering education, large projects are widely recognized as a useful way of exposing students to the real-world difficulties of team software development. But large projects are difficult to put into practice. First, educators rarely have additional time to manage software projects. Second, classrooms have inherent limitations that…

  7. Comb-drive actuators for large displacements

    NARCIS (Netherlands)

    Legtenberg, Rob; Groeneveld, A.W.; Elwenspoek, M.

    1996-01-01

    The design, fabrication and experimental results of lateral-comb-drive actuators for large displacements at low driving voltages is presented. A comparison of several suspension designs is given, and the lateral large deflection behaviour of clamped - clamped beams and a folded flexure design is mod

  8. Large destructive facial hemangioma in PHACE syndrome

    Directory of Open Access Journals (Sweden)

    Nagdeve N

    2009-01-01

    Full Text Available We report an infant who presented with large facial hemangioma associated with Dandy-Walker cyst and atrial septal defect. This case is peculiar in that the large facial hemangioma in posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of aorta and other cardiac defects (PHACE syndrome resulted in massive tissue destruction.

  9. CFRP lightweight structures for extremely large telescopes

    DEFF Research Database (Denmark)

    Jessen, Niels Christian; Nørgaard-Nielsen, Hans Ulrik; Schroll, J.

    2008-01-01

    Telescope structures are traditionally built out of steel. To improve the possibility of realizing the ambitious extremely large telescopes, materials with a higher specific stiffness and a lower coefficient of thermal expansion are needed. An important possibility is Carbon Fibre Reinforced...... Plastic (CFRP). The advantages of using CFRP for the secondary mirror support structure of the European overwhelmingly large telescope are discussed....

  10. Large Nonferrous Metals Deposits Found in Yunnan

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    <正>According to the Department of Land and Resources of Yunnan, Yunnan has made great achievements since implementation of the geological prospecting action plan. 5 ultra-large deposits and several large deposits have been found, and a group of key areas with favorable ore-forming prospect have been pinpointed.

  11. The algebras of large N matrix mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Halpern, M.B.; Schwartz, C.

    1999-09-16

    Extending early work, we formulate the large N matrix mechanics of general bosonic, fermionic and supersymmetric matrix models, including Matrix theory: The Hamiltonian framework of large N matrix mechanics provides a natural setting in which to study the algebras of the large N limit, including (reduced) Lie algebras, (reduced) supersymmetry algebras and free algebras. We find in particular a broad array of new free algebras which we call symmetric Cuntz algebras, interacting symmetric Cuntz algebras, symmetric Bose/Fermi/Cuntz algebras and symmetric Cuntz superalgebras, and we discuss the role of these algebras in solving the large N theory. Most important, the interacting Cuntz algebras are associated to a set of new (hidden!) local quantities which are generically conserved only at large N. A number of other new large N phenomena are also observed, including the intrinsic nonlocality of the (reduced) trace class operators of the theory and a closely related large N field identification phenomenon which is associated to another set (this time nonlocal) of new conserved quantities at large N.

  12. Wakes in large offshore wind farms

    DEFF Research Database (Denmark)

    Berthelmie, Rebecca J.; Frandsen, Sten Tronæs; Rathmann, Ole

    2008-01-01

    Power losses due to wind turbine wakes are of the order of 10 and 20% of total power output in large wind farms. The focus of this research carried out within the EC funded UPWIND project is wind speed and turbulence modelling for large wind farms/wind turbines in complex terrain and offshore in ...

  13. Large- quantum chromodynamics and harmonic sums

    Indian Academy of Sciences (India)

    Eduardo De Rafael

    2012-06-01

    In the large- limit of QCD, two-point functions of local operators become harmonic sums. I review some properties which follow from this fact and which are relevant for phenomenological applications. This has led us to consider a class of analytic number theory functions as toy models of large- QCD which also is discussed.

  14. Large scale parallel document image processing

    NARCIS (Netherlands)

    van der Zant, Tijn; Schomaker, Lambert; Valentijn, Edwin; Yanikoglu, BA; Berkner, K

    2008-01-01

    Building a system which allows to search a very large database of document images. requires professionalization of hardware and software, e-science and web access. In astrophysics there is ample experience dealing with large data sets due to an increasing number of measurement instruments. The

  15. The algebras of large N matrix mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Halpern, M.B.; Schwartz, C.

    1999-09-16

    Extending early work, we formulate the large N matrix mechanics of general bosonic, fermionic and supersymmetric matrix models, including Matrix theory: The Hamiltonian framework of large N matrix mechanics provides a natural setting in which to study the algebras of the large N limit, including (reduced) Lie algebras, (reduced) supersymmetry algebras and free algebras. We find in particular a broad array of new free algebras which we call symmetric Cuntz algebras, interacting symmetric Cuntz algebras, symmetric Bose/Fermi/Cuntz algebras and symmetric Cuntz superalgebras, and we discuss the role of these algebras in solving the large N theory. Most important, the interacting Cuntz algebras are associated to a set of new (hidden!) local quantities which are generically conserved only at large N. A number of other new large N phenomena are also observed, including the intrinsic nonlocality of the (reduced) trace class operators of the theory and a closely related large N field identification phenomenon which is associated to another set (this time nonlocal) of new conserved quantities at large N.

  16. Large Scale Computations in Air Pollution Modelling

    DEFF Research Database (Denmark)

    Zlatev, Z.; Brandt, J.; Builtjes, P. J. H.

    Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998......Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998...

  17. Possibility of Large EW Penguin contribution

    CERN Document Server

    Mishima, S; Mishima, Satoshi; Yoshikawa, Tadashi

    2005-01-01

    We discuss a possibility of large electroweak(EW) penguin contribution in B-->K pi and pi pi. The recent experimental data may be still suggesting that there are some discrepancies between the data and theoretical estimations. In B --> K pi decays, to explain several theoretical relations among the branching ratios, a slightly large electroweak penguin contribution and large strong phase differences or quite large color suppressed tree contribution seem to be needed. The contributions should appear also in B --> pi pi. We show, as an example, a solution to solve the discrepancies in both B --> K pi and B --> pi pi. It may be suggesting to need the large electroweak penguin contribution with new weak phases and some SU(3) breaking effects by new physics in both QCD and electroweak penguin type processes.

  18. Triggering of volcanic eruptions by large earthquakes

    Science.gov (United States)

    Nishimura, Takeshi

    2017-08-01

    When a large earthquake occurs near an active volcano, there is often concern that volcanic eruptions may be triggered by the earthquake. In this study, recently accumulated, reliable data were analyzed to quantitatively evaluate the probability of the occurrence of new eruptions of volcanoes located near the epicenters of large earthquakes. For volcanoes located within 200 km of large earthquakes of magnitude 7.5 or greater, the eruption occurrence probability increases by approximately 50% for 5 years after the earthquake origin time. However, no significant increase in the occurrence probability of new eruptions was observed at distant volcanoes or for smaller earthquakes. The present results strongly suggest that new eruptions are likely triggered by static stress changes and/or strong ground motions caused by nearby large earthquakes. This is not similar to the previously presented evidence that volcanic earthquakes at distant volcanoes are remotely triggered by surface waves generated by large earthquakes.

  19. Large Scale Metal Additive Techniques Review

    Energy Technology Data Exchange (ETDEWEB)

    Nycz, Andrzej [ORNL; Adediran, Adeola I [ORNL; Noakes, Mark W [ORNL; Love, Lonnie J [ORNL

    2016-01-01

    In recent years additive manufacturing made long strides toward becoming a main stream production technology. Particularly strong progress has been made in large-scale polymer deposition. However, large scale metal additive has not yet reached parity with large scale polymer. This paper is a review study of the metal additive techniques in the context of building large structures. Current commercial devices are capable of printing metal parts on the order of several cubic feet compared to hundreds of cubic feet for the polymer side. In order to follow the polymer progress path several factors are considered: potential to scale, economy, environment friendliness, material properties, feedstock availability, robustness of the process, quality and accuracy, potential for defects, and post processing as well as potential applications. This paper focuses on current state of art of large scale metal additive technology with a focus on expanding the geometric limits.

  20. Generically large nongaussianity in small multifield inflation

    Energy Technology Data Exchange (ETDEWEB)

    Bramante, Joseph [Department of Physics, University of Notre Dame,Notre Dame, IN, 46556 (United States)

    2015-07-07

    If forthcoming measurements of cosmic photon polarization restrict the primordial tensor-to-scalar ratio to r<0.01, small field inflation will be a principal candidate for the origin of the universe. Here we show that small multifield inflation, without the hybrid mechanism, typically results in large squeezed nongaussianity. Small multifield potentials contain multiple flat field directions, often identified with the gauge invariant field directions in supersymmetric potentials. We find that unless these field directions have equal slopes, large nongaussianity arises. After identifying relevant differences between large and small two-field potentials, we demonstrate that the latter naturally fulfill the Byrnes-Choi-Hall large nongaussianity conditions. Computations of the primordial power spectrum, spectral index, and squeezed bispectrum, reveal that small two-field models which otherwise match observed primordial perturbations, produce excludably large nongaussianity if the inflatons’ field directions have unequal slopes.

  1. Range contractions of the world's large carnivores.

    Science.gov (United States)

    Wolf, Christopher; Ripple, William J

    2017-07-01

    The majority of the world's terrestrial large carnivores have undergone substantial range contractions and many of these species are currently threatened with extinction. However, there has been little effort to fully quantify the extent of large carnivore range contractions, which hinders our ability to understand the roles and relative drivers of such trends. Here we present and analyse a newly constructed and comprehensive set of large carnivore range contraction maps. We reveal the extent to which ranges have contracted since historical times and identify regions and biomes where range contractions have been particularly large. In summary, large carnivores that have experienced the greatest range contractions include the red wolf (Canis rufus) (greater than 99%), Ethiopian wolf (Canis simensis) (99%), tiger (Panthera tigris) (95%) and lion (Panthera leo) (94%). In general, the greatest range contractions occurred in Southeastern Asia and Africa. Motivated by the ecological importance of intact large carnivore guilds, we also examined the spatial extent of intact large carnivore guilds both for the entire world and regionally. We found that intact carnivore guilds occupy just 34% of the world's land area. This compares to 96% in historic times. Spatial modelling of range contractions showed that contractions were significantly more likely in regions with high rural human population density, cattle density or cropland. Our results offer new insights into how best to prevent further range contractions for the world's largest carnivores, which will assist efforts to conserve these species and their important ecological effects.

  2. Experimental verification of a large flexible manipulator

    Science.gov (United States)

    Lee, Jac Won; Huggins, James D.; Book, Wayne J.

    1988-01-01

    A large experimental lightweight manipulator would be useful for material handling, for welding, or for ultrasonic inspection of a large structure, such as an airframe. The flexible parallel link mechanism is designed for high rigidity without increasing weight. This constrained system is analyzed by singular value decomposition of the constraint Jacobian matrix. A verification of the modeling using the assumed mode method is presented. Eigenvalues and eigenvectors of the linearized model are compared to the measured system natural frequencies and their associated mode shapes. The modeling results for large motions are compared to the time response data from the experiments. The hydraulic actuator is verified.

  3. Topological Routing in Large-Scale Networks

    DEFF Research Database (Denmark)

    Pedersen, Jens Myrup; Knudsen, Thomas Phillip; Madsen, Ole Brun

    2004-01-01

    A new routing scheme, Topological Routing, for large-scale networks is proposed. It allows for efficient routing without large routing tables as known from traditional routing schemes. It presupposes a certain level of order in the networks, known from Structural QoS. The main issues in applying...... Topological Routing to large-scale networks are discussed. Hierarchical extensions are presented along with schemes for shortest path routing, fault handling and path restoration. Further reserach in the area is discussed and perspectives on the prerequisites for practical deployment of Topological Routing...

  4. Topological Routing in Large-Scale Networks

    DEFF Research Database (Denmark)

    Pedersen, Jens Myrup; Knudsen, Thomas Phillip; Madsen, Ole Brun

    A new routing scheme, Topological Routing, for large-scale networks is proposed. It allows for efficient routing without large routing tables as known from traditional routing schemes. It presupposes a certain level of order in the networks, known from Structural QoS. The main issues in applying...... Topological Routing to large-scale networks are discussed. Hierarchical extensions are presented along with schemes for shortest path routing, fault handling and path restoration. Further reserach in the area is discussed and perspectives on the prerequisites for practical deployment of Topological Routing...

  5. Very Large System Dynamics Models - Lessons Learned

    Energy Technology Data Exchange (ETDEWEB)

    Jacob J. Jacobson; Leonard Malczynski

    2008-10-01

    This paper provides lessons learned from developing several large system dynamics (SD) models. System dynamics modeling practice emphasize the need to keep models small so that they are manageable and understandable. This practice is generally reasonable and prudent; however, there are times that large SD models are necessary. This paper outlines two large SD projects that were done at two Department of Energy National Laboratories, the Idaho National Laboratory and Sandia National Laboratories. This paper summarizes the models and then discusses some of the valuable lessons learned during these two modeling efforts.

  6. Large scale network-centric distributed systems

    CERN Document Server

    Sarbazi-Azad, Hamid

    2014-01-01

    A highly accessible reference offering a broad range of topics and insights on large scale network-centric distributed systems Evolving from the fields of high-performance computing and networking, large scale network-centric distributed systems continues to grow as one of the most important topics in computing and communication and many interdisciplinary areas. Dealing with both wired and wireless networks, this book focuses on the design and performance issues of such systems. Large Scale Network-Centric Distributed Systems provides in-depth coverage ranging from ground-level hardware issu

  7. Large-bandwidth planar photonic crystal waveguides

    DEFF Research Database (Denmark)

    Søndergaard, Thomas; Lavrinenko, Andrei

    2002-01-01

    A general design principle is presented for making finite-height photonic crystal waveguides that support leakage-free guidance of light over large frequency intervals. The large bandwidth waveguides are designed by introducing line defects in photonic crystal slabs, where the material in the line...... defect has appropriate dispersion properties relative to the photonic crystal slab material surrounding the line defect. A three-dimensional theoretical analysis is given for large-bandwidth waveguide designs based on a silicon-air photonic crystal slab suspended in air. In one example, the leakage...

  8. Virion Proteomics of Large DNA Viruses

    Institute of Scientific and Technical Information of China (English)

    Ran-ran WANG; Zhi-hong HU; Hua-lin WANG; Fei DENG

    2009-01-01

    Large DNA viruses normally have complex structures with many of protein components derived from both viral and host origins. The development in proteomics, especially mass spectrometry identification techniques provide powerful tools for analyzing large viruses. In this review, we have summarized the recent achievements on proteomic studies of large DNA viruses, such as herpesvirus, poxvirus, nimavirus and baculoviruse. The proteomics of baculovirus occlusion-derived virions (ODV) were emphasized. Different mass spectrometry techniques used on ,carious baculoviruses were introduced, and the identified structurally associated proteins of baculoviruses are summarized.

  9. Network robustness under large-scale attacks

    CERN Document Server

    Zhou, Qing; Liu, Ruifang; Cui, Shuguang

    2014-01-01

    Network Robustness under Large-Scale Attacks provides the analysis of network robustness under attacks, with a focus on large-scale correlated physical attacks. The book begins with a thorough overview of the latest research and techniques to analyze the network responses to different types of attacks over various network topologies and connection models. It then introduces a new large-scale physical attack model coined as area attack, under which a new network robustness measure is introduced and applied to study the network responses. With this book, readers will learn the necessary tools to evaluate how a complex network responds to random and possibly correlated attacks.

  10. The ESO Large Programme First Stars

    CERN Document Server

    Bonifacio, P; Andrievsky, S; Barbuy, B; Beers, T C; Caffau, E; Cayrel, R; Depagne, E; François, P; Hernandez, J I Gonzalez; Hansen, C J; Herwig, F; Hill, V; Korotin, S A; Ludwig, H -G; Molaro, P; Nordström, B; Plez, B; Primas, F; Sivarani, T; Spite, F; Spite, M

    2008-01-01

    In ESO period 65 (April-September 2000) the large programme 165.N-0276, led by Roger Cayrel, began making use of UVES at the Kueyen VLT telescope. Known within the Team and outside as ``First Stars'', it was aimed at obtaining high resolution, high signal-to-noise ratio spectra in the range 320 nm -- 1000 nm for a large sample of extremely metal-poor (EMP) stars identified from the HK objective prism survey.In this contribution we highlight the main results of the large programme.

  11. Bird Ingestion into Large Turbofan Engines

    Science.gov (United States)

    1992-05-01

    AD-A255 863 DOT/FA°• I•T91/17 Bird Ingestion into Large FAA Technical Center AtlanticCity International AirportN 4urbofan Engines L -TIC ýEP 1992...Gov.ernm.nt Accistton No, 3, Rec.p.ent’s Catalog No. DOT/FAA/CT-91/1 7 4. Title and Subtitle 5. Report fote May 1992 BIRD INGESTION INTO LARGE TURBOFAN...study of bird ingestion into certain modern, large high bypass turbofan engines. The engines under consideration were certificated to current FAA

  12. Large area perovskite solar cell module

    Science.gov (United States)

    Cai, Longhua; Liang, Lusheng; Wu, Jifeng; Ding, Bin; Gao, Lili; Fan, Bin

    2017-01-01

    The recent dramatic rise in power conversion efficiencies (PCE) of perovskite solar cells has triggered intense research worldwide. However, their practical development is hampered by poor stability and low PCE values with large areas devices. Here, we developed a gas-pumping method to avoid pinholes and eliminate local structural defects over large areas of perovskite film, even for 5 × 5 cm2 modules, the PCE reached 10.6% and no significant degradation was found after 140 days of outdoor testing. Our approach enables the realization of high performance large-area PSCs for practical application.

  13. Enhanced performance large volume dissolution-DNP

    DEFF Research Database (Denmark)

    Bowen, Sean; Ardenkjær-Larsen, Jan Henrik

    2014-01-01

    A systematic study of the performance of the dissolution process in dissolution-DNP is presented. A relatively simple set of modifications is made to the standard Hypersense dissolution system to enable polarization of large volume samples. These consist of a large volume sample cup along...... with supporting modifications to the dissolution head and related components. Additional modifications were made to support the mapping of the temperature/pressure space of the dissolution process as well as enabling the use of large volumes of solvent and improving the robustness of the system. No loss...

  14. South African red data book - large mammals

    CSIR Research Space (South Africa)

    Skinner, JD

    1977-11-01

    Full Text Available Data sheets are provided for 22 threatened South African large mammals, one exterminated (Liechtenstein1s hartebeest), eight endangered (cheetah, hunting dog, dugong, Cape mountain zebra, black rhinoceros, tsessebe, roan antelope, suni), one...

  15. Large Deviations in Quantum Spin Chain

    CERN Document Server

    Ogata, Yoshiko

    2008-01-01

    We show the full large deviation principle for KMS-states and $C^*$-finitely correlated states on a quantum spin chain. We cover general local observables. Our main tool is Ruelle's transfer operator method.

  16. Large Numbers and Calculators: A Classroom Activity.

    Science.gov (United States)

    Arcavi, Abraham; Hadas, Nurit

    1989-01-01

    Described is an activity demonstrating how a scientific calculator can be used in a mathematics classroom to introduce new content while studying a conventional topic. Examples of reading and writing large numbers, and reading hidden results are provided. (YP)

  17. Bipartite Graphs of Large Clique-Width

    Science.gov (United States)

    Korpelainen, Nicholas; Lozin, Vadim V.

    Recently, several constructions of bipartite graphs of large clique-width have been discovered in the literature. In the present paper, we propose a general framework for developing such constructions and use it to obtain new results on this topic.

  18. Hawaii Large Capacity Cesspools (LCC) Compliant

    Data.gov (United States)

    U.S. Environmental Protection Agency — LCC Compliant: Large Capacity Cesspools that have been properly abandoned or converted to a seepage pit that is associated with a State approved IWS. These LCCs are...

  19. On Carleman estimates with two large parameters

    Energy Technology Data Exchange (ETDEWEB)

    Le Rousseau, Jerome, E-mail: jlr@univ-orleans.fr [Jerome Le Rousseau. Universite d' Orleans, Laboratoire Mathematiques et Applications, Physique Mathematique d' Orleans, CNRS UMR 6628, Federation Denis-Poisson, FR CNRS 2964, B.P. 6759, 45067 Orleans cedex 2 (France)

    2011-04-01

    We provide a general framework for the analysis and the derivation of Carleman estimates with two large parameters. For an appropriate form of weight functions strong pseudo-convexity conditions are shown to be necessary and sufficient.

  20. Large deviations for a random speed particle

    CERN Document Server

    Lefevere, Raphael; Zambotti, Lorenzo

    2011-01-01

    We investigate large deviations for the empirical measure of the position and momentum of a particle traveling in a box with hot walls. The particle travels with uniform speed from left to right, until it hits the right boundary. Then it is absorbed and re-emitted from the left boundary with a new random speed, taken from an i.i.d. sequence. It turns out that this simple model, often used to simulate a heat bath, displays unusually complex large deviations features, that we explain in detail. In particular, if the tail of the update distribution of the speed is sufficiently oscillating, then the empirical measure does not satisfy a large deviations principle, and we exhibit optimal lower and upper large deviations functionals.

  1. Cryoloading: introducing large molecules into live synaptosomes

    National Research Council Canada - National Science Library

    Nath, Arup R; Chen, Robert H C; Stanley, Elise F

    2014-01-01

    ... the introduction of non-membrane permeable test substances such as peptides and drugs. We have developed a method to introduce large alien compounds of at least 150 kDa into functional synaptosomes...

  2. Trust dynamics in a large system implementation

    DEFF Research Database (Denmark)

    Schlichter, Bjarne Rerup; Rose, Jeremy

    2013-01-01

    A large information systems implementation (such as Enterprise Resource Planning systems) relies on the trust of its stakeholders to succeed. Such projects impact diverse groups of stakeholders, each with their legitimate interests and expectations. Levels of stakeholder trust can be expected...... outcomes, but largely ignored the dynamics of trust relations. Giddens, as part of his study of modernity, theorises trust dynamics in relation to abstract social systems, though without focusing on information systems. We use Giddens’ concepts to investigate evolving trust relationships in a longitudinal...... to vary in large-scale implementations (which can take several years), and cannot be taken for granted. Previous studies have largely focused on the taxonomic deconstruction of the trust construct, through point-in-time variance studies. They have identified the relationship between trust and project...

  3. Teaching a Large Physics Class at Cornell.

    Science.gov (United States)

    Orear, Jay

    1979-01-01

    A professor discusses the advantages and disadvantages of teaching a physics class in a large research-oriented university. Various innovative teaching techniques and the ways in which they benefit the students, are presented. (SA)

  4. Large plaque parapsoriasis in a child

    OpenAIRE

    Das Jayanta; Gangopadhyay Asok

    2005-01-01

    A case of large plaque parapsoriasis with extensive skin lesions is presented for its unusual clinical features. The controversial issue of its nosological position is discussed as it has a considerable impact on the management of such cases.

  5. Gravitational waves and large field inflation

    CERN Document Server

    Linde, Andrei

    2016-01-01

    According to the famous Lyth bound, one can confirm large field inflation by finding tensor modes with sufficiently large tensor-to-scalar ratio $r$. Here we will try to answer two related questions: Is it possible to rule out all large field inflationary models by not finding tensor modes with $r$ above some critical value, and what can we say about the scale of inflation by measuring $r$? However, in order to answer these questions one should distinguish between two different definitions of the large field inflation and three different definitions of the scale of inflation. We will examine these issues using the theory of cosmological $\\alpha$-attractors as a convenient testing ground.

  6. Interference Mitigation in Large Random Wireless Networks

    CERN Document Server

    Aldridge, Matthew

    2011-01-01

    A central problem in the operation of large wireless networks is how to deal with interference -- the unwanted signals being sent by transmitters that a receiver is not interested in. This thesis looks at ways of combating such interference. In Chapters 1 and 2, we outline the necessary information and communication theory background, including the concept of capacity. We also include an overview of a new set of schemes for dealing with interference known as interference alignment, paying special attention to a channel-state-based strategy called ergodic interference alignment. In Chapter 3, we consider the operation of large regular and random networks by treating interference as background noise. We consider the local performance of a single node, and the global performance of a very large network. In Chapter 4, we use ergodic interference alignment to derive the asymptotic sum-capacity of large random dense networks. These networks are derived from a physical model of node placement where signal strength d...

  7. Gravitational waves and large field inflation

    Science.gov (United States)

    Linde, Andrei

    2017-02-01

    According to the famous Lyth bound, one can confirm large field inflation by finding tensor modes with sufficiently large tensor-to-scalar ratio r. Here we will try to answer two related questions: is it possible to rule out all large field inflationary models by not finding tensor modes with r above some critical value, and what can we say about the scale of inflation by measuring r? However, in order to answer these questions one should distinguish between two different definitions of the large field inflation and three different definitions of the scale of inflation. We will examine these issues using the theory of cosmological α-attractors as a convenient testing ground.

  8. Finite N from Resurgent Large N

    CERN Document Server

    Couso-Santamaría, Ricardo; Vaz, Ricardo

    2015-01-01

    Due to instanton effects, gauge-theoretic large N expansions yield asymptotic series, in powers of 1/N^2. The present work shows how to generically make such expansions meaningful via their completion into resurgent transseries, encoding both perturbative and nonperturbative data. Large N resurgent transseries compute gauge-theoretic finite N results nonperturbatively (no matter how small N is). Explicit calculations are carried out within the gauge theory prototypical example of the quartic matrix model. Due to integrability in the matrix model, it is possible to analytically compute (fixed integer) finite N results. At the same time, the large N resurgent transseries for the free energy of this model was recently constructed. Together, it is shown how the resummation of the large N resurgent transseries matches the analytical finite N results up to remarkable numerical accuracy. Due to lack of Borel summability, Stokes phenomena has to be carefully taken into account, implying that instantons play a dominan...

  9. Electron Transfer for Large Molecules through Delocalization

    Energy Technology Data Exchange (ETDEWEB)

    Neuhauser, D.; Reslan, R.; Hernandez, S.; Arnsen, C.; Lopata, K.; Govind, N.; Gao, Y.; Tolbert, S.; Schwartz, B.; Rubin, Y.; Nardes, A.; Kopidakis, N.

    2012-01-01

    Electron transfer for large molecules lies in between a Marcus-Theory two-state transfer and a Landauer description. We discuss a delocalization formalism which,through the introduction of artificial electric fields which emulate bulk dipole fields, allows calculation between a pair of identical molecules (A+A- (R)A-+A) with several open states. Dynamical electron polarization effects can be inserted with TDDFT and are crucial for large separations.

  10. High Resolution RPCs for Large TOF Systems

    CERN Document Server

    Ferreira-Marques, R; CERN. Geneva; Carolino, N; Policarpo, Armando; Fonte, P

    1999-01-01

    Here we report on a particular type of RPC that presents above 95% efficiency for minimum ionizing particles and a very sharp time resolution, below 80 ps sigma. Our 9cm2 cells, made with glass and metal electrodes that form accurately spaced gaps of a few hundred micrometers, are operated at atmospheric pressure in non-flammable gases and can be economically produced in large quantities, opening perspectives for the construction of large area timeof flight systems.

  11. Large deviations for tandem queueing systems

    Directory of Open Access Journals (Sweden)

    Roland L. Dobrushin

    1994-01-01

    Full Text Available The crude asymptotics of the large delay probability in a tandem queueing system is considered. The main result states that one of the two channels in the tandem system defines the crude asymptotics. The constant that determines the crude asymptotics is given. The results obtained are based on the large deviation principle for random processes with independent increments on an infinite interval recently established by the authors.

  12. Rectangular Wilson Loops at Large N

    CERN Document Server

    Lohmayer, Robert

    2012-01-01

    This work is about pure Yang Mills theory in four Euclidean dimensions with gauge group SU(N). We study rectangular smeared Wilson loops on the lattice at large N and relatively close to the large-N transition point in their eigenvalue density. We show that the string tension can be extracted from these loops but obtain a shape dependence different from the prediction of effective string theory.

  13. Third International Conference on Large Meteorite Impacts

    Science.gov (United States)

    2003-01-01

    The Third International Conference on Large Meteorite Impacts (formerly Large Meteorite Impacts and Planetary Evolution) was held August 5-7, 2003, at the Kloesterle, Noerdlingen. The conference addressed a wide range of topics relating to planetary impacts and their effects on planetary crusts, climate, life on Earth, rocks, and rock-forming minerals. This CD-ROM contains the preface, table of contents, program, abstracts and indexes.

  14. On large N solution of ABJM theory

    Energy Technology Data Exchange (ETDEWEB)

    Suyama, Takao, E-mail: suyama@phya.snu.ac.k [Center for Theoretical Physics, Seoul National University, Seoul 151-747 (Korea, Republic of)

    2010-07-21

    We investigate the large N limit of the expectation value W(lambda) of a BPS Wilson loop in ABJM theory, using an integral expression of the partition function obtained recently by Kapustin et al. Certain saddle-point equations provide the correct perturbative expansion of W(lambda). The large lambda behavior of W(lambda) is also obtained from the saddle-point equations. The result is consistent with AdS/CFT correspondence.

  15. Large deviations for fractional Poisson processes

    CERN Document Server

    Beghin, Luisa

    2012-01-01

    We present large deviation results for two versions of fractional Poisson processes: the main version which is a renewal process, and the alternative version where all the random variables are weighted Poisson distributed. We also present a sample path large deviation result for suitably normalized counting processes; finally we show how this result can be applied to the two versions of fractional Poisson processes considered in this paper.

  16. Effective Language Teaching in Large Classes

    Institute of Scientific and Technical Information of China (English)

    张丽丽

    2010-01-01

    <正>With more and more people who are jumping into the line of learning the second language (especially English),and also due to the limited resources in language teaching,many foreign language teachers are nowadays confronting the large classes when teaching.So how to teach foreign language effectively in large classes has become an issue as well as a special field to make researches in.

  17. The large deviations theorem and ergodicity

    Energy Technology Data Exchange (ETDEWEB)

    Gu Rongbao [School of Finance, Nanjing University of Finance and Economics, Nanjing 210046 (China)

    2007-12-15

    In this paper, some relationships between stochastic and topological properties of dynamical systems are studied. For a continuous map f from a compact metric space X into itself, we show that if f satisfies the large deviations theorem then it is topologically ergodic. Moreover, we introduce the topologically strong ergodicity, and prove that if f is a topologically strongly ergodic map satisfying the large deviations theorem then it is sensitively dependent on initial conditions.

  18. Holographic Analysis of Large Vehicle Structures

    Science.gov (United States)

    1982-07-01

    47 5.35 Driver’s Door, Engine Speed 3000 RPM, t=14ms 48 v Figure No. Figure Title Page No. 6.1 Graphic Illustration of the Relative Phase Shift Between...global dynamic information over large sections of the vibrating vehicle surface. This information provides a means for improving vehicle desing and...sensitivity which is important for large amplitude measurements. The resulting CW fringe pattern for the beam displacement is graphically illustrated in Figure

  19. Workflow management in large distributed systems

    Science.gov (United States)

    Legrand, I.; Newman, H.; Voicu, R.; Dobre, C.; Grigoras, C.

    2011-12-01

    The MonALISA (Monitoring Agents using a Large Integrated Services Architecture) framework provides a distributed service system capable of controlling and optimizing large-scale, data-intensive applications. An essential part of managing large-scale, distributed data-processing facilities is a monitoring system for computing facilities, storage, networks, and the very large number of applications running on these systems in near realtime. All this monitoring information gathered for all the subsystems is essential for developing the required higher-level services—the components that provide decision support and some degree of automated decisions—and for maintaining and optimizing workflow in large-scale distributed systems. These management and global optimization functions are performed by higher-level agent-based services. We present several applications of MonALISA's higher-level services including optimized dynamic routing, control, data-transfer scheduling, distributed job scheduling, dynamic allocation of storage resource to running jobs and automated management of remote services among a large set of grid facilities.

  20. Síndrome frágil X: correlación clínica, citogenética y molecular en una familia

    Directory of Open Access Journals (Sweden)

    Aracely Lantigua Cruz

    1997-08-01

    Full Text Available Estudios recientes han permitido caracterizar molecularmente el defecto genético o mutación FMR-1 del síndrome frágil X. Esta mutación consiste en variaciones de repeticiones del triplete CGG del gen, que varían del rango normal a la mutación completa y pasan por rangos intermedios o premutaciones. Debido a que el individuo afectado además expresa un porcentaje variable de sitio frágil Xq27.3 (FRAXA en su cariotipo, en este trabajo se presenta una correlación clínica y citogenética con la caracterización molecular del gen FMR-1 realizada por 2 métodos directos: Southern blot y reacción en cadena de la polimerasa (PCR en 5 varones afectados y 5 mujeres portadoras, a propósito del diagnóstico prenatal en una de ellas. El análisis de las caracterizaciones clínicas, físicas y neuropsicológicas previamente delineadas, llevaron a la conclusión de que éstas, así como la frecuencia en porcentaje de FRAXA, se correlacionan en los varones afectados con la elongación que experimenta la mutación al trasmitirse de una generación a la siguiente a través de mujeres portadoras, en quienes por otra parte, estas características son heterogéneas y susceptibles a sobrelapamiento tanto por efecto genómico como por factores ambientales psicofamiliares.Recent studies have allowed to characterize molecularly the genetic defect or FMR-1 mutation of the fragile X syndrome. This mutation consists in variations of repetitions of the gene's CGG triplet that came from the normal range to the complete mutation, passing through intermediate ranges or premutations. Due to the fact that the affected individual also shows a variable percentage of Xq27.3 fragile site (FRAXA in his karyotype, it is presented in this paper a clinical and cytogenetic correlation with the molecular characterization of the FMR-1 gen carried out by 2 direct methods: Southern Blot and polymerase chain reaction (PCR in 5 affected males and 5 female carriers, one of them with

  1. Large Payload Ground Transportation and Test Considerations

    Science.gov (United States)

    Rucker, Michelle A.

    2016-01-01

    Many spacecraft concepts under consideration by the National Aeronautics and Space Administration’s (NASA’s) Evolvable Mars Campaign take advantage of a Space Launch System payload shroud that may be 8 to 10 meters in diameter. Large payloads can theoretically save cost by reducing the number of launches needed--but only if it is possible to build, test, and transport a large payload to the launch site in the first place. Analysis performed previously for the Altair project identified several transportation and test issues with an 8.973 meters diameter payload. Although the entire Constellation Program—including Altair—has since been canceled, these issues serve as important lessons learned for spacecraft designers and program managers considering large payloads for future programs. A transportation feasibility study found that, even broken up into an Ascent and Descent Module, the Altair spacecraft would not fit inside available aircraft. Ground transportation of such large payloads over extended distances is not generally permitted, so overland transportation alone would not be an option. Limited ground transportation to the nearest waterway may be possible, but water transportation could take as long as 67 days per production unit, depending on point of origin and acceptance test facility; transportation from the western United States would require transit through the Panama Canal to access the Kennedy Space Center launch site. Large payloads also pose acceptance test and ground processing challenges. Although propulsion, mechanical vibration, and reverberant acoustic test facilities at NASA’s Plum Brook Station have been designed to accommodate large spacecraft, special handling and test work-arounds may be necessary, which could increase cost, schedule, and technical risk. Once at the launch site, there are no facilities currently capable of accommodating the combination of large payload size and hazardous processing such as hypergolic fuels

  2. Geological characteristics of large gas provinces and large gas fields in China

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Based on the examination of the global researches on oil and gas provinces and large gas fields and the analysis of the features,attributes and distribution of large gas provinces and gas fields,this paper puts forward three indicators of determining large oil and gas provinces:spatial indicator,reservoir-forming indicator and resource indicator.It classifies the gas accumulated areas and large gas provinces in China and analyzes the controlling factors on the distribution of large gas provinces and large gas fields:the lateral distribution is mainly controlled by high-energy sedimentary facies and constructive diagenetic facies,palaeo-highs and their periclinal zones,deep faults,etc,and the vertical distribution is mainly controlled by unconformities,series of evaporates and deep low-velocity highly-conductive beds,etc.It also reveals the main geological characteristics of large gas provinces and large gas fields in China.Large gas fields in four-type basins have their own characteristics and onland large gas fields are dominantly developed in foreland basins and craton basins;there are three types of gas sources,of which,coal is the main source with high gas generating intensity and varying origins;reservoir rocks of the large gas fields(provinces)are of various types and dominated generally by low-middle permeability and porosity pore-type reservoirs;structural traps and litho-stratigraphic traps coexist in Chinese large gas fields and form dense high abundance and large-area low and middle-abundance large gas fields;most of the large gas fields have late hydrocarbon-generation peaks and reservoir formation,and experienced the process of multiple-stage charging and late finalization; large gas provinces(fields)have good sealing and preservation conditions,and evaporates seals are largely developed in large and extra-large gas fields.This paper intends to shed light on the exploration and development of large gas fields(provinces)through analyzing their

  3. Metrology of Large Parts. Chapter 5

    Science.gov (United States)

    Stahl, H. Philip

    2012-01-01

    As discussed in the first chapter of this book, there are many different methods to measure a part using optical technology. Chapter 2 discussed the use of machine vision to measure macroscopic features such as length and position, which was extended to the use of interferometry as a linear measurement tool in chapter 3, and laser or other trackers to find the relation of key points on large parts in chapter 4. This chapter looks at measuring large parts to optical tolerances in the sub-micron range using interferometry, ranging, and optical tools discussed in the previous chapters. The purpose of this chapter is not to discuss specific metrology tools (such as interferometers or gauges), but to describe a systems engineering approach to testing large parts. Issues such as material warpage and temperature drifts that may be insignificant when measuring a part to micron levels under a microscope, as will be discussed in later chapters, can prove to be very important when making the same measurement over a larger part. In this chapter, we will define a set of guiding principles for successfully overcoming these challenges and illustrate the application of these principles with real world examples. While these examples are drawn from specific large optical testing applications, they inform the problems associated with testing any large part to optical tolerances. Manufacturing today relies on micrometer level part performance. Fields such as energy and transportation are demanding higher tolerances to provide increased efficiencies and fuel savings. By looking at how the optics industry approaches sub-micrometer metrology, one can gain a better understanding of the metrology challenges for any larger part specified to micrometer tolerances. Testing large parts, whether optical components or precision structures, to optical tolerances is just like testing small parts, only harder. Identical with what one does for small parts, a metrologist tests large parts and optics

  4. Large-scale multimedia modeling applications

    Energy Technology Data Exchange (ETDEWEB)

    Droppo, J.G. Jr.; Buck, J.W.; Whelan, G.; Strenge, D.L.; Castleton, K.J.; Gelston, G.M.

    1995-08-01

    Over the past decade, the US Department of Energy (DOE) and other agencies have faced increasing scrutiny for a wide range of environmental issues related to past and current practices. A number of large-scale applications have been undertaken that required analysis of large numbers of potential environmental issues over a wide range of environmental conditions and contaminants. Several of these applications, referred to here as large-scale applications, have addressed long-term public health risks using a holistic approach for assessing impacts from potential waterborne and airborne transport pathways. Multimedia models such as the Multimedia Environmental Pollutant Assessment System (MEPAS) were designed for use in such applications. MEPAS integrates radioactive and hazardous contaminants impact computations for major exposure routes via air, surface water, ground water, and overland flow transport. A number of large-scale applications of MEPAS have been conducted to assess various endpoints for environmental and human health impacts. These applications are described in terms of lessons learned in the development of an effective approach for large-scale applications.

  5. Development of large aperture composite adaptive optics

    Science.gov (United States)

    Kmetik, Viliam; Vitovec, Bohumil; Jiran, Lukas; Nemcova, Sarka; Zicha, Josef; Inneman, Adolf; Mikulickova, Lenka; Pavlica, Richard

    2015-01-01

    Large aperture composite adaptive optics for laser applications is investigated in cooperation of Institute of Plasma Physic, Department of Instrumentation and Control Engineering FME CTU and 5M Ltd. We are exploring opportunity of a large-size high-power-laser deformable-mirror production using a lightweight bimorph actuated structure with a composite core. In order to produce a sufficiently large operational free aperture we are developing new technologies for production of flexible core, bimorph actuator and deformable mirror reflector. Full simulation of a deformable-mirrors structure was prepared and validated by complex testing. A deformable mirror actuation and a response of a complicated structure are investigated for an accurate control of the adaptive optics. An original adaptive optics control system and a bimorph deformable mirror driver were developed. Tests of material samples, components and sub-assemblies were completed. A subscale 120 mm bimorph deformable mirror prototype was designed, fabricated and thoroughly tested. A large-size 300 mm composite-core bimorph deformable mirror was simulated and optimized, fabrication of a prototype is carried on. A measurement and testing facility is modified to accommodate large sizes optics.

  6. Hot seeding using large Y-123 seeds

    Energy Technology Data Exchange (ETDEWEB)

    Scruggs, S J; Putman, P T; Zhou, Y X; Fang, H; Salama, K [Department of Mechanical Engineering, University of Houston, 4800 Calhoun Road, Houston, TX 77204 (United States)

    2006-07-15

    There are several motivations for increasing the diameter of melt textured single domain discs. The maximum magnetic field produced by a trapped field magnet is proportional to the radius of the sample. Furthermore, the availability of trapped field magnets with large diameter could enable their use in applications that have traditionally been considered to require wound electromagnets, such as beam bending magnets for particle accelerators and electric propulsion. We have investigated the possibility of using large area epitaxial growth instead of the conventional point nucleation growth mechanism. This process involves the use of large Y123 seeds for the purpose of increasing the maximum achievable Y123 single domain size. The hot seeding technique using large Y-123 seeds was employed to seed Y-123 samples. Trapped field measurements indicate that single domain samples were indeed grown by this technique. Microstructural evaluation indicates that growth can be characterized by a rapid nucleation followed by the usual peritectic grain growth which occurs when large seeds are used. Critical temperature measurements show that no local T{sub c} suppression occurs in the vicinity of the seed. This work supports the suggestion of using an iterative method for increasing the size of Y-123 single domains that can be grown.

  7. Astronomy Outreach for Large and Unique Audiences

    Science.gov (United States)

    Lubowich, D.; Sparks, R. T.; Pompea, S. M.; Kendall, J. S.; Dugan, C.

    2013-04-01

    In this session, we discuss different approaches to reaching large audiences. In addition to star parties and astronomy events, the audiences for some of the events include music concerts or festivals, sick children and their families, minority communities, American Indian reservations, and tourist sites such as the National Mall. The goal is to bring science directly to the public—to people who attend astronomy events and to people who do not come to star parties, science museums, or science festivals. These programs allow the entire community to participate in astronomy activities to enhance the public appreciation of science. These programs attract large enthusiastic crowds often with young children participating in these family learning experiences. The public will become more informed, educated, and inspired about astronomy and will also be provided with information that will allow them to continue to learn after this outreach activity. Large and unique audiences often have common problems, and their solutions and the lessons learned will be presented. Interaction with the participants in this session will provide important community feedback used to improve astronomy outreach for large and unique audiences. New ways to expand astronomy outreach to new large audiences will be discussed.

  8. Identifying large chondrites using cosmogenic radionuclides

    Energy Technology Data Exchange (ETDEWEB)

    Welten, K.C. [Space Sciences Laboratory, University of California, Berkeley, CA 94720-7450 (United States); Caffee, M.W., E-mail: mcaffee@purdue.ed [PRIME Laboratory, Purdue University, West Lafayette, IN 47907 (United States); Hillegonds, D.J. [Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550 (United States); Masarik, J. [Department of Nuclear Physics, Comenius University, Bratislava (Slovakia); Nishiizumi, K. [Space Sciences Laboratory, University of California, Berkeley, CA 94720-7450 (United States)

    2010-04-15

    We measured the concentrations of the cosmogenic radionuclides {sup 10}Be, {sup 26}Al, {sup 36}Cl and {sup 41}Ca in the metal and stone fractions of three large chondrite showers to determine their pre-atmospheric size. Large chondrites are characterized by substantial contributions of neutron-capture {sup 41}Ca in the stone fraction (up to approx2 dpm/gCa), low radionuclide concentrations in the metal fraction and high {sup 10}Be(stone)/{sup 10}Be(metal) ratios. Based on the measured concentrations in comparison with calculated cosmogenic nuclide depth profiles, using a semi-empirical and a purely physical model, we conclude that these objects had pre-atmospheric radii ranging from approx80 cm to >3 m. We conclude that the semi-empirical model is more reliable for spallogenic production rates in large objects, while the purely physical model is more reliable for neutron-capture products.

  9. The Design of Large Technological Systems

    DEFF Research Database (Denmark)

    Pineda, Andres Felipe Valderrama

    This is a study of the processes of design of large technological systems based on a two-case study: the rapid transit bus system, Transmilenio, in Bogotá, Colombia, and the urban rail system, Metro, in Copenhagen, Denmark. The research focused especially on the process by which designers define...... material scripts during the conception, construction, implementation and operation of large technological systems. The main argument is that designers define scripts in a process in which three parallel developments are at play: first, a reading takes place of the history (past, present, future...... dynamics involved in the design processes of large technological systems by revealing how their constitution produces a reconfiguration of the arena of development of urban transport. This dynamic substantiates the co-evolution of technological systems and the city....

  10. Challenges in engineering large customized bone constructs.

    Science.gov (United States)

    Forrestal, David P; Klein, Travis J; Woodruff, Maria A

    2017-06-01

    The ability to treat large tissue defects with customized, patient-specific scaffolds is one of the most exciting applications in the tissue engineering field. While an increasing number of modestly sized tissue engineering solutions are making the transition to clinical use, successfully scaling up to large scaffolds with customized geometry is proving to be a considerable challenge. Managing often conflicting requirements of cell placement, structural integrity, and a hydrodynamic environment supportive of cell culture throughout the entire thickness of the scaffold has driven the continued development of many techniques used in the production, culturing, and characterization of these scaffolds. This review explores a range of technologies and methods relevant to the design and manufacture of large, anatomically accurate tissue-engineered scaffolds with a focus on the interaction of manufactured scaffolds with the dynamic tissue culture fluid environment. Biotechnol. Bioeng. 2017;114: 1129-1139. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. The Large Scale Organization of Turbulent Channels

    CERN Document Server

    del Alamo, Juan C

    2013-01-01

    We have investigated the organization and dynamics of the large turbulent structures that develop in the logarithmic and outer layers of high-Reynolds-number wall flows. These structures have sizes comparable to the flow thickness and contain most of the turbulent kinetic energy. They produce a substantial fraction of the skin friction and play a key role in turbulent transport. In spite of their significance, there is much less information about the large structures far from the wall than about the small ones of the near-wall region. The main reason for this is the joint requirements of large measurement records and high Reynolds numbers for their experimental analysis. Their theoretical analysis has been hampered by the lack of succesful models for their interaction with the background small-scale turbulence.

  12. Accelerating sustainability in large-scale facilities

    CERN Multimedia

    Marina Giampietro

    2011-01-01

    Scientific research centres and large-scale facilities are intrinsically energy intensive, but how can big science improve its energy management and eventually contribute to the environmental cause with new cleantech? CERN’s commitment to providing tangible answers to these questions was sealed in the first workshop on energy management for large scale scientific infrastructures held in Lund, Sweden, on the 13-14 October.   Participants at the energy management for large scale scientific infrastructures workshop. The workshop, co-organised with the European Spallation Source (ESS) and  the European Association of National Research Facilities (ERF), tackled a recognised need for addressing energy issues in relation with science and technology policies. It brought together more than 150 representatives of Research Infrastrutures (RIs) and energy experts from Europe and North America. “Without compromising our scientific projects, we can ...

  13. Phonetic search methods for large speech databases

    CERN Document Server

    Moyal, Ami; Tetariy, Ella; Gishri, Michal

    2013-01-01

    “Phonetic Search Methods for Large Databases” focuses on Keyword Spotting (KWS) within large speech databases. The brief will begin by outlining the challenges associated with Keyword Spotting within large speech databases using dynamic keyword vocabularies. It will then continue by highlighting the various market segments in need of KWS solutions, as well as, the specific requirements of each market segment. The work also includes a detailed description of the complexity of the task and the different methods that are used, including the advantages and disadvantages of each method and an in-depth comparison. The main focus will be on the Phonetic Search method and its efficient implementation. This will include a literature review of the various methods used for the efficient implementation of Phonetic Search Keyword Spotting, with an emphasis on the authors’ own research which entails a comparative analysis of the Phonetic Search method which includes algorithmic details. This brief is useful for resea...

  14. Design of Large Momentum Acceptance Transport Systems

    CERN Document Server

    Douglas, David

    2005-01-01

    The use of energy recovery to enable high power linac operation often gives rise to an attendant challenge - the transport of high power beams subtending large phase space volumes. In particular applications - such as FEL driver accelerators - this manifests itself as a requirement for beam transport systems with large momentum acceptance. We will discuss the design, implementation, and operation of such systems. Though at times counterintuitive in behavior (perturbative descriptions may, for example, be misleading), large acceptance systems have been successfully utilized for generations as spectrometers and accelerator recirculators.* Such systems are in fact often readily designed using appropriate geometric descriptions of beam behavior; insight provided using such a perspective may in addition reveal inherent symmetries that simplify construction and improve operability. Our discussion will focus on two examples: the Bates-clone recirculator used in the Jefferson Lab 10 kW IR Upgrade FEL (which has an ob...

  15. Large bulk Micromegas detectors for TPC applications

    CERN Document Server

    Anvar, S; Boyer, M; Beucher, J; Calvet, D; Colas, P; De La Broise, X; Delagnes, E; Delbart, A; Druillole, F; Emery, S; Giganti, C; Giomataris, I; Mazzucato, E; Monmarthe, E; Nizery, F; Pierre, F; Ritou, J L; Sarrat, A; Zito, M; Catanesi, M G; Radicioni, E; De Oliveira, R; Blondel, A; Di Marco, M; Ferrere, D; Perrin, E; Ravonel, M; Jover, G; Lux, T; Rodriguez, A Y; Sanchez, F; Cervera, A; Hansen, C; Monfregola, L

    2009-01-01

    A large volume TPC will be used in the near future in a variety of experiments including T2K. The bulk Micromegas detector for this TPC is built using a novel production technique particularly suited for compact, thin and robust low mass detectors. The capability to pave a large surface with a simple mounting solution and small dead space is of particular interest for these applications. We have built several large bulk Micromegas detectors () and we have tested one in the former HARP field cage with a magnetic field. Prototypes cards of the T2K front end electronics, based on the AFTER ASIC chip, have been used in this TPC test for the first time. Cosmic ray data have been acquired in a variety of experimental conditions. Good detector performances, space point resolution and energy loss measurement have been achieved.

  16. Bulk micromegas detectors for large TPC applications

    CERN Document Server

    Bouchez, J; Cavata, Ch; Colas, P; De La Broise, X; Delbart, A; Giganon, Arnaud; Giomataris, Ioanis; Graffin, P; Mols, J Ph; Pierre, F; Ritou, J L; Sarrat, A; Virique, E; Zito, M; Radicioni, E; De Oliveira, R; Dumarchez, J; Abgrall, N; Bene, P; Blondel, A; Cervera-Villanueva, Anselmo; Ferrère, D; Maschiocchi, F; Perrin, E; Richeux, J P; Schroeter, R; Jover, G; Lux,; Rodriguez, A Y; Sánchez, F

    2007-01-01

    A large volume TPC will be used in the near future in a variety of experiments including T2K. The bulk Micromegas detector for this TPC is built using a novel production technique particularly suited for compact and robust low mass detectors. The capability to pave a large surface with a simple mounting solution and small dead space between modules is of particular interest for these applications. We have built several large bulk Micromegas detectors and we have tested them in the former HARP field cage setup with a magnetic field. Cosmic ray data have been acquired in a variety of experimental conditions. Good detector performances and space point resolution have been achieved.

  17. On large deviations for ensembles of distributions

    Science.gov (United States)

    Khrychev, D. A.

    2013-11-01

    The paper is concerned with the large deviations problem in the Freidlin-Wentzell formulation without the assumption of the uniqueness of the solution to the equation involving white noise. In other words, it is assumed that for each \\varepsilon>0 the nonempty set \\mathscr P_\\varepsilon of weak solutions is not necessarily a singleton. Analogues of a number of concepts in the theory of large deviations are introduced for the set \\{\\mathscr P_\\varepsilon,\\,\\varepsilon>0\\}, hereafter referred to as an ensemble of distributions. The ensembles of weak solutions of an n-dimensional stochastic Navier-Stokes system and stochastic wave equation with power-law nonlinearity are shown to be uniformly exponentially tight. An idempotent Wiener process in a Hilbert space and idempotent partial differential equations are defined. The accumulation points in the sense of large deviations of the ensembles in question are shown to be weak solutions of the corresponding idempotent equations. Bibliography: 14 titles.

  18. Large subconjunctival emphysema causing diplopia and lagophthalmos.

    Science.gov (United States)

    Kaiserman, I

    2003-01-01

    To describe a patient who developed diplopia, lagophthalmos and exposure keratopathy due to a large subconjunctival emphysema. A 24-year-old man sustained an injury in his left eye from a compressed air hose. The patient complained of pain and diplopia. He underwent slit-lamp examination, funduscopy and computed tomography. Ophthalmic examination revealed a decrease in vision in the left eye to 0.5, a conjunctival laceration adjacent to the medial limbus, subconjunctival hemorrhage, a large subconjunctival emphysema, lagophthalmos, hypertropia and superficial punctate keratopathy. The posterior pole was intact as were the orbital bones. Two weeks after the injury the conjunctival emphysema, diplopia, lagophthalmos and superficial keratopathy resolved, and visual acuity improved to 1. Large subconjunctival emphysema can result in diplopia, lagophthalmos and exposure keratopathy.

  19. Large molecules in diffuse interstellar clouds

    Science.gov (United States)

    Lepp, S.; Dalgarno, A.; Van Dishoeck, E. F.; Black, J. H.

    1988-01-01

    The effects of the presence of a substantial component of large molecules on the chemistry of diffuse molecular clouds are explored, and detailed models of the zeta Persei and zeta Ophiuchi clouds are constructed. The major consequence is a reduction in the abundances of singly charged atomic species. The long-standing discrepancy between cloud densities inferred from rotational and fine-structure level populations and from the ionization balance can be resolved by postulating a fractional abundance of large molecules of 1 x 10 to the -7th for zeta Persei and 6 x 10 to the -7th for zeta Ophiuchi. If the large molecules are polycyclic aromatic hydrocarbons (PAH) containing about 50 carbon atoms, they contain 1 percent of the carbon in zeta Persei and 7 percent in zeta Ophiuchi. Other consequences of the possible presence of PAH molecules are discussed.

  20. Large-scale structure of the Universe

    Energy Technology Data Exchange (ETDEWEB)

    Shandarin, S.F.; Doroshkevich, A.G.; Zel' dovich, Ya.B. (Inst. Prikladnoj Matematiki, Moscow, USSR)

    1983-01-01

    A review of theory of the large-scale structure of the Universe is given, including formation of clusters and superclusters of galaxies as well as large voids. Particular attention is paid to the theory of neutrino dominated Universe - the cosmological model where neutrinos with the rest mass of several tens eV dominate the mean density. Evolution of small perturbations is discussed, estimates of microwave backgorund radiation fluctuations is given for different angular scales. Adiabatic theory of the Universe structure formation, known as ''cake'' scenario and their successive fragmentation is given. This scenario is based on approximate nonlinear theory of gravitation instability. Results of numerical experiments, modeling the processes of large-scale structure formation are discussed.