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

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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.

Fragile X premutation carriers: A systematic review of neuroimaging findings.

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Brown, Stephanie S G; Stanfield, Andrew C

2015-05-15

Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between 55 and 200 repeats is known as the fragile X premutation. Carriers of the fragile X premutation may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS). Recent evidence suggests that premutation carriers experience other psychiatric difficulties throughout their lifespan. Medline, EMBASE and PsychINFO were searched for all appropriate English language studies published between January 1990 and December 2013. 419 potentially relevant articles were identified and screened. 19 articles were included in the analysis. We discuss key structural magnetic resonance imaging (MRI) findings such as the MCP sign and white matter atrophy. Additionally, we discuss how functional MRI results have progressed our knowledge of how FXTAS may manifest, including reduced brain activation during social and memory tasks in multiple regions. This systematic review may have been limited by the search for articles on just 3 scientific databases. Differing techniques and methods of analyses between research groups and primary research articles may have caused differences in results between studies. Current MRI studies into the fragile X premutation have been important in the diagnosis of FXTAS and identifying potential pathophysiological mechanisms. Associations with blood based measures have also demonstrated that neurodevelopmental and neurodegenerative aspects of the fragile X premutation could be functionally and pathologically separate. Larger longitudinal studies will be required to investigate these conclusions. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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Hoyos, Luis R; Thakur, Mili

2017-03-01

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.

Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation.

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Wang, Jun Yi; Hessl, David; Hagerman, Randi J; Simon, Tony J; Tassone, Flora; Ferrer, Emilio; Rivera, Susan M

2017-07-01

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder typically affecting male premutation carriers with 55-200 CGG trinucleotide repeat expansions in the FMR1 gene after age 50. The aim of this study was to examine whether cerebellar and brainstem changes emerge during development or aging in late life. We retrospectively analyzed magnetic resonance imaging scans from 322 males (age 8-81 years). Volume changes in the cerebellum and brainstem were contrasted with those in the ventricles and whole brain. Compared to the controls, premutation carriers without FXTAS showed significantly accelerated volume decrease in the cerebellum and whole brain, flatter inverted U-shaped trajectory of the brainstem, and larger ventricles. Compared to both older controls and premutation carriers without FXTAS, carriers with FXTAS exhibited significant volume decrease in the cerebellum and whole brain and accelerated volume decrease in the brainstem. We therefore conclude that cerebellar and brainstem volumes were likely affected during both development and progression of neurodegeneration in premutation carriers, suggesting that interventions may need to start early in adulthood to be most effective. Copyright © 2017 Elsevier Inc. All rights reserved.

Low-Normal FMR1 CGG Repeat Length: Phenotypic Associations

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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.

Fear-Specific Amygdala Function in Children and Adolescents on the Fragile X Spectrum: A Dosage Response of the FMR1 Gene

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Kim, So-Yeon; Burris, Jessica; Bassal, Frederick; Koldewyn, Kami; Chattarji, Sumantra; Tassone, Flora; Hessl, David; Rivera, Susan M.

2014-01-01

Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). The presence of significant socioemotional problems has been well documented in FXS although the brain basis of those deficits remains unspecified. Here, we investigated amygdala dysfunction and its relation to socioemotional deficits and FMR1 gene expression in children and adolescents on the FX spectrum (i.e., individuals whose trinucleotide CGG repeat expansion from 55 to over 200 places them somewhere within the fragile X diagnostic range from premutation to full mutation). Participants performed an fMRI task in which they viewed fearful, happy, and scrambled faces. Neuroimaging results demonstrated that FX participants revealed significantly attenuated amygdala activation in Fearful > Scrambled and Fearful > Happy contrasts compared with their neurotypical counterparts, while showing no differences in amygdala volume. Furthermore, we found significant relationships between FMR1 gene expression, anxiety/social dysfunction scores, and reduced amygdala activation in the FX group. In conclusion, we report novel evidence regarding a dosage response of the FMR1 gene on fear-specific functions of the amygdala, which is associated with socioemotional deficits in FXS. PMID:23146966

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

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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.

Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

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Castro, Hoanna; Kul, Emre; Buijsen, Ronald A M; Severijnen, Lies-Anne W F M; Willemsen, Rob; Hukema, Renate K; Stork, Oliver; Santos, Mónica

2017-06-01

A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

β-glucuronidase use as a single internal control gene may confound analysis in FMR1 mRNA toxicity studies.

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Kraan, Claudine M; Cornish, Kim M; Bui, Quang M; Li, Xin; Slater, Howard R; Godler, David E

2018-01-01

Relationships between Fragile X Mental Retardation 1 (FMR1) mRNA levels in blood and intragenic FMR1 CGG triplet expansions support the pathogenic role of RNA gain of function toxicity in premutation (PM: 55-199 CGGs) related disorders. Real-time PCR (RT-PCR) studies reporting these findings normalised FMR1 mRNA level to a single internal control gene called β-glucuronidase (GUS). This study evaluated FMR1 mRNA-CGG correlations in 33 PM and 33 age- and IQ-matched control females using three normalisation strategies in peripheral blood mononuclear cells (PBMCs): (i) GUS as a single internal control; (ii) the mean of GUS, Eukaryotic Translation Initiation Factor 4A2 (EIF4A2) and succinate dehydrogenase complex flavoprotein subunit A (SDHA); and (iii) the mean of EIF4A2 and SDHA (with no contribution from GUS). GUS mRNA levels normalised to the mean of EIF4A2 and SDHA mRNA levels and EIF4A2/SDHA ratio were also evaluated. FMR1mRNA level normalised to the mean of EIF4A2 and SDHA mRNA levels, with no contribution from GUS, showed the most significant correlation with CGG size and the greatest difference between PM and control groups (p = 10-11). Only 15% of FMR1 mRNA PM results exceeded the maximum control value when normalised to GUS, compared with over 42% when normalised to the mean of EIF4A2 and SDHA mRNA levels. Neither GUS mRNA level normalised to the mean RNA levels of EIF4A2 and SDHA, nor to the EIF4A2/SDHA ratio were correlated with CGG size. However, greater variability in GUS mRNA levels were observed for both PM and control females across the full range of CGG repeat as compared to the EIF4A2/SDHA ratio. In conclusion, normalisation with multiple control genes, excluding GUS, can improve assessment of the biological significance of FMR1 mRNA-CGG size relationships.

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

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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

Investigating the relationship between FMR1 allele length and cognitive ability in children: a subtle effect of the normal allele range on the normal ability range?

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Loat, C S; Craig, G; Plomin, R; Craig, I W

2006-09-01

The FMR1 gene contains a trinucleotide repeat tract which can expand from a normal size of around 30 repeats to over 200 repeats, causing mental retardation (Fragile X Syndrome). Evidence suggests that premutation males (55-200 repeats) are susceptible to a late-onset tremor/ataxia syndrome and females to premature ovarian failure, and that intermediate alleles ( approximately 41-55 repeats) and premutations may be in excess in samples with special educational needs. We explored the relationship between FMR1 allele length and cognitive ability in 621 low ability and control children assessed at 4 and 7 years, as well as 122 students with high IQ. The low and high ability and control samples showed no between-group differences in incidence of longer alleles. In males there was a significant negative correlation between allele length and non-verbal ability at 4 years (p = 0.048), academic achievement in maths (p = 0.003) and English (p = 0.011) at 7 years, and IQ in the high ability group (p = 0.018). There was a significant negative correlation between allele length and a standardised score for IQ and general cognitive ability at age 7 in the entire male sample (p = 0.002). This suggests that, within the normal spectrum of allele length, increased repeat numbers may have a limiting influence on cognitive performance.

Capturing the fragile X premutation phenotypes: a collaborative effort across multiple cohorts.

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Hunter, Jessica Ezzell; Sherman, Stephanie; Grigsby, Jim; Kogan, Cary; Cornish, Kim

2012-03-01

To capture the neuropsychological profile among male carriers of the FMR1 premutation allele (55-200 CGG repeats) who do not meet diagnostic criteria for the late-onset fragile X-associated tremor/ataxia syndrome, FXTAS. We have initiated a multicenter collaboration that includes 3 independent cohorts, totaling 100 carriers of the premutation and 216 noncarriers. The initial focus of this collaboration has been on executive function. Four executive function scores are shared among the 3 cohorts (Controlled Oral Word Association Test, Stroop Color-Word Test, and Wechsler backward digit span and letter-number sequencing) whereas additional executive function scores are available for specific cohorts (Behavior Dyscontrol Scale, Hayling Sentence Completion Test Part B, and Wisconsin Card Sorting Test). Raw scores were analyzed by using statistical models that adjust for cohort-specific effects as well as age and education. Carriers scored significantly lower compared to noncarriers on the Stroop Color-Word Test (p = .01), Hayling Sentence Completion Test Part B (p < .01), and Behavioral Dyscontrol Scale (p = .03), with the Hayling displaying a significant age-related decline (p = .01), as assessed by an age and repeat length-group interaction. Follow-up analysis of the collective data did not identify any specific age groups or repeat length ranges (i.e., low premutation = 55-70 repeats, midpremutation = 71-100 repeats, high premutation = 101-199 repeats) that were associated with an increased risk of executive function deficits. Preliminary analyses do not indicate global executive function impairment among male carriers without FXTAS compared to noncarriers. However, impairment in inhibitory capacity may be present among a subset of carriers, though the risk factors for this group do not appear to be related to age or repeat length.

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

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Hagerman, R J; Leehey, M; Heinrichs, W; Tassone, F; Wilson, R; Hills, J; Grigsby, J; Gage, B; Hagerman, P J

2001-07-10

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

FMR1 Knockout mice: A model to study fragile X mental retardation

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Oostra, B.A.; Bakker, C.E.; Reyniers, E. [Erasmus Univ., Rotterdam (Netherlands)] [and others

1994-09-01

The fragile X syndrome is the most frequent form of inherited mental retardation in humans with an incidence of 1 in 1250 males and 1 in 2500 females. The clinical syndrome includes moderate to severe mental retardation, autistic behavior, macroorchidism, and facial features, such as long face with mandibular prognathism and large, everted ears. The molecular basis for this disease is a large expansion of a triplet repeat (CGG){sub n} in the 5{prime} untranslated region of the FMR1 gene. Due to this large expansion of the CGG repeat, the promoter region becomes methylated and the FMR1 gene is subsequently silenced. Hardly anything is known about the physiologic function of FMR1 and the pathologic mechanisms leading to these symptoms. Since the FMR1 gene is highly conserved in the mouse, we used the mouse to design a knockout model for the fragile X syndrome. These knockout mice lacking Fmrp have normal litter size suggesting that FMR1 is not essential in human gametogenesis and embryonic development. The knockout mice show the abnormalities also seen in the affected organs of human patients. Mutant mice show a gradual development through time of macroorchidism. In the knockout mice we observed cognitive defects in the form of deficits in learning (as shown by the hidden platform Morris water maze task) and behavioral abnormalities such as increased exploratory behavior and hyperactivity. Therefore this knockout mouse may serve as a valuable tool in studying the role of FMR1 in the fragile X syndrome and may serve as a model to elucidate the mechanisms involved in macroorchidism, abnormal behavior, and mental retardation.

In Silico Analysis of FMR1 Gene Missense SNPs.

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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.

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

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Stephen C Collins

2010-03-01

Full Text Available 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.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.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.

Influence of the fragile X mental retardation (FMR1) gene on the brain and working memory in men with normal FMR1 alleles

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Wang, Jun Yi; Hessl, David; Iwahashi, Christine; Cheung, Katherine; Schneider, Andrea; Hagerman, Randi J.; Hagerman, Paul J.; Rivera, Susan M.

2012-01-01

The fragile X mental retardation 1 (FMR1) gene plays an important role in the development and maintenance of neuronal circuits that are essential for cognitive functioning. We explored the functional linkage(s) among lymphocytic FMR1 gene expression, brain structure, and working memory in healthy adult males. We acquired T1-weighted and diffusion tensor imaging from 34 males (18–80 years, mean ± SD = 43.6 ± 18.4 years) with normal FMR1 alleles and performed genetic and working memory assessme...

A nonsense mutation in FMR1 causing fragile X syndrome

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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....... 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...... 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...

FMR1 epigenetic silencing commonly occurs in undifferentiated fragile X-affected embryonic stem cells.

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Avitzour, Michal; Mor-Shaked, Hagar; Yanovsky-Dagan, Shira; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Levy-Lahad, Ephrat; Epsztejn-Litman, Silvina; Eiges, Rachel

2014-11-11

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5'-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.

FMR1 Epigenetic Silencing Commonly Occurs in Undifferentiated Fragile X-Affected Embryonic Stem Cells

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Michal Avitzour

2014-11-01

Full Text Available Fragile X syndrome (FXS is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5′-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%. In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.

Fragile X syndrome and fragile X-associated tremor ataxia syndrome.

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Hall, Deborah A; Berry-Kravis, Elizabeth

2018-01-01

Fragile X-associated disorders encompass several conditions, which are caused by expansion mutations in the fragile X mental retardation 1 (FMR1) gene. Fragile X syndrome is the most common inherited etiology of intellectual disability and results from a full mutation or >200 CGG repeats in FMR1. It is associated with developmental delay, autism spectrum disorder, and seizures. Fragile X-associated tremor/ataxia syndrome is a progressive neurodegenerative disease that occurs in premutation carriers of 55-200 CGG repeats in FMR1 and is characterized by kinetic tremor, gait ataxia, parkinsonism, executive dysfunction, and neuropathy. Fragile X-associated primary ovarian insufficiency also occurs in premutation carrier women and manifests with infertility and early menopause. The diseases constituting fragile X-associated disorders differ mechanistically, due to the distinct molecular properties of premutation versus full mutations. Fragile X syndrome occurs when there is a lack of fragile X mental retardation protein (FMRP) due to FMR1 methylation and silencing. In fragile X-associated tremor ataxia syndrome, a toxic gain of function is postulated with the production of excess CGG repeat-containing FMR1 mRNA, abnormal translation of the repeat sequence leading to production of polyglycine, polyalanine, and other polypeptides and to outright deficits in translation leading to reduced FMRP at larger premutation sizes. The changes in underlying brain chemistry due to FMR1 mutations have led to therapeutic studies in these disorders, with some progress being made in fragile X syndrome. This paper also summarizes indications for testing, genetic counseling issues, and what the future holds for these disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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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.

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

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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…

Fragile X mental retardation 1 (FMR1) intron 1 methylation in blood predicts verbal cognitive impairment in female carriers of expanded FMR1 alleles: evidence from a pilot study.

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Godler, David E; Slater, Howard R; Bui, Quang M; Storey, Elsdon; Ono, Michele Y; Gehling, Freya; Inaba, Yoshimi; Francis, David; Hopper, John L; Kinsella, Glynda; Amor, David J; Hagerman, Randi J; Loesch, Danuta Z

2012-03-01

Cognitive status in females with mutations in the FMR1 (fragile X mental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X-related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. Study participants included 74 control females (Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ 200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. A methylation analysis of intron 1 CpG sites 10-12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10(-5)) after adjustment for multiple measures. The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment in FM females, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

Detection and Quantification of the Fragile X Mental Retardation Protein 1 (FMRP).

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LaFauci, Giuseppe; Adayev, Tatyana; Kascsak, Richard; Brown, W Ted

2016-12-09

The final product of FMR1 gene transcription, Fragile X Mental Retardation Protein 1 (FMRP), is an RNA binding protein that acts as a repressor of translation. FMRP is expressed in several tissues and plays important roles in neurogenesis, synaptic plasticity, and ovarian functions and has been implicated in a number of neuropsychological disorders. The loss of FMRP causes Fragile X Syndrome (FXS). In most cases, FXS is due to large expansions of a CGG repeat in FMR1 -normally containing 6-54 repeats-to over 200 CGGs and identified as full mutation (FM). Hypermethylation of the repeat induces FMR1 silencing and lack of FMRP expression in FM male. Mosaic FM males express low levels of FMRP and present a less severe phenotype that inversely correlates with FMRP levels. Carriers of pre-mutations (55-200 CGG) show increased mRNA, and normal to reduced FMRP levels. Alternative splicing of FMR1 mRNA results in 24 FMRP predicted isoforms whose expression are tissues and developmentally regulated. Here, we summarize the approaches used by several laboratories including our own to (a) detect and estimate the amount of FMRP in different tissues, developmental stages and various pathologies; and (b) to accurately quantifying FMRP for a direct diagnosis of FXS in adults and newborns.

Immune mediated disorders in women with a fragile X expansion and FXTAS.

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Jalnapurkar, Isha; Rafika, Nuva; Tassone, Flora; Hagerman, Randi

2015-01-01

Premutation alleles in fragile X mental retardation 1 (FMR1) can cause the late-onset neurodegenerative disorder, fragile X-associated tremor ataxia syndrome (FXTAS) and/or the fragile X-associated primary ovarian insufficiency in approximately 20% of heterozygotes. Heterozygotes of the FMR1 premutation have a higher incidence of immune mediated disorders such as autoimmune thyroid disorder, especially when accompanied by FXTAS motor signs. We describe the time course of symptoms of immune mediated disorders and the subsequent development of FXTAS in four women with an FMR1 CGG expansion, including three with the premutation and one with a gray zone expansion. These patients developed an immune mediated disorder followed by neurological symptoms that become consistent with FXTAS. In all patients we observed a pattern involving an initial appearance of disease symptoms-often after a period of heightened stress (depression, anxiety, divorce, general surgery) followed by the onset of tremor and/or ataxia. Immune mediated diseases are associated with the manifestations of FXTAS temporally, although further studies are needed to clarify this association. If a cause and effect relationship can be established, treatment of pre-existing immune mediated disorders may benefit patients with pathogenic FMR1 mutations. © 2014 Wiley Periodicals, Inc.

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

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Sørensen, Emilie M; Bertelsen, Freja; Weikop, Pia; Skovborg, Maria M; Banke, Tue; Drasbek, Kim R; Scheel-Krüger, Jørgen

2015-12-01

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. Monoamines were measured by HPLC: Fmr1 KO mice showed an increase in the striatal dopamine level. We conclude that the fragile X syndrome model seems to be useful for understanding certain aspects of ASD and may have translational interest for studies of social behaviour when hyperactivity coexists in ASD patients.

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

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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.

Detection and Quantification of the Fragile X Mental Retardation Protein 1 (FMRP

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Giuseppe LaFauci

2016-12-01

Full Text Available The final product of FMR1 gene transcription, Fragile X Mental Retardation Protein 1 (FMRP, is an RNA binding protein that acts as a repressor of translation. FMRP is expressed in several tissues and plays important roles in neurogenesis, synaptic plasticity, and ovarian functions and has been implicated in a number of neuropsychological disorders. The loss of FMRP causes Fragile X Syndrome (FXS. In most cases, FXS is due to large expansions of a CGG repeat in FMR1—normally containing 6–54 repeats—to over 200 CGGs and identified as full mutation (FM. Hypermethylation of the repeat induces FMR1 silencing and lack of FMRP expression in FM male. Mosaic FM males express low levels of FMRP and present a less severe phenotype that inversely correlates with FMRP levels. Carriers of pre-mutations (55–200 CGG show increased mRNA, and normal to reduced FMRP levels. Alternative splicing of FMR1 mRNA results in 24 FMRP predicted isoforms whose expression are tissues and developmentally regulated. Here, we summarize the approaches used by several laboratories including our own to (a detect and estimate the amount of FMRP in different tissues, developmental stages and various pathologies; and (b to accurately quantifying FMRP for a direct diagnosis of FXS in adults and newborns.

FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile.

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Santa María, L; Pugin, A; Alliende, M A; Aliaga, S; Curotto, B; Aravena, T; Tang, H-T; Mendoza-Morales, G; Hagerman, R; Tassone, F

2014-10-01

Carriers of an FMR1 premutation allele (55-200 CGG repeats) often develop the neurodegenerative disorders, fragile X-associated tremor/ataxia syndrome (FXTAS). Neurological signs of FXTAS, parkinsonism and rapid onset of cognitive decline have not been reported in individuals with an unmethylated full mutation (FM). Here, we report a Chilean family affected with FXS, inherited from a parent carrier of an FMR1 unmethylated full mosaic allele, who presented with a fast progressing FXTAS. This case suggests that the definition of FXTAS may need to be broadened to not only include those with a premutation but also those with an expanded allele in FM range with a lack of methylation leading to elevated FMR1-mRNA expression levels and subsequent RNA toxicity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

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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.

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

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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.

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

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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.

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

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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.

Wild-type male offspring of fmr-1+/- mothers exhibit characteristics of the fragile X phenotype.

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Zupan, Bojana; Toth, Miklos

2008-10-01

Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Males are more severely affected than heterozygote (H) females, who, as carriers, have a 50% chance of transmitting the mutated allele in each pregnancy. fmr-1 knockout (KO) mice reproduce fragile X symptoms, including hyperactivity, seizures, and abnormal sensory processing. In contrast to the expectation that wild-type (WT) males born to H (fmr-1(+/-)) mothers (H>WT) are behaviorally normal and indistinguishable from WT males born to WT mothers (WT>WT); here, we show that H>WT offspring are more active than WT>WT offspring and that their hyperactivity is similar to male KO mice born to H or KO (fmr-1(-/-)) mothers (H>KO/KO>KO). H>WT mice, however, do not exhibit seizures or abnormal sensory processing. Consistent with their hyperactivity, the effect of the D2 agonist quinpirole is reduced in H>WT as well as in H>KO and KO>KO mice compared to WT>WT offspring, suggesting a diminished feedback inhibition of dopamine release. Our data indicate that some aspects of hyperactivity and associated dopaminergic changes in 'fragile X' mice are a maternal fmr-1 genotype rather than an offspring fmr-1 genotype effect.

Fragile X-associated primary ovarian insufficiency: evidence for additional genetic contributions to severity.

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Hunter, Jessica Ezzell; Epstein, Michael P; Tinker, Stuart W; Charen, Krista H; Sherman, Stephanie L

2008-09-01

The fragile X mental retardation gene (FMR1) contains a CGG repeat sequence in its 5' untranslated region that can become unstable and expand in length from generation to generation. Alleles with expanded repeats in the range of approximately 55-199, termed premutation alleles, are associated with an increased risk for fragile-X-associated primary ovarian insufficiency (FXPOI). However, not all women who carry the premutation develop FXPOI. To determine if additional genes could explain variability in onset and severity, we used a random-effects Cox proportional hazards model to analyze age at menopause on 680 women from 225 families who have a history of fragile X syndrome and 321 women from 219 families from the general population. We tested for the presence of a residual additive genetic effect after adjustment for FMR1 repeat length, race, smoking, body mass index, and method of ascertainment. Results showed significant familial aggregation of age at menopause with an estimated additive genetic variance of 0.55-0.96 depending on the parameterization of FMR1 repeat size and definition of age at menopause (P-values ranging between 0.0002 and 0.0027). This is the first study to analyze familial aggregation of FXPOI. This result is important for proper counseling of women who carry FMR1 premutation alleles and for guidance of future studies to identify additional genes that influence ovarian insufficiency. (c) 2008 Wiley-Liss, Inc.

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

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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.

Fragile X-associated disorders: Don't miss them.

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Birch, Rachael C; Cohen, Jonathan; Trollor, Julian N

2017-01-01

Fragile X-associated disorders are a family of inherited disorders caused by expansions in the Fragile X Mental Retardation 1 (FMR1) gene. Premutation expansions of the FMR1 gene confer risk for fragile X-associated primary ovarian insufficiency and fragile X-associated tremor ataxia syndrome, as well as other medical and psychiatric comorbidities. Premutation expansions of the FMR1 gene are common in the general population. However, fragile X-associated disorders are frequently under-recognised and often misdiagnosed. The aim of this article is to describe fragile X-associated disorders and identify specific considerations for general practitioners (GPs) during identification and management of these disorders. GPs have a critical role in the identification of fragile X-associated disorders, as well as coordination of complex care needs. Prompt recognition and appropriate management of these disorders and potential medical and psychiatric comorbidities will have important implications not only for the affected patient, but also other family members who may be at risk.

FMR1 gene expansion and scans without evidence of dopaminergic deficits in parkinsonism patients.

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Hall, D A; Jennings, D; Seibyl, J; Tassone, F; Marek, K

2010-11-01

To determine if patients with parkinsonism and fragile X mental retardation 1 (FMR1) gene expansions have a striatal dopamine deficit similar to Parkinson disease (PD) patients. The authors studied three patients with parkinsonism carrying small expansions in the FMR1 gene (41-60 CGG) with [(123)I]β-CIT SPECT imaging. The patients responded to dopaminergic medications, but had preserved dopamine transporter density. These results suggest that parkinsonism associated with smaller FMR1 expansions may be related to mechanisms other than pre-synaptic dopaminergic changes and may represent a potential explanation for at least some parkinsonian cases with scans without evidence of dopaminergic deficits (SWEDD). Copyright © 2010 Elsevier Ltd. All rights reserved.

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

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Gong, Xi; Zhang, Kunshan; Wang, Yanlu; Wang, Junbang; Cui, Yaru; Li, Siguang; Luo, Yuping

2013-01-01

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

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

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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.

Activity Induces Fmr1-Sensitive Synaptic Capture of Anterograde Circulating Neuropeptide Vesicles.

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Cavolo, Samantha L; Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2016-11-16

Synaptic neuropeptide and neurotrophin stores are maintained by constitutive bidirectional capture of dense-core vesicles (DCVs) as they circulate in and out of the nerve terminal. Activity increases DCV capture to rapidly replenish synaptic neuropeptide stores following release. However, it is not known whether this is due to enhanced bidirectional capture. Here experiments at the Drosophila neuromuscular junction, where DCVs contain neuropeptides and a bone morphogenic protein, show that activity-dependent replenishment of synaptic neuropeptides following release is evident after inhibiting the retrograde transport with the dynactin disruptor mycalolide B or photobleaching DCVs entering a synaptic bouton by retrograde transport. In contrast, photobleaching anterograde transport vesicles entering a bouton inhibits neuropeptide replenishment after activity. Furthermore, tracking of individual DCVs moving through boutons shows that activity selectively increases capture of DCVs undergoing anterograde transport. Finally, upregulating fragile X mental retardation 1 protein (Fmr1, also called FMRP) acts independently of futsch/MAP-1B to abolish activity-dependent, but not constitutive, capture. Fmr1 also reduces presynaptic neuropeptide stores without affecting activity-independent delivery and evoked release. Therefore, presynaptic motoneuron neuropeptide storage is increased by a vesicle capture mechanism that is distinguished from constitutive bidirectional capture by activity dependence, anterograde selectivity, and Fmr1 sensitivity. These results show that activity recruits a separate mechanism than used at rest to stimulate additional synaptic capture of DCVs for future release of neuropeptides and neurotrophins. Synaptic release of neuropeptides and neurotrophins depends on presynaptic accumulation of dense-core vesicles (DCVs). At rest, DCVs are captured bidirectionally as they circulate through Drosophila motoneuron terminals by anterograde and retrograde

[Fragile X syndrome and white matter abnormalities: Case study of two brothers].

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Wallach, E; Bieth, E; Sevely, A; Cances, C

2017-03-01

Fragile X syndrome is the most usual cause of hereditary intellectual deficiency. Typical symptoms combine intellectual deficiency, social anxiety, intense emotional vigilance, and a characteristic facial dysmorphy. This is subsequent to a complete mutation of the FMR1 gene, considering a semidominant transmission linked to the unstable X. The expansion of the CGG triplet greater than 200 units combined with a high methylation pattern lead to a transcriptional silence of the FMR1 gene, and the protein product, the FMRP, is not synthesized. This protein is involved in synaptic plasticity. Brain MRI can show an increased volume of the caudate nucleus and hippocampus, combined with hypoplasia of the cerebellar vermis. Fragile X Associated Tremor Ataxia Syndrome (FXTAS) syndrome is a neurodegenerative disorder occurring in carriers of the premutation in FMR1. Brain MRI shows an increased T2 signal in the middle cerebellar peduncles. This syndrome is linked to a premutation in the FMR1 gene. We report here the case of two brothers presenting a typical fragile X symptomatology. Brain MRI showed hyperintensities of the middle cerebellar peduncles. Such MRI findings support the assumption of a genetic mosaicism. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

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Quartier, Angélique; Poquet, Hélène; Gilbert-Dussardier, Brigitte; Rossi, Massimiliano; Casteleyn, Anne-Sophie; Portes, Vincent des; Feger, Claire; Nourisson, Elsa; Kuentz, Paul; Redin, Claire; Thevenon, Julien; Mosca-Boidron, Anne-Laure; Callier, Patrick; Muller, Jean; Lesca, Gaetan; Huet, Frédéric; Geoffroy, Véronique; El Chehadeh, Salima; Jung, Matthieu; Trojak, Benoit; Le Gras, Stéphanie; Lehalle, Daphné; Jost, Bernard; Maury, Stéphanie; Masurel, Alice; Edery, Patrick; Thauvin-Robinet, Christel; Gérard, Bénédicte; Mandel, Jean-Louis; Faivre, Laurence; Piton, Amélie

2017-01-01

Fragile-X syndrome (FXS) is a frequent genetic form of intellectual disability (ID). The main recurrent mutagenic mechanism causing FXS is the expansion of a CGG repeat sequence in the 5′-UTR of the FMR1 gene, therefore, routinely tested in ID patients. We report here three FMR1 intragenic pathogenic variants not affecting this sequence, identified using high-throughput sequencing (HTS): a previously reported hemizygous deletion encompassing the last exon of FMR1, too small to be detected by array-CGH and inducing decreased expression of a truncated form of FMRP protein, in three brothers with ID (family 1) and two splice variants in boys with sporadic ID: a de novo variant c.990+1G>A (family 2) and a maternally inherited c.420-8A>G variant (family 3). After clinical reevaluation, the five patients presented features consistent with FXS (mean Hagerman's scores=15). We conducted a systematic review of all rare non-synonymous variants previously reported in FMR1 in ID patients and showed that six of them are convincing pathogenic variants. This study suggests that intragenic FMR1 variants, although much less frequent than CGG expansions, are a significant mutational mechanism leading to FXS and demonstrates the interest of HTS approaches to detect them in ID patients with a negative standard work-up. PMID:28176767

A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome.

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Ahmad M Khalil

2008-01-01

Full Text Available Several genome-wide transcriptomics efforts have shown that a large percentage of the mammalian genome is transcribed into RNAs, however, only a small percentage (1-2% of these RNAs is translated into proteins. Currently there is an intense interest in characterizing the function of the different classes of noncoding RNAs and their relevance to human disease. Using genomic approaches we discovered FMR4, a primate-specific noncoding RNA transcript (2.4 kb that resides upstream and likely shares a bidirectional promoter with FMR1. FMR4 is a product of RNA polymerase II and has a similar half-life to FMR1. The CGG expansion in the 5' UTR of FMR1 appears to affect transcription in both directions as we found FMR4, similar to FMR1, to be silenced in fragile X patients and up-regulated in premutation carriers. Knockdown of FMR4 by several siRNAs did not affect FMR1 expression, nor vice versa, suggesting that FMR4 is not a direct regulatory transcript for FMR1. However, FMR4 markedly affected human cell proliferation in vitro; siRNAs knockdown of FMR4 resulted in alterations in the cell cycle and increased apoptosis, while the overexpression of FMR4 caused an increase in cell proliferation. Collectively, our results demonstrate an antiapoptotic function of FMR4 and provide evidence that a well-studied genomic locus can show unexpected functional complexity. It cannot be excluded that altered FMR4 expression might contribute to aspects of the clinical presentation of fragile X syndrome and/or related disorders.

Fragile X syndrome and fragile X-associated disorders [version 1; referees: 2 approved

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Akash Rajaratnam

2017-12-01

Full Text Available Fragile X syndrome (FXS is caused by a full mutation on the FMR1 gene and a subsequent lack of FMRP, the protein product of FMR1. FMRP plays a key role in regulating the translation of many proteins involved in maintaining neuronal synaptic connections; its deficiency may result in a range of intellectual disabilities, social deficits, psychiatric problems, and dysmorphic physical features. A range of clinical involvement is also associated with the FMR1 premutation, including fragile X-associated tremor ataxia syndrome, fragile X-associated primary ovarian insufficiency, psychiatric problems, hypertension, migraines, and autoimmune problems. Over the past few years, there have been a number of advances in our knowledge of FXS and fragile X-associated disorders, and each of these advances offers significant clinical implications. Among these developments are a better understanding of the clinical impact of the phenomenon known as mosaicism, the revelation that various types of mutations can cause FXS, and improvements in treatment for FXS.

Neurological and endocrine phenotypes of fragile X carrier women.

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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. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Young Adult Female Fragile X Premutation Carriers Show Age- and Genetically-Modulated Cognitive Impairments

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Goodrich-Hunsaker, Naomi J.; Wong, Ling M.; McLennan, Yingratana; Srivastava, Siddharth; Tassone, Flora; Harvey, Danielle; Rivera, Susan M.; Simon, Tony J.

2011-01-01

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here…

Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice.

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Susanna Pietropaolo

Full Text Available BACKGROUND: No animal models of autism spectrum disorders (ASD with good construct validity are currently available; using genetic models of pathologies characterized by ASD-like deficits, but with known causes, may be therefore a promising strategy. The Fmr1-KO mouse is an example of this approach, modeling Fragile X syndrome, a well-known genetic disorder presenting ASD symptoms. The Fmr1-KO is available on different genetic backgrounds (FVB versus C57BL/6, which may explain some of the conflicting results that have been obtained with these mutants up till now. METHODS: Fmr1 KO and their wild-type littermates on both the FVB and C57BL/6 genetic backgrounds were examined on a battery of tests modeling the clinical symptoms of ASD, including the triad of core symptoms (alterations in social interaction and communication, presence of repetitive behaviors, as well as the secondary symptoms (disturbances in sensori-motor reactivity and in circadian patterns of activity, epileptic events. RESULTS: Fmr1-KO mice displayed autistic-like core symptoms of altered social interaction and occurrence of repetitive behaviors with additional hyperactivity. The genetic background modulated the effects of the Fmr1 deletion and it appears that the C57BL/6 background may be more suitable for further research on core autistic-like symptoms. CONCLUSIONS: The Fmr1-mouse line does not recapitulate all of the main core and secondary ASD symptoms, but still can be useful to elucidate the neurobiological mechanisms underlying specific ASD-like endophenotypes.

Deletion of Fmr1 results in sex-specific changes in behavior.

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Nolan, Suzanne O; Reynolds, Conner D; Smith, Gregory D; Holley, Andrew J; Escobar, Brianna; Chandler, Matthew A; Volquardsen, Megan; Jefferson, Taylor; Pandian, Ashvini; Smith, Tileena; Huebschman, Jessica; Lugo, Joaquin N

2017-10-01

In this study, we used a systemic Fmr1 knockout in order to investigate both genotype- and sex-specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear-related learning and memory. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes. Using wild-type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose-poke assay, accelerating rotarod, social partition task, three-chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects. Our results indicate several sex-specific changes in Fmr1 knockout mice, including male-specific increases in activity levels, and female-specific increases in repetitive behaviors on both the nose-poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks. These findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex-specific therapeutics.

Emerging topics in FXTAS

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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....

FMRP Associates with Cytoplasmic Granules at the Onset of Meiosis in the Human Oocyte.

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Roseanne Rosario

Full Text Available Germ cell development and primordial follicle formation during fetal life is critical in establishing the pool of oocytes that subsequently determines the reproductive lifespan of women. Fragile X-associated primary ovarian insufficiency (FXPOI is caused by inheritance of the FMR1 premutation allele and approximately 20% of women with the premutation allele develop ovarian dysfunction and premature ovarian insufficiency. However, the underlying disease mechanism remains obscure, and a potential role of FMRP in human ovarian development has not been explored. We have characterised the expression of FMR1 and FMRP in the human fetal ovary at the time of germ cell entry into meiosis through to primordial follicle formation. FMRP expression is exclusively in germ cells in the human fetal ovary. Increased FMRP expression in germ cells coincides with the loss of pluripotency-associated protein expression, and entry into meiosis is associated with FMRP granulation. In addition, we have uncovered FMRP association with components of P-bodies and stress granules, suggesting it may have a role in mRNA metabolism at the time of onset of meiosis. Therefore, this data support the hypothesis that FMRP plays a role regulating mRNAs during pivotal maturational processes in fetal germ cells, and ovarian dysfunction resulting from FMR1 premutation may have its origins during these stages of oocyte development.

High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

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Basuta, Kirin; Schneider, Andrea; Gane, Louise; Polussa, Jonathan; Woodruff, Bryan; Pretto, Dalyir; Hagerman, Randi; Tassone, Flora

2015-09-01

Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc.

A 15-year-long Southern blotting analysis of FMR1 to detect female carriers and for prenatal diagnosis of fragile X syndrome in Taiwan.

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Tzeng, C-C; Tsai, L-P; Chang, Y-K; Hung, Y-J; Chang, Y-Y; Su, Y-P; Jiang, J-J; Liang, H-M

2017-08-01

Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15-year period. In total, 725 high-risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low-risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low-risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156-1/539). A total of 100 carriers were found to be in the high-risk group, thus revealing a significantly higher frequency than the low-risk group (100/725 vs 2/3911, P<0.0001). Eight of the 14 foetuses that inherited the maternal mutant allele were verified to have a full mutation, with the smallest maternal pre-mutation allele carrying 56 CGG repeats. The overall findings confirmed that the carrier prevalence among low-risk women in Taiwan is significantly lower than that reported in western countries. Therefore, the most important step for preventing FXS in Taiwan would be to focus on high-risk women by promoting general awareness of this disease and spreading knowledge regarding the benefits of carrier screening and prenatal testing. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Simple, High-Throughput Assay for Fragile X Expanded Alleles Using Triple Repeat Primed PCR and Capillary Electrophoresis

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Lyon, Elaine; Laver, Thomas; Yu, Ping; Jama, Mohamed; Young, Keith; Zoccoli, Michael; Marlowe, Natalia

2010-01-01

Population screening has been proposed for Fragile X syndrome to identify premutation carrier females and affected newborns. We developed a PCR-based assay capable of quickly detecting the presence or absence of an expanded FMR1 allele with high sensitivity and specificity. This assay combines a triplet repeat primed PCR with high-throughput automated capillary electrophoresis. We evaluated assay performance using archived samples sent for Fragile X diagnostic testing representing a range of Fragile X CGG-repeat expansions. Two hundred five previously genotyped samples were tested with the new assay. Data were analyzed for the presence of a trinucleotide “ladder” extending beyond 55 repeats, which was set as a cut-off to identify expanded FMR1 alleles. We identified expanded FMR1 alleles in 132 samples (59 premutation, 71 full mutation, 2 mosaics) and normal FMR1 alleles in 73 samples. We found 100% concordance with previous results from PCR and Southern blot analyses. In addition, we show feasibility of using this assay with DNA extracted from dried-blood spots. Using a single PCR combined with high-throughput fragment analysis on the automated capillary electrophoresis instrument, we developed a rapid and reproducible PCR-based laboratory assay that meets many of the requirements for a first-tier test for population screening. PMID:20431035

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

NARCIS (Netherlands)

S.C. Collins (Stephen); B. Coffee (Brad); P.J. Benke (Paul); E.M. Berry-Kravis (Elizabeth); F. Gilbert (Fred); B.A. Oostra (Ben); D. Halley (Dicky); M.E. Zwick (Michael); D.J. Cutler (David); S.T. Warren (Stephen)

2010-01-01

textabstractBackground: 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

Phenotypic Involvement in Females with the FMR1 Gene Mutation.

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Riddle, J. E.; Cheema, A.; Sobesky, W. E.; Gardner, S. C.; Taylor, A. K.; Pennington, B. F.; Hagerman, R. J.

1998-01-01

A study investigated phenotypic effects seen in 114 females with premutation and 41 females (ages 18-58) with full Fragile X mental retardation gene mutation. Those with the full mutation had a greater incidence of hand-flapping, eye contact problems, special education help for reading and math, and grade retention. (Author/CR)

Dopamine transporter imaging study in parkinsonism occurring in fragile X premutation carriers.

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Ceravolo, R; Antonini, A; Volterrani, D; Rossi, C; Goldwurm, S; Di Maria, E; Kiferle, L; Bonuccelli, U; Murri, L

2005-12-27

The authors studied four patients with parkinsonism carrying the fragile X premutation using SPECT with ([23)I]FP-CIT. They found evidence of preserved presynaptic nigrostriatal function, suggesting that parkinsonism in the X fragile premutation might be related to postsynaptic dopaminergic changes or different neurotransmitter alterations.

Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome.

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Martin, Henry G S; Lassalle, Olivier; Brown, Jonathan T; Manzoni, Olivier J

2016-05-01

The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. The Fmr1 knockout (Fmr1KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC of Fmr1KO mice from 2 to 12 months. In young adult Fmr1KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-old Fmr1KO mice. We found that acute pharmacological blockade of mGlu5 receptor in 12-month-old Fmr1KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP in Fmr1KO mice, which may correlate to some of the complex age-related deficits in FXS. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Chronic minocycline treatment improves social recognition memory in adult male Fmr1 knockout mice.

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Yau, Suk Yu; Chiu, Christine; Vetrici, Mariana; Christie, Brian R

2016-10-01

Fragile X syndrome (FXS) is caused by a mutation in the Fmr1 gene that leads to silencing of the gene and a loss of its gene product, Fragile X mental retardation protein (FMRP). Some of the key behavioral phenotypes for FXS include abnormal social anxiety and sociability. Here we show that Fmr1 knock-out (KO) mice exhibit impaired social recognition when presented with a novel mouse, and they display normal social interactions in other sociability tests. Administering minocycline to Fmr1 KO mice throughout critical stages of neural development improved social recognition memory in the novel mouse recognition task. To determine if synaptic changes in the prefrontal cortex (PFC) could have played a role in this improvement, we examined PSD-95, a member of the membrane-associated guanylate kinase family, and signaling molecules (ERK1/2, and Akt) linked to synaptic plasticity in the PFC. Our analyses indicated that while minocycline treatment can enhance behavioral performance, it does not enhance expression of PSD-95, ERK1/2 or Akt in the PFC. Copyright © 2016 Elsevier B.V. All rights reserved.

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

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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.

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

International Nuclear Information System (INIS)

Jarem, Daniel A.; Delaney, Sarah

2011-01-01

Highlights: ► First structural and thermodynamic analysis of premutation allele of HD. ► Premutation allele of HD adopts a stem-loop non-B conformation. ► Healthy and premutation length stem-loops are hyper-susceptible to oxidative damage. ► Stability of stem-loop structures increases linearly with repeat length. ► 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) 10 , the premutation length sequence (CAG) 36 forms a stem-loop hairpin and contains a hot spot for DNA damage. Additionally, calorimetric analysis of a series of (CAG) 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.

Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex.

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Ventura, R; Pascucci, T; Catania, M V; Musumeci, S A; Puglisi-Allegra, S

2004-09-01

Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

OpenAIRE

Zupan, Bojana; Toth, Miklos

2008-01-01

Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Males are more severely affected than heterozygote (H) females, who, as carriers, have a 50% chance of transmitting the mutated allele in each pregnancy. fmr-1 knockout (KO) mice reproduce fragile X symptoms, including hyperactivity, seizures, and abnormal sensory processing. In contrast ...

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...

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

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Usdin, Karen; Hayward, Bruce E.; Kumari, Daman; Lokanga, Rachel A.; Sciascia, Nicholas; Zhao, Xiao-Nan

2014-01-01

The Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor/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 Fragile X mental retardation 1 (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, Fragile X mental retardation 1 protein (FMRP). Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by an FMRP deficiency, the clinical picture is turning out to be more complex than once appreciated. Added complications result from the fact that increasing repeat numbers make the alleles somatically unstable. Thus many individuals have a complex mixture of different sized alleles in different cells. 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. PMID:25101111

Inhibitors of Histone Deacetylases Are Weak Activators of the FMR1 Gene in Fragile X Syndrome Cell Lines

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Alexander A. Dolskiy

2017-01-01

Full Text Available Fragile X syndrome is the most common cause of inherited intellectual disability in humans. It is a result of CGG repeat expansion in the 5′ untranslated region (5′ UTR of the FMR1 gene. This gene encodes the FMRP protein that is involved in neuronal development. Repeat expansion leads to heterochromatinization of the promoter, gene silencing, and the subsequent absence of FMRP. To date, there is no specific therapy for the syndrome. All treatments in clinic practice provide symptomatic therapy. The development of drug therapy for Fragile X syndrome treatment is connected with the search for inhibitors of enzymes that are responsible for heterochromatinization. Here, we report a weak transcriptional activity of the FMR1 gene and the absence of FMRP protein after Fragile X syndrome cell lines treatment with two FDA approved inhibitors of histone deacetylases, romidepsin and vorinostat. We demonstrate that romidepsin, an inhibitor of class I histone deacetylases, does not activate FMR1 expression in patient cell cultures, whereas vorinostat, an inhibitor of classes I and II histone deacetylases, activates a low level of FMR1 expression in some patient cell lines.

Prenatal diagnosis of the fragile X syndrome : loss of mutation owing to a double recombinant or gene conversion event at the FMR1 locus

NARCIS (Netherlands)

Losekoot, M; Hoogendoorn, E; Olmer, R; Jansen, CCAM; Oosterwijk, JC; vandenOuweland, AMW; Halley, DJJ; Warren, ST; Willemsen, R; Oostra, BA; Bakker, E

1997-01-01

The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMR1 gene. In patients with an expanded repeat the FMR1 promoter is methylated and, consequently, the gene is silenced and no FMR1 protein (FMRP) is produced, thus leading to

Selective Spatial Processing Deficits in an At-Risk Subgroup of the Fragile X Premutation

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Hocking, Darren R.; Kogan, Cary S.; Cornish, Kim M.

2012-01-01

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated…

The FMR1 gene and fragile X-associated tremor/ataxia syndrome

NARCIS (Netherlands)

J. Brouwer (Jaap); R.A. Willemsen (Ralph); B.A. Oostra (Ben)

2009-01-01

textabstractThe CGG-repeat present in the 5′UTR of the FMR1 gene is unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In fragile X patients, a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat

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

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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.

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

International Nuclear Information System (INIS)

Milewski, Michal; Bal, Jerzy; Obersztyn, Ewa; Bocian, Ewa; Mazurczak, Tadeusz; Zygulska, Marta; Horst, Juergen; Deelen, Wout H.; Halley, Dicky J.J.

1996-01-01

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

Premutation female carriers of fragile X syndrome: a pilot study on brain anatomy and metabolism.

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Murphy, D G; Mentis, M J; Pietrini, P; Grady, C L; Moore, C J; Horwitz, B; Hinton, V; Dobkin, C S; Schapiro, M B; Rapoport, S I

1999-10-01

It was thought that premutation carriers of fragile X syndrome (FraX) have no neurobiological abnormalities, but there have been no quantitative studies of brain morphometry and metabolism. Thus the authors investigated brain structure and metabolism in premutation carriers of FraX. Eight normal IQ, healthy female permutation FraX carriers aged 39 +/- 9 years (mean +/- SD) and 32 age-sex-handedness-matched controls (39 +/- 10 years) were studied; in vivo brain morphometry was measured using volumetric magnetic resonances imaging, and regional cerebral metabolic rates for glucose were measured using positron emission tomography and (18F)-2-fluoro-2-deoxy-D-glucose. Compared with controls, FraX premutation carriers had a significant (1) decrease in volume of whole brain, and caudate and thalamic nuclei bilaterally; (2) increase in volume of hippocampus and peripheral CSF bilaterally, and third ventricle; (3) relative hypometabolism of right parietal, temporal, and occipital association areas; (4) bilateral relative hypermetabolism of hippocampus; (5) relative hypermetabolism of left cerebellum; and (6) difference in right-left asymmetry of the Wernicke and Broca language areas. Premutation carriers of FraX, as defined by analysis of peripheral lymphocytes, have abnormalities in brain anatomy and metabolism. The biological basis for this is unknown, but most likely it includes tissue heterogeneity for mutation status. The findings may be of relevance to people counseling families with FraX and to understanding other neuropsychiatric disorders which are associated with expansion of triplet repeats and genetic anticipation.

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

International Nuclear Information System (INIS)

Xu, Qin; Zhu, Zhiwei; Xu, Jialu; Gu, Weizhong; Zhao, Zhengyan

2012-01-01

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

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.

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.

Increased transient Na+ conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1-/y mouse.

Science.gov (United States)

Routh, Brandy N; Rathour, Rahul K; Baumgardner, Michael E; Kalmbach, Brian E; Johnston, Daniel; Brager, Darrin H

2017-07-01

Layer 2/3 neurons of the prefrontal cortex display higher gain of somatic excitability, responding with a higher number of action potentials for a given stimulus, in fmr1 -/y mice. In fmr1 -/y L2/3 neurons, action potentials are taller, faster and narrower. Outside-out patch clamp recordings revealed that the maximum Na + conductance density is higher in fmr1 -/y L2/3 neurons. Measurements of three biophysically distinct K + currents revealed a depolarizing shift in the activation of a rapidly inactivating (A-type) K + conductance. Realistic neuronal simulations of the biophysical observations recapitulated the elevated action potential and repetitive firing phenotype. Fragile X syndrome is the most common form of inherited mental impairment and autism. The prefrontal cortex is responsible for higher order cognitive processing, and prefrontal dysfunction is believed to underlie many of the cognitive and behavioural phenotypes associated with fragile X syndrome. We recently demonstrated that somatic and dendritic excitability of layer (L) 5 pyramidal neurons in the prefrontal cortex of the fmr1 -/y mouse is significantly altered due to changes in several voltage-gated ion channels. In addition to L5 pyramidal neurons, L2/3 pyramidal neurons play an important role in prefrontal circuitry, integrating inputs from both lower brain regions and the contralateral cortex. Using whole-cell current clamp recording, we found that L2/3 pyramidal neurons in prefrontal cortex of fmr1 -/y mouse fired more action potentials for a given stimulus compared with wild-type neurons. In addition, action potentials in fmr1 -/y neurons were significantly larger, faster and narrower. Voltage clamp of outside-out patches from L2/3 neurons revealed that the transient Na + current was significantly larger in fmr1 -/y neurons. Furthermore, the activation curve of somatic A-type K + current was depolarized. Realistic conductance-based simulations revealed that these biophysical changes in Na

Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited.

Science.gov (United States)

Niu, Yu-Qiong; Yang, Jin-Chen; Hall, Deborah A; Leehey, Maureen A; Tassone, Flora; Olichney, John M; Hagerman, Randi J; Zhang, Lin

2014-04-01

Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures. Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor. Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS. Copyright © 2014 Elsevier Ltd. All rights reserved.

Fragile X Premutation Carrier Epidemiology and Symptomatology in Israel-Results from a Tertiary Child Developmental Center.

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Gabis, Lidia V; Gruber, Noah; Berkenstadt, Michal; Shefer, Shahar; Attia, Odelia Leon; Mula, Dana; Cohen, Yoram; Elizur, Shai E

2016-10-01

Fragile X syndrome (FXS) is the most prevalent known genetically inherited cause for autism and intellectual disability. Premutation state can cause several clinical disorders as well. We aimed to perform a nesting approach to acquire data with regard to first degree relatives of index fragile X cases at the largest child development center in Israel in order to map characteristics of Israeli FXS permutation women carriers. Seventy-nine women were referred due to a related fragile X syndrome patient, mainly an offspring or sibling. General information regarding demographics, ethnicity, and associated medical conditions were collected using interviews and structured questionnaires. Thirteen (17 %) of the women who were referred as "carrier" were proven to be actually full mutation. The mean years of education were 14 (±1.51, range 12-17). Twenty-one women (27 %) originated from Tunisia (mainly from the island of Djerba). Ten women (13 %) reported delivery of their affected offspring beyond 41 gestational weeks. Twenty-two percent of women with premutation reported symptoms consistent with learning difficulties, mainly dyscalculia, and 14 % reported ADHD symptoms. Awareness about clinical disorders of the carriers was existent only in 25 % of the patients. Increased awareness and knowledge dissemination concerning premutation symptomatology and associated medical conditions are warranted. We suggest a national registry to be installed in different countries in order to identify fragile X premutation carriers at increased risk for various medical complications.

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

. Monoamines were measured by HPLC: Fmr1 KO mice showed an increase in the striatal dopamine level. We conclude that the fragile X syndrome model seems to be useful for understanding certain aspects of ASD and may have translational interest for studies of social behaviour when hyperactivity coexists in ASD...

Dementia in Fragile X-associated Tremor/Ataxia Syndrome

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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.

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.

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

2011-01-01

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. PMID:21912443

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Changes in expression of the long noncoding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells

Directory of Open Access Journals (Sweden)

Veronica Julia Peschansky

2015-08-01

Full Text Available CGG repeat expansions in the Fragile X mental retardation 1 (FMR1 gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS, or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS. However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs, whose expression is altered by repeat expansion mutations.The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. Full-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4. Furthermore, we found that in differentiating human neural precursor cells (hNPCs, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4 and MBD4.We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.

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

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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.

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.

FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome.

Science.gov (United States)

Rajan-Babu, Indhu-Shree; Lian, Mulias; Cheah, Felicia S H; Chen, Min; Tan, Arnold S C; Prasath, Ethiraj B; Loh, Seong Feei; Chong, Samuel S

2017-07-19

Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all 'embryos'. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion-negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided.

Detecting bacterial magnetite in sediments: strengths and limitations of FMR spectroscopy

Science.gov (United States)

Winklhofer, M.

2012-04-01

Ferromagnetic resonance spectroscopy (FMR) is increasingly being used as a diagnostic tool for identifying bacterial magnetite in sediments [e.g., Kopp et al. 2007; Kind et al. 2011, Roberts et al. 2011 ], the reason being that magnetic bacteria have a characteristic FMR fingerprint which is not known from inorganic geological samples [Kopp & Kirschvink, 2008]. The diagnostic FMR features of single-stranded magnetite chains are a g-value 2, quite opposite to what we know from single-stranded chains. Therefore, in order to better understand possible biogenic FMR fingerprints and to refine the screen, there is a clear need to acquire FMR spectra of magnetic bacteria with different chain configurations and, in particular, of greigite producing bacteria.

Impacts of yttrium substitution on FMR line-width and magnetic properties of nickel spinel ferrites

Energy Technology Data Exchange (ETDEWEB)

Ishaque, M., E-mail: ishaqdgk1@gmail.com [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan); Khan, Muhammad Azhar, E-mail: azhar.khan@iub.edu.pk [Department of Physics, The Islamia University of Bahawalpur, Bahawalpur 63100 (Pakistan); Ali, Irshad; Khan, Hasan M. [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan); Iqbal, M. Asif [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan); College of E & ME, National University of Science and Technology, Islamabad (Pakistan); Islam, M.U. [Department of Physics, Bahauddin Zakariya University, Multan 60800 (Pakistan); Warsi, Muhammad Farooq [Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100 (Pakistan)

2015-05-15

The influence of yttrium (Y) substitution on ferromagnetic resonance (FMR), initial permeability, and magnetic properties of NiFe{sub 2}O{sub 4} ferrites were investigated. It was observed that the FMR line-width decreases with yttrium contents for the substitution level 0≤×≤0.06. Beyond this, the FMR line-width increases with yttrium contents. The nominal composition NiY{sub 0.12}Fe{sub 1.88}O{sub 4} exhibited the smallest FMR line-width ~282 Oe. A significant change in FMR position of nickel–yttrium (Ni–Y) ferrites was observed and it found to exist between 4150 and 4600 Oe. The saturation magnetization was observed to decrease with the increase of yttrium contents and this was referred to the redistribution of cations on octahedral. The coercivity increased from 15 Oe to 59 Oe by increasing the yttrium concentration. The initial permeability decreased from 110 to 35 at 1 MHz by the incorporation of yttrium and this was attributed to the smaller grains which may obstruct the domain wall movement and impede the domain wall motion. The magnetic loss factors of substituted samples exhibit decreasing behavior in the frequency range 1 kHz to 10 MHz. The smaller FMR line-width and reduced magnetic loss factor of the investigated samples suggest the possible use of these materials in high frequency applications. - Highlights: • Influence of Y{sup 3+} substitution on the properties of nickel ferrites is investigated. • Very small FMR line-width (282 Oe) is exhibited by these substituted ferrites. • Fourfold increase in coercivity was observed for NiY{sub 0.24}Fe{sub 1.76}O{sub 4} ferrites.

76 FR 6792 - Federal Management Regulation; FMR Bulletin PBS-2011-B1; Redesignations of Federal Buildings

Science.gov (United States)

2011-02-08

... Management Regulation; FMR Bulletin PBS-2011-B1; Redesignations of Federal Buildings AGENCY: Public Buildings... announces the redesignations of three Federal buildings. DATES: Expiration Date: This bulletin announcement expires June 30, 2011. The building redesignations remain in effect until canceled or superseded by...

78 FR 36723 - Federal Management Regulation (FMR); Restrictions on International Transportation of Freight and...

Science.gov (United States)

2013-06-19

..., Sequence 1] RIN 3090-AJ34 Federal Management Regulation (FMR); Restrictions on International Transportation... Administration (GSA). ACTION: Proposed rule. SUMMARY: GSA is proposing to amend the Federal Management Regulation... Federal Management Regulation (FMR) to state clearly that this part applies to all agencies and wholly...

A Special Extract of Bacopa monnieri (CDRI-08-Restored Memory in CoCl2-Hypoxia Mimetic Mice Is Associated with Upregulation of Fmr-1 Gene Expression in Hippocampus

Directory of Open Access Journals (Sweden)

Anupama Rani

2015-01-01

Full Text Available Fragile X mental retardation protein (FMRP is a neuronal translational repressor and has been implicated in learning, memory, and cognition. However, the role of Bacopa monnieri extract (CDRI-08 in enhancing cognitive abilities in hypoxia-induced memory impairment via Fmr-1 gene expression is not known. Here, we have studied effects of CDRI-08 on the expression of Fmr-1 gene in the hippocampus of well validated cobalt chloride (CoCl2-induced hypoxia mimetic mice and analyzed the data with alterations in spatial memory. Results obtained from Morris water maze test suggest that CoCl2 treatment causes severe loss of spatial memory and CDRI-08 is capable of reversing it towards that in the normal control mice. Our semiquantitative RT-PCR, Western blot, and immunofluorescence microscopic data reveal that CoCl2-induced hypoxia significantly upregulates the expression of Hif-1α and downregulates the Fmr-1 expression in the hippocampus, respectively. Further, CDRI-08 administration reverses the memory loss and this is correlated with significant downregulation of Hif-1α and upregulation of Fmr-1 expression. Our data are novel and may provide mechanisms of hypoxia-induced impairments in the spatial memory and action of CDRI-08 in the recovery of hypoxia led memory impairment involving Fmr-1 gene encoded protein called FMRP.

The fragile X syndrome: Isolation of the FMR-1 gene and characterization of the fragile X mutation

NARCIS (Netherlands)

B.A. Oostra (Ben); A. Verkerk

1992-01-01

markdownabstractConclusion Rapid progress has been made in the analysis of the fragile X syndrome during 1991. Different groups have discovered that fragile X chromosomes are preferentially methylated. In these X chromosomes an insertion has been found in the methylated region. The FMR-1 gene,

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.

Nonlinear FMR spectra in yttrium iron garnet

Directory of Open Access Journals (Sweden)

Yu.M. Bunkov, P.M. Vetoshko, I.G. Motygullin, T.R. Safin, M.S. Tagirov, N.A. Tukmakova

2015-12-01

Full Text Available Results of demagnetizing effect studies in yttrium iron garnet Y3Fe5O12 thin films are reported. Experiments were performed on X-Band of electron paramagnetic resonance spectrometer at room temperature. The ferromagnetic resonance (FMR spectra were obtained for one-layer single crystal YIG films for different values of the applied microwave power. Nonlinear FMR spectra transformation by the microwave power increasing in various directions of magnetic field sweep was observed. It is explained by the influence of the demagnetization action of nonequilibrium magnons.

A 5 tesla superconducting magnet and cryostats for an EPR/FMR spectrometer

NARCIS (Netherlands)

Reuvekamp, E.M.C.M.; Gerritsma, G.J.; ten Kate, Herman H.J.; van de Klundert, L.J.M.

1988-01-01

A description is given of the cryogenic part of an electron paramagnetic resonance (EPR)/ferromagnetic resonance (FMR) spectrometer using Ka-band (26.5-40 GHz) and U-band (40-60 GHz) frequencies for resonance measurements on large magnetic thin-films. The unit has two cryostats; the first has a

Electric-field tunable spin diode FMR in patterned PMN-PT/NiFe structures

Energy Technology Data Exchange (ETDEWEB)

Ziętek, Slawomir, E-mail: zietek@agh.edu.pl; Skowroński, Witold; Stobiecki, Tomasz [AGH University of Science and Technology, Department of Electronics, Al. Mickiewicza 30, 30-059 Kraków (Poland); Ogrodnik, Piotr, E-mail: piotrogr@if.pw.edu.pl [AGH University of Science and Technology, Department of Electronics, Al. Mickiewicza 30, 30-059 Kraków (Poland); Faculty of Physics, Warsaw University of Technology, ul. Koszykowa 75, 00-662 Warszawa (Poland); Stobiecki, Feliks [Institute of Molecular Physics, Polish Academy of Sciences, ul. Smoluchowskiego 17, 60-179 Poznań (Poland); Dijken, Sebastiaan van [NanoSpin, Department of Applied Physics, Aalto University School of Science, P.O. Box 15100, FI-00076 Aalto (Finland); Barnaś, Józef [Faculty of Physics, Adam Mickiewicz University, ul. Umultowska 85, 61-614 Poznań (Poland); Institute of Molecular Physics, Polish Academy of Sciences, ul. Smoluchowskiego 17, 60-179 Poznań (Poland)

2016-08-15

Dynamic properties of NiFe thin films on PMN-PT piezoelectric substrate are investigated using the spin-diode method. Ferromagnetic resonance (FMR) spectra of microstrips with varying width are measured as a function of magnetic field and frequency. The FMR frequency is shown to depend on the electric field applied across the substrate, which induces strain in the NiFe layer. Electric field tunability of up to 100 MHz per 1 kV/cm is achieved. An analytical model based on total energy minimization and the Landau-Lifshitz-Gilbert equation, taking into account the magnetostriction effect, is used to explain the measured dynamics. Based on this model, conditions for optimal electric-field tunable spin diode FMR in patterned NiFe/PMN-PT structures are derived.

Recent advances in assays for the fragile X-related disorders.

Science.gov (United States)

Hayward, Bruce E; Kumari, Daman; Usdin, Karen

2017-10-01

The fragile X-related disorders are a group of three clinical conditions resulting from the instability of a CGG-repeat tract at the 5' end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55-200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging, in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings.

Visual Pathway Deficit in Female Fragile X Premutation Carriers: A Potential Endophenotype

Science.gov (United States)

Keri, Szabolcs; Benedek, Gyorgy

2009-01-01

Previous studies indicated impaired magnocellular (M) and relatively spared parvocellular (P) visual pathway functioning in patients with fragile X syndrome. In this study, we assessed M and P pathways in 22 female fragile X premutation carriers with normal intelligence and in 20 healthy non-carrier controls. Testing procedure included visual…

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.

41 CFR 102-2.30 - Where and in what formats is the FMR published?

Science.gov (United States)

2010-07-01

... formats is the FMR published? 102-2.30 Section 102-2.30 Public Contracts and Property Management Federal... published? Proposed rules are published in the Federal Register. FMR bulletins are published in looseleaf format. FMR interim and final rules are published in the following formats— (a) Federal Register under...

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.

Validation of a screening tool for the rapid and reliable detection of CGG trinucleotide repeat expansions in FMR1.

Science.gov (United States)

Basehore, Monica J; Marlowe, Natalia M; Jones, Julie R; Behlendorf, Deborah E; Laver, Thomas A; Friez, Michael J

2012-06-01

Most individuals with intellectual disability and/or autism are tested for Fragile X syndrome at some point in their lifetime. Greater than 99% of individuals with Fragile X have an expanded CGG trinucleotide repeat motif in the promoter region of the FMR1 gene, and diagnostic testing involves determining the size of the CGG repeat as well as methylation status when an expansion is present. Using a previously described triplet repeat-primed polymerase chain reaction, we have performed additional validation studies using two cohorts with previous diagnostic testing results available for comparison purposes. The first cohort (n=88) consisted of both males and females and had a high percentage of abnormal samples, while the second cohort (n=624) consisted of only females and was not enriched for expansion mutations. Data from each cohort were completely concordant with the results previously obtained during the course of diagnostic testing. This study further demonstrates the utility of using laboratory-developed triplet repeat-primed FMR1 testing in a clinical setting.

78 FR 49994 - Federal Management Regulation (FMR); Obligating Authority

Science.gov (United States)

2013-08-16

... Party Logistics (3PL) is an entity that provides multiple logistics services for use by customers. Among... Logistics (3PL) or Transportation Service Provider (TSP), issue bills of lading, and otherwise perform the... GENERAL SERVICES ADMINISTRATION 41 CFR Part 102-117 [FMR Case 2013-102-1; Docket 2013-0009...

Modelamiento de Fluidos Magnetoreológicos (FMR Producidos con Magnetita Mineral

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Claudia Molina

2015-07-01

Full Text Available Esta investigación establece la correlación entre los resultados del cambio de densidad de un FMR, expuesto a un campo magnético de intensidad variable, con los resultados de la simulación del sistema por elementos finitos, en ANSYS. A nivel de laboratorio se prepararon doce muestras de FMR, con: magnetita mineral como material magnético molida a 325, 400 y 500 mallas; aceites 20W30 y 20W50 como fluidos de transporte y, aditivos antigravitacionales y antiaglomerantes. Con el FMR de mayor estabilidad fisicoquímica (baja reactividad y sedimentación, se realizaron pruebas de variación de la densidad, en función de la intensidad de un campo magnético. La correlación de los resultados de las pruebas de laboratorio con los resultados de la simulación, fue de 0.92, lo cual indica que la predicción del comportamiento de la densidad del FMR, en presencia de un campo magnético de intensidad variable, es un procedimiento confiable.

Early Retinal Defects in Fmr1-/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

Science.gov (United States)

Perche, Olivier; Felgerolle, Chloé; Ardourel, Maryvonne; Bazinet, Audrey; Pâris, Arnaud; Rossignol, Rafaëlle; Meyer-Dilhet, Géraldine; Mausset-Bonnefont, Anne-Laure; Hébert, Betty; Laurenceau, David; Montécot-Dubourg, Céline; Menuet, Arnaud; Bizot, Jean-Charles; Pichon, Jacques; Ranchon-Cole, Isabelle; Briault, Sylvain

2018-01-01

Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1 -/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO) is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1 -/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1 -/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions.

Age- and region-specific imbalances of basal amino acids and monoamine metabolism in limbic regions of female Fmr1 knock-out mice.

Science.gov (United States)

Gruss, Michael; Braun, Katharina

2004-07-01

The Fragile X syndrome, a common form of mental retardation in humans, originates from the loss of expression of the Fragile X mental retardation gene leading to the absence of the encoded Fragile X mental retardation protein 1 (FMRP). A broad pattern of morphological and behavioral abnormalities is well described for affected humans as well as Fmr1 knock-out mice, a transgenic animal model for the human Fragile X syndrome. In the present study, we examined neurochemical differences between female Fmr1 knock-out and wildtype mice with particular focus on neurotransmission. Significant age- and region-specific differences of basal tissue neurotransmitter and metabolite levels measured by high performance liquid chromatography were found. Those differences were more numerous in juvenile animals (postnatal day (PND) 28-31) compared to adults (postnatal day 209-221). In juvenile female knock-out mice, especially aspartate and taurine were increased in cortical regions, striatum, cerebellum, and brainstem. Furthermore, compared to the wildtype animals, the juvenile knock-out mice displayed an increased level of neuronal inhibition in the hippocampus and brainstem reflected by decreased ratios of (aspartate + glutamate)/(taurine + GABA), as well as an increased dopamine (DA) turnover in cortical regions, striatum, and hippocampus. These results provide the first evidence that the lack of FMRP expression in female Fmr1 knock-out mice is accompanied by age-dependent, region-specific alterations in brain amino acids, and monoamine turnover, which might be related to the reported synaptical and behavioural alterations in these animals.

CoCr/NiFe double layers studied by FMR and VSM

NARCIS (Netherlands)

Stam, M.T.H.C.W.; Gerritsma, G.J.; Lodder, J.C.; Popma, T.J.A.

1987-01-01

CoCr/NiFe double layers were investigated by FMR and VSM. The FMR linewidth of NiFe of the double layer is about twice that of a single NiFe layer. The resonance field is the same in both cases. Using the VSM the coercive field of the CoCr layer of the double layer was obtained. It is approximately

Molecular analysis and test of linkage between the FMR-I gene and infantile autism in multiplex families

Energy Technology Data Exchange (ETDEWEB)

Hallmayer, J.; Pintado, E.; Lotspeich, L.; Spiker, D.; Kraemer, H.C.; Lee Wong, D.; Lin, A.; Herbert, J.; Cavalli-Sforza, L.L.; Ciaranello, R.D. [Stanford Univ., CA (United States)] [and others

1994-11-01

Approximately 2%-5% of autistic children show cytogenetic evidence of the fragile X syndrome. This report tests whether infantile autism in multiplex autism families arises from an unusual manifestion of the fragile X syndrome. This could arise either by expansion of the (CGG)n trinucleotide repeat in FMR-1 or from a mutation elsewhere in the gene. We studied 35 families that met stringent criteria for multiplex autism. Amplification of the trinucleotide repeat and analysis of methylation status were performed in 79 autistic children and in 31 of their unaffected siblings by Southern blot analysis. No examples of amplified repeats were seen in the autistic or control children or in their parents or grandparents. We next examined the hypothesis that there was a mutation elsewhere in the FMR-1 gene, by linkage analysis in 32 of these families. We tested four different dominant models and a recessive model. Linkage to FMR-1 could be excluded (lod score between -24 and -62) in all models by using probes DXS548, FRAXAC1, and FRAXAC2 and the CGG repeat itself. Tests for heterogeneity in this sample were negative, and the occurrence of positive lod scores in this data set could be attributed to chance. Analysis of the data by the affected-sib method also did not show evidence for linkage of any marker to autism. These results enable us to reject the hypothesis that multiplex autism arises from expansion of the (CGG)n trinucleotide repeat in FMR-1. Further, because the overall lod scores for all probes in all models tested were highly negative, linkage to FMR-1 can also be ruled out in multiplex autistic families. 35 refs., 2 figs., 5 tabs.

Early Retinal Defects in Fmr1−/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

Science.gov (United States)

Perche, Olivier; Felgerolle, Chloé; Ardourel, Maryvonne; Bazinet, Audrey; Pâris, Arnaud; Rossignol, Rafaëlle; Meyer-Dilhet, Géraldine; Mausset-Bonnefont, Anne-Laure; Hébert, Betty; Laurenceau, David; Montécot-Dubourg, Céline; Menuet, Arnaud; Bizot, Jean-Charles; Pichon, Jacques; Ranchon-Cole, Isabelle; Briault, Sylvain

2018-01-01

Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1−/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO) is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1−/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1−/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions. PMID:29681800

Early Retinal Defects in Fmr1−/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

Directory of Open Access Journals (Sweden)

Olivier Perche

2018-04-01

Full Text Available Fragile X Syndrome (FXS is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1−/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1−/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1−/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions.

Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice.

Directory of Open Access Journals (Sweden)

Cara J Westmark

Full Text Available Fragile X syndrome (FXS is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP, which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP mRNA. Cleavage of AβPP can produce β-amyloid (Aβ, a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD and Down syndrome (DS. Aβ is over-expressed in the brain of Fmr1(KO mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS, anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR-mediated long-term depression (LTD in Fmr1(KO mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ(1-42 was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.

FMR study of carbon nanotubes filled with Fe{sub 3}O{sub 4} nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Kopyl, S., E-mail: svitlanakopyl@ua.pt [NRD-TEMA, Department of Mechanical Engineering, Aveiro Institute of Nanotechnology (AIN), University of Aveiro, Aveiro 3810-193 (Portugal); Timopheev, A.A., E-mail: andreyt@ua.pt [Physics Department and I3N, University of Aveiro, Aveiro 3810-193 (Portugal); Bystrov, V.S. [Department of Materials and Ceramic Engineering and CICECO, University of Aveiro, Aveiro 3810-193 (Portugal); Institute of Mathematical Problems of Biology RAS, 142290 Pushchino (Russian Federation); Bdikin, I. [NRD-TEMA, Department of Mechanical Engineering, Aveiro Institute of Nanotechnology (AIN), University of Aveiro, Aveiro 3810-193 (Portugal); Teixeira, B.M.S. [Physics Department and I3N, University of Aveiro, Aveiro 3810-193 (Portugal); Maevskij, E. [Institute of Theoretical and Experimental Biophysics RAS, 142290 Puschino (Russian Federation); Sobolev, N.A. [Physics Department and I3N, University of Aveiro, Aveiro 3810-193 (Portugal); Sousa, A.C.M. [NRD-TEMA, Department of Mechanical Engineering, Aveiro Institute of Nanotechnology (AIN), University of Aveiro, Aveiro 3810-193 (Portugal)

2014-05-01

Ordered arrays of carbon nanotubes were produced using a non-catalytic chemical vapour deposition. The multiwall nanotubes with an inner diameter of 120 nm were grown inside porous alumina templates and then filled with a magnetic colloid of 7.5 nm Fe{sub 3}O{sub 4} particles. X-ray diffraction, electron microscopy and ferromagnetic resonance (FMR) were used to characterize structural and magnetic properties of the grown samples. To estimate the filling factor from the angular dependence of the FMR resonance field, we have derived an effective demagnetization factor for our system using the formalism proposed by Skomsky and Dubowik. Angular dependence of the FMR line width allows one to conclude about the non-uniform filling, while temperature dependent measurements reflect typical features of a superparamagnetic resonance. - Highlights: • Synthesis of CNTs inside of alumina membrane and filling it with Fe{sub 3}O{sub 4} particles. • X-ray diffraction and electron microscopy study of the samples. • Magnetic properties of the samples studied by FMR. • Filling factor has been determined from the angular dependences of FMR. • Resulted magnetic CNTs are attractive for production of magnetic nanofluids.

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

Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment

Directory of Open Access Journals (Sweden)

Deborah A. Hall

2012-05-01

Full Text Available Fragile X-associated tremor/ataxia syndrome (FXTAS is a progressive degenerative movement disorder characterized by kinetic tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. This disorder occurs in both males and females, frequently in families with children who have fragile X syndrome. The clinical features of this disorder, both classic and newly described, are summarized in this paper. In screening studies, fragile X mental retardation 1 (FMR1 gene premutation (55–200 CGG expansions are most frequently seen in men with ataxia who have tested negative for spinocerebellar ataxias. Since the original description, the classic FXTAS phenotype has now been reported in females and in carriers of smaller (45–54 CGG and larger (>200 CGG expansions in FMR1. Premutation carriers may present with a Parkinson disease phenotype or hypotension, rather than with tremor and/or ataxia. Parkinsonism and gait ataxia may also be seen in individuals with gray zone (41–54 CGG expansions. Studies regarding medication to treat the symptoms in FXTAS are few in number and suggest that medications targeted to specific symptoms, such as kinetic tremor or gait ataxia, may be most beneficial. Great progress has been made in regards to FXTAS research, likely given the readily available gene test and the screening of multiple family members, including parents and grandparents, of fragile X syndrome children. Expansion of genotypes and phenotypes in the disorder may suggest that a broader disease definition might be necessary in the future.

Characterization and validation of noninvasive oxygen tension measurements in human glioma xenografts by 19F-MR relaxometry

International Nuclear Information System (INIS)

Sanden, Boudewijn P.J. van der; Heerschap, Arend; Simonetti, Arjan W.; Rijken, Paul F.J.W.; Peters, Hans P.W.; Stbeen, Georg; Kogel, Albert J. van der

1999-01-01

Purpose: The aim of this study was to characterize and to validate noninvasive 19 F-magnetic resonance relaxometry for the measurement of oxygen tensions in human glioma xenografts in nude mice. The following three questions were addressed: 1. When perfluorocarbon compounds (PFCs) are administrated intravenously, which tumor regions are assessed by 19 F-MR relaxometry? 2. Are oxygen tension as detected by 19 F-MR relaxometry (pO 2/relaxo ) comparable to Eppendorf O 2 -electrode measurements (pO 2/electrode )? 3. Can 19 F-MR relaxometry be used to detect oxygen tension changes in tumor tissue during carbogen breathing? Methods and Materials: Slice-selective 19 F-MR relaxometry was carried out with perfluoro-15-crown-5-ether as oxygen sensor. The PFC was injected i.v. 3 days before the 19 F-MR experiments. Two datasets were acquired before and two after the start of carbogen breathing. The distribution of PFCs and necrotic areas were analyzed in 19 F-Spin Echo (SE) density MR images and T 2 -weighted 1 H-SE MR images, respectively. One day after the MR investigations, oxygen tensions were measured by oxygen electrodes in the same slice along two perpendicular tracks. These measurements were followed by (immuno)histochemical analysis of the 2D distribution of perfused microvessels, hypoxic cells, necrotic areas, and macrophages. Results: The PFCs mainly became sequestered in perfused regions at the tumor periphery; thus, 19 F-MR relaxometry probed mean oxygen tensions in these regions throughout the selected MR slice. In perfused regions of the tumor, mean pO 2/relaxo values were comparable to mean pO 2/electrode values, and varied from 0.03 to 9 mmHg. Median pO 2/electrode values of both tracks were lower than mean pO 2/relaxo values, because low pO 2/electrode values that originate from hypoxic and necrotic areas were also included in calculations of median pO 2/electrode values. After 8-min carbogen breathing, the average pO 2/relaxo increase was 3.3 ± 0.8 (SEM

The history of magnetization process influence on FMR response of particle systems

International Nuclear Information System (INIS)

Dumitru, Ioan; Stancu, Alexandru

2007-01-01

In order to express the history of magnetization process dependence on ferromagnetic resonance (FMR) for a particle system we use a statistical model based on the Preisach model. The precedent magnetization processes define in Preisach plane a configuration of particle magnetization orientations. The particles are considered single domain and saturated and are modeled as Stoner-Wohlfarth particles. The FMR response of the system is computed by summarizing the individual dynamic susceptibility of the particles, keeping account of the initial directions of the particle magnetizations. The FMR spectra of the particle system is determined considering three initial magnetization states: the demagnetized state, the positive saturated state in which all the particles have the magnetization in the static field direction and the negative saturated state when all the particles have the magnetization in the opposite field direction. The static field dependence of the resonance frequency and linewidth are determined as functions of the initial magnetization states

Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathology and mechanisms

Science.gov (United States)

Hagerman, Paul

2013-01-01

Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers. PMID:23793382

Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome.

Science.gov (United States)

Robin, Gaëlle; López, José R; Espinal, Glenda M; Hulsizer, Susan; Hagerman, Paul J; Pessah, Isaac N

2017-07-15

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological disorder that affects premutation carriers with 55-200 CGG-expansion repeats (preCGG) in FMR1, presenting with early alterations in neuronal network formation and function that precede neurodegeneration. Whether intranuclear inclusions containing DNA damage response (DDR) proteins are causally linked to abnormal synaptic function, neuronal growth and survival are unknown. In a mouse that harbors a premutation CGG expansion (preCGG), cortical and hippocampal FMRP expression is moderately reduced from birth through adulthood, with greater FMRP reductions in the soma than in the neurite, despite several-fold elevation of Fmr1 mRNA levels. Resting cytoplasmic calcium concentration ([Ca2+]i) in cultured preCGG hippocampal neurons is chronically elevated, 3-fold compared to Wt; elevated ROS and abnormal glutamatergic responses are detected at 14 DIV. Elevated µ-calpain activity and a higher p25/p35 ratio in the cortex of preCGG young adult mice indicate abnormal Cdk5 regulation. In support, the Cdk5 substrate, ATM, is upregulated by 1.5- to 2-fold at P0 and 6 months in preCGG brain, as is p-Ser1981-ATM. Bax:Bcl-2 is 30% higher in preCGG brain, indicating a greater vulnerability to apoptotic activation. Elevated [Ca2+]i, ROS, and DDR signals are normalized with dantrolene. Chronic [Ca2+]i dysregulation amplifies Cdk5-ATM signaling, possibly linking impaired glutamatergic signaling and DDR to neurodegeneration in preCGG brain. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

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

2016-01-01

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 cause 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. PMID:27255703

Magnetic characterization by SQUID and FMR of a biocompatible ferrofluid based on Fe3O4

International Nuclear Information System (INIS)

Gamarra, L F; Amaro Jr, E; Pontuschka, W M; Mamani, J B; Cornejo, D R; Oliveira, T R; Vieira, E D; Costa-Filho, A J

2009-01-01

Biocompatible superparamagnetic iron oxide nanoparticles of magnetite coated with dextran were magnetically characterized using the techniques of SQUID (superconducting quantum interference device) magnetometry and ferromagnetic resonance (FMR). The SQUID magnetometry characterization was performed by isothermal measurements under applied magnetic field using the methods of zero-field-cooling (ZFC) and field-cooling (FC). The magnetic behavior of the nanoparticles indicated their superparamagnetic nature and it was assumed that they consisted exclusively of monodomains. The transition to a blocked state was observed at the temperature T B = (43 ± 1) K for frozen ferrofluid and at (52 ± 1) K for the lyophilized ferrofluid samples. The FMR analysis showed that the derivative peak-to-peak linewidth (ΔH PP ), gyromagnetic factor (g), number of spins (N S ), and spin-spin relaxation time (T 2 ) were strongly dependent on both temperature and super-exchange interaction. This information is important for possible nanotechnological applications, mainly those which are strongly dependent on the magnetic parameters.

The magnetic-resonance properties study of nanostructures for spintronics by FMR

International Nuclear Information System (INIS)

Kupriyanova, G; Zyubin, A; Astashonok, A; Orlova, A; Prokhorenko, E

2011-01-01

In this work we report the study of the magnetic-resonance properties such as magnetic anisotropy, magnetic damping, and interlayer exchange coupling between ferromagnetic layers separated by a nonmagnetic spacer by FMR to assess their applicability in a functional magnetic tunnel junction.

EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders

Science.gov (United States)

Biancalana, Valérie; Glaeser, Dieter; McQuaid, Shirley; Steinbach, Peter

2015-01-01

Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing. PMID:25227148

41 CFR 102-2.5 - What is the Federal Management Regulation (FMR)?

Science.gov (United States)

2010-07-01

... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false What is the Federal Management Regulation (FMR)? 102-2.5 Section 102-2.5 Public Contracts and Property Management Federal... MANAGEMENT REGULATION SYSTEM Regulation System General § 102-2.5 What is the Federal Management Regulation...

Avanços tecnológicos e variabilidade genética da expansão CGG da região promotora do gene FMR1

OpenAIRE

Gigonzac, Marc Alexandre Duarte

2016-01-01

A Síndrome do X-Frágil (SXF) é a principal causa de deficiência intelectual herdável no mundo e a segunda de etiologia genética, com uma prevalência estimada de 1/4000 homens e 1/8000 mulheres. O mecanismo molecular mais comum na SXF é decorrente de alterações na expressão do gene FMR1, localizado em Xq27.3, devido a expansões trinucleotídicas CGG na região promotora e subsequente metilação do gene. Apesar de apresentar achados clínicos consistentes, os mesmos não são exclusivos, e a existênc...

Pseudo-reorganization of language cortical function at fMR imaging: a consequence of tumor-induced neurovascular uncoupling.

Science.gov (United States)

Ulmer, John L; Krouwer, Hendrikus G; Mueller, Wade M; Ugurel, M Sahin; Kocak, Mehmet; Mark, Leighton P

2003-02-01

A left-handed patient with a grade II left frontal lobe astrocytoma had spontaneous seizures causing speech arrest and uncontrolled right upper extremity movements. Word-generation functional MR (fMR) imaging showed activity nearly exclusively in the right inferior frontal gyrus. The clinical history of the speech arrest and the intraoperative mapping proved left-hemisphere language dominance. Tumor involvement of the left inferior frontal gyrus caused uncoupling of the blood oxygenation level-dependent (BOLD) and neuronal response, leading to the erroneous fMR imaging appearance of right-hemisphere language dominance. Discrepancies between BOLD and intraoperative mapping in areas near lesions illustrate the complementary nature of these techniques.

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice

Science.gov (United States)

Radwan, Basma; Dvorak, Dino; Fenton, André

2016-01-01

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). Absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions. PMID:26792400

77 FR 40358 - Federal Management Regulation; FMR Bulletin PBS-2012-03; Redesignations of Federal Buildings...

Science.gov (United States)

2012-07-09

... Management Regulation; FMR Bulletin PBS-2012-03; Redesignations of Federal Buildings: Correction AGENCY: Public Buildings Service (PBS), General Services Administration (GSA). ACTION: Notice of a bulletin..., 2012, a bulletin announcing the designation and redesignation of three Federal buildings. Inadvertently...

77 FR 35393 - Federal Management Regulation; FMR Bulletin PBS-2012-03; Redesignations of Federal Buildings

Science.gov (United States)

2012-06-13

... Management Regulation; FMR Bulletin PBS-2012-03; Redesignations of Federal Buildings AGENCY: Public Buildings... bulletin announces the designation and redesignation of three Federal buildings. Expiration Date: This bulletin announcement expires October 31, 2012. The building designation and redesignations remains in...

Altered structural brain connectome in young adult fragile X premutation carriers.

Science.gov (United States)

Leow, Alex; Harvey, Danielle; Goodrich-Hunsaker, Naomi J; Gadelkarim, Johnson; Kumar, Anand; Zhan, Liang; Rivera, Susan M; Simon, Tony J

2014-09-01

Fragile X premutation carriers (fXPC) are characterized by 55-200 CGG trinucleotide repeats in the 5' untranslated region on the Xq27.3 site of the X chromosome. Clinically, they are associated with the fragile X-Associated Tremor/Ataxia Syndrome, a late-onset neurodegenerative disorder with diffuse white matter neuropathology. Here, we conducted first-ever graph theoretical network analyses in fXPCs using 30-direction diffusion-weighted magnetic resonance images acquired from 42 healthy controls aged 18-44 years (HC; 22 male and 20 female) and 46 fXPCs (16 male and 30 female). Globally, we found no differences between the fXPCs and HCs within each gender for all global graph theoretical measures. In male fXPCs, global efficiency was significantly negatively associated with the number of CGG repeats. For nodal measures, significant group differences were found between male fXPCs and male HCs in the right fusiform and the right ventral diencephalon (for nodal efficiency), and in the left hippocampus [for nodal clustering coefficient (CC)]. In female fXPCs, CC in the left superior parietal cortex correlated with counting performance in an enumeration task. Copyright © 2014 Wiley Periodicals, Inc.

41 CFR 102-2.140 - What elements of plain language appear in the FMR?

Science.gov (United States)

2010-07-01

... MANAGEMENT REGULATION SYSTEM Plain Language Regulatory Style § 102-2.140 What elements of plain language... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false What elements of plain language appear in the FMR? 102-2.140 Section 102-2.140 Public Contracts and Property Management Federal...

76 FR 54772 - Federal Management Regulation; FMR Bulletin PBS-2011-B2; Redesignations of Federal Buildings

Science.gov (United States)

2011-09-02

... Management Regulation; FMR Bulletin PBS-2011-B2; Redesignations of Federal Buildings AGENCY: Public Buildings... announces the designation and redesignation of two Federal buildings. Expiration Date: This bulletin announcement expires January 31, 2012. The building designation and redesignation remains in effect until...

75 FR 69080 - Federal Management Regulation; FMR Bulletin PBS-2010-B5; Redesignations of Federal Buildings

Science.gov (United States)

2010-11-10

... Management Regulation; FMR Bulletin PBS-2010-B5; Redesignations of Federal Buildings AGENCY: Public Buildings... announces the designation and redesignation of two Federal buildings. DATES: Expiration Date: This bulletin announcement expires April 30, 2011. The building designation and redesignation remains in effect until...

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.

CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve.

Science.gov (United States)

Lekovich, Jovana; Man, Limor; Xu, Kangpu; Canon, Chelsea; Lilienthal, Debra; Stewart, Joshua D; Pereira, Nigel; Rosenwaks, Zev; Gerhardt, Jeannine

2017-12-21

PurposeFragile X premutation (PM) carriers may experience difficulties conceiving a child probably due to fragile X-associated diminished ovarian reserve (FXDOR). We investigated which subgroups of carriers with a PM are at higher risk of FXDOR, and whether the number of AGG interruptions within the repeat sequence further ameliorates the risk.MethodsWe compared markers of ovarian reserve, including anti-Müllerian hormone, antral follicle count, and number of oocytes retrieved between different subgroups of patients with a PM.ResultsWe found that carriers with midrange repeats size (70-90 CGG) demonstrate significantly lower ovarian reserve. Additionally, the number of AGG interruptions directly correlated with parameters of ovarian reserve. Patients with longer uninterrupted CGG repeats post-AGG interruptions had the lowest ovarian reserve.ConclusionThis study connects AGG interruptions and certain CGG repeat length to reduced ovarian reserve in carriers with a PM. A possible explanation for our findings is the proposed gonadotoxicity of the FMR1 transcripts. Reduction of AGG interruptions could increase the likelihood that secondary RNA structures in the FMR1 messenger RNA are formed, which could cause cell dysfunction within the ovaries. These findings may provide women with guidance regarding their fertility potential and accordingly assist with their family planning.GENETICS in MEDICINE advance online publication, 21 December 2017; doi:10.1038/gim.2017.220.

75 FR 44264 - Federal Management Regulation; FMR Bulletin PBS-2010-B4; Redesignation of Federal Building

Science.gov (United States)

2010-07-28

... Management Regulation; FMR Bulletin PBS-2010-B4; Redesignation of Federal Building AGENCY: Public Buildings... announces the redesignation of a Federal building. DATES: Expiration Date: This bulletin expires December 31, 2010. However, the building redesignation announced by this bulletin will remain in effect until...

41 CFR 102-2.145 - To what do pronouns refer when used in the FMR?

Science.gov (United States)

2010-07-01

... MANAGEMENT REGULATION SYSTEM Plain Language Regulatory Style § 102-2.145 To what do pronouns refer when used... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false To what do pronouns refer when used in the FMR? 102-2.145 Section 102-2.145 Public Contracts and Property Management Federal...

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.

One dimensional FexCo1-x nanowires; ferromagnetic resonance and magnetization dynamics

Directory of Open Access Journals (Sweden)

Shehreen Aslam

2017-05-01

Full Text Available Soft magnetic nanowires (NWs are widely used for microwave and mm-wave components. The investigation of magnetization damping behavior of NWs have attracted great interest due to large influence of loss to the device, like integrated microwave device, magnetic sensors, and magnetic random access memory. With increasing operational frequency and degree of integration, the requirements to characterize 1-dimensional NWs become increasingly high. The purpose of this work is to study the magnetization dynamics in FexCo1-x NWs. A series of FexCo1-x (x=0, 0.25, 0.5, 0.75, 1 NWs were grown by controlled electro-deposition. By adjusting FexCo1-x concentration (x=0 to 1, the saturation magnetization, increased more than 20%. Ferromagnetic resonance (FMR both in field and frequency sweep mode are employed to characterize the NWs in flip-chip geometry. It is observed that FMR field (Hr increases with increase in applied frequency. At a fixed frequency, Fe NWs resonate at a lower field than the Co substituted NWs. FMR field linewidth (ΔH as well as frequency width (Δf are largest for Co NWs and decreased for Fe NWs. Whereas ΔH and Δf decreased further for FexCo1-x nanowires with increasing x.

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.

Boyne View House, Dublin Road, Drogheda, Louth.

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.

Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

Science.gov (United States)

Dvorak, Dino; Radwan, Basma; Sparks, Fraser T.; Talbot, Zoe Nicole

2018-01-01

Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal Cornu Ammonis 1 (CA1) hippocampus. During a shocked-place avoidance task, slow gamma (SG) (30–50 Hz) dominates mid-frequency gamma (MG) (70–90 Hz) oscillations 2–3 s before successful avoidance, but not failures. Wild-type (WT) but not Fmr1-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdom) decrease in WT but not in cognitively inflexible Fmr1-null mice. During SGdom, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, WT ensembles represent distant locations near the currently correct shock zone, but Fmr1-null ensembles represent the formerly correct zone. These findings indicate that recollection occurs when CA1 SG dominates MG and that accurate recollection of inappropriate memories explains Fmr1-null cognitive inflexibility. PMID:29346381

Measurement of magnetization of Ga1−xMnxAs by ferromagnetic resonance

International Nuclear Information System (INIS)

Hagmann, J.A.; Traudt, K.; Zhou, Y.Y.; Liu, X.; Dobrowolska, M.; Furdyna, J.K.

2014-01-01

In this paper, we extend ferromagnetic resonance (FMR) studies of thin layers of the ferromagnetic semiconductor Ga 1−x Mn x As to the analysis of the integrated intensity of the resonance in order to obtain information on the total spin in the sample directly involved in ferromagnetically-ordered magnetization. A theoretical model is proposed for the dependences of the FMR integrated intensity and linewidth on the orientation of the applied magnetic field as the field direction is varied from in-plane to normal-to-the-plane of the Ga 1−x Mn x As layer. The strain-induced magnetic anisotropy of Ga 1−x Mn x As presents a significant challenge to conventional FMR linewidth and integrated intensity models. The new model predicts that the integrated FMR intensity is proportional to the saturation magnetization M S of the sample, with the constant of proportionality varying as a function of the polar and azimuthal angles of the applied magnetic field. The angular and temperature behaviors of the integrated intensity and linewidth of the FMR predicted by the proposed model are in good qualitative agreement with measurements. - Highlights: • We extend ferromagnetic resonance to the analysis of total magnetization of thin film Ga 1−x Mn x As. • We formulate a theoretical model for FMR integrated intensity and linewidth. • The model predicts that integrated FMR intensity is proportional to magnetization. • Predictions made by the model are in good qualitative agreement with measurements

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.

High specific radioactivity (1R,2S)-4-[18F]fluorometaraminol: a PET radiotracer for mapping sympathetic nerves of the heart

International Nuclear Information System (INIS)

Langer, Oliver; Valette, Heric; Dolle, Frederic; Halldin, Christer; Loc'h, Christian; Fuseau, Chantal; Coulon, Christine; Ottaviani, Michele; Bottlaender, Michel; Maziere, Bernard; Crouzel, Christian

2000-01-01

The radiolabeled catecholamine analogue (1R,2S)-6-[ 18 F]fluorometaraminol (6-[ 18 F]FMR) is a substrate for the neuronal norepinephrine transporter. It has been used as a positron emission tomography (PET) ligand to map sympathetic nerves in dog heart. 6-[ 18 F]FMR could be only synthesized with low specific radioactivity, which precluded its use in human subjects. We have recently prepared (1R,2S)-4-[ 18 F]fluorometaraminol (4-[ 18 F]FMR), a new fluoro-analogue of metaraminol, with high specific radioactivity (56-106 GBq/μmol). In the present study, we demonstrate in rats that 4-[ 18 F]FMR possesses similar affinity toward myocardial norepinephrine transport mechanisms as 6-[ 18 F]FMR. When compared with control animals, an 80% and 76% reduction in myocardial uptake was observed in animals pretreated with desipramine (an inhibitor of the neuronal norepinephrine transporter) and with reserpine (a blocker of the vesicular storage of monoamines), respectively. The entire radioactivity in rat myocardium represented unmetabolized parent tracer as determined by high performance liquid chromatography analysis of tissue extracts. In dogs, myocardial kinetics of 4-[ 18 F]FMR were assessed using PET. A rapid and high uptake was observed, followed by prolonged cardiac retention. A heart-to-lung ratio of 15 was reached 10 min after injection of the radiotracer. Pretreatment with desipramine reduced the heart half-life of 4-[ 18 F]FMR by 90% compared with control. Moreover, an infusion of tyramine caused a rapid decline of radioactivity in the heart. This demonstrates that 4-[ 18 F]FMR specifically visualizes sympathetic neurons in dog heart. High specific radioactivity 4-[ 18 F]FMR is a promising alternative to 6-[ 18 F]FMR for myocardial neuronal mapping with PET in humans

High specific radioactivity (1R,2S)-4-[{sup 18}F]fluorometaraminol: a PET radiotracer for mapping sympathetic nerves of the heart

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Langer, Oliver; Valette, Heric; Dolle, Frederic E-mail: dolle@dsvidf.cea.fr; Halldin, Christer; Loc' h, Christian; Fuseau, Chantal; Coulon, Christine; Ottaviani, Michele; Bottlaender, Michel; Maziere, Bernard; Crouzel, Christian

2000-04-01

The radiolabeled catecholamine analogue (1R,2S)-6-[{sup 18}F]fluorometaraminol (6-[{sup 18}F]FMR) is a substrate for the neuronal norepinephrine transporter. It has been used as a positron emission tomography (PET) ligand to map sympathetic nerves in dog heart. 6-[{sup 18}F]FMR could be only synthesized with low specific radioactivity, which precluded its use in human subjects. We have recently prepared (1R,2S)-4-[{sup 18}F]fluorometaraminol (4-[{sup 18}F]FMR), a new fluoro-analogue of metaraminol, with high specific radioactivity (56-106 GBq/{mu}mol). In the present study, we demonstrate in rats that 4-[{sup 18}F]FMR possesses similar affinity toward myocardial norepinephrine transport mechanisms as 6-[{sup 18}F]FMR. When compared with control animals, an 80% and 76% reduction in myocardial uptake was observed in animals pretreated with desipramine (an inhibitor of the neuronal norepinephrine transporter) and with reserpine (a blocker of the vesicular storage of monoamines), respectively. The entire radioactivity in rat myocardium represented unmetabolized parent tracer as determined by high performance liquid chromatography analysis of tissue extracts. In dogs, myocardial kinetics of 4-[{sup 18}F]FMR were assessed using PET. A rapid and high uptake was observed, followed by prolonged cardiac retention. A heart-to-lung ratio of 15 was reached 10 min after injection of the radiotracer. Pretreatment with desipramine reduced the heart half-life of 4-[{sup 18}F]FMR by 90% compared with control. Moreover, an infusion of tyramine caused a rapid decline of radioactivity in the heart. This demonstrates that 4-[{sup 18}F]FMR specifically visualizes sympathetic neurons in dog heart. High specific radioactivity 4-[{sup 18}F]FMR is a promising alternative to 6-[{sup 18}F]FMR for myocardial neuronal mapping with PET in humans.

Síndrome frágil X: correlación clínica, citogenética y molecular en una familia

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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

Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome

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Xu Zhao-Hui

2012-05-01

Full Text Available Abstract Background Fragile X syndrome (FXS is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP, encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP by D1 receptor is impaired in Fmr1 knockout (KO mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied. Results Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2 in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs at Tyr-1472 (p-NR2B-Tyr1472 in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice. Conclusion The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.

THE GAS PHASE MASS METALLICITY RELATION FOR DWARF GALAXIES: DEPENDENCE ON STAR FORMATION RATE AND HI GAS MASS

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Jimmy; Tran, Kim-Vy [George P. and Cynthia W. Mitchell Institute for Fundamental Physics and Astronomy, Department of Physics and Astronomy, Texas A and M University, College Station, TX 77843 (United States); Saintonge, Amélie; Accurso, Gioacchino [Department of Physics and Astronomy, University College London, Gower Place, London WC1E 6BT (United Kingdom); Brough, Sarah; Oliva-Altamirano, Paola [Australian Astronomical Observatory, P.O. Box 915, North Ryde, NSW 1670 (Australia)

2015-10-20

Using a sample of dwarf galaxies observed using the VIMOS IFU on the Very Large Telescope, we investigate the mass–metallicity relation (MZR) as a function of star formation rate (FMR{sub SFR}) as well as HI-gas mass (FMR{sub HI}). We combine our IFU data with a subsample of galaxies from the ALFALFA HI survey crossmatched to the Sloan Digital Sky Survey (SDSS) to study the FMR{sub SFR} and FMR{sub HI} across the stellar mass range 10{sup 6.6}–10{sup 8.8} M{sub ⊙}, with metallicities as low as 12 + log(O/H) = 7.67. We find the 1σ mean scatter in the MZR to be 0.05 dex. The 1σ mean scatter in the FMR{sub SFR} (0.02 dex) is significantly lower than that of the MZR. The FMR{sub SFR} is not consistent between the IFU observed galaxies and the ALFALFA/SDSS galaxies for SFRs lower than 10{sup −2.4} M{sub ⊙} yr{sup −1}, however, this could be the result of limitations of our measurements in that regime. The lowest mean scatter (0.01 dex) is found in the FMR{sub HI}. We also find that the FMR{sub HI} is consistent between the IFU observed dwarf galaxies and the ALFALFA/SDSS crossmatched sample. We introduce the fundamental metallicity luminosity counterpart to the FMR, again characterized in terms of SFR (FML{sub SFR}) and HI-gas mass (FML{sub HI}). We find that the FML{sub HI} relation is consistent between the IFU observed dwarf galaxy sample and the larger ALFALFA/SDSS sample. However, the 1σ scatter for the FML{sub HI} relation is not improved over the FMR{sub HI} scenario. This leads us to conclude that the FMR{sub HI} is the best candidate for a physically motivated fundamental metallicity relation.

Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

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Limor Man

2017-09-01

Full Text Available Fragile X syndrome (FXS, is caused by a loss-of-function mutation in the FMR1 gene located on the X-chromosome, which leads to the most common cause of inherited intellectual disability in males and the leading single-gene defect associated with autism. A full mutation (FM is represented by more than 200 CGG repeats within the FMR1 gene, resulting in FXS. A FM is inherited from women carrying a FM or a premutation (PM; 55–200 CGG repeats allele. PM is associated with phenotypes distinct from those associated with FM. Some manifestations of the PM are unique; fragile-X-associated tremor/ataxia syndrome (FXTAS, and fragile-X-associated primary ovarian insufficiency (FXPOI, while others tend to be non-specific such as intellectual disability. In addition, women carrying a PM may suffer from subfertility or infertility. There is a need to elucidate whether the impairment of ovarian function found in PM carriers arises during the primordial germ cell (PGC development stage, or due to a rapidly diminishing oocyte pool throughout life or even both. Due to the possibility of expansion into a FM in the next generation, and other ramifications, carrying a PM can have an enormous impact on one’s life; therefore, preconception counseling for couples carrying the PM is of paramount importance. In this review, we will elaborate on the clinical manifestations in female PM carriers and propose the definition of fragile-X-associated diminished ovarian reserve (FXDOR, then we will review recent scientific findings regarding possible mechanisms leading to FXDOR and FXPOI. Lastly, we will discuss counseling, preventative measures and interventions available for women carrying a PM regarding different aspects of their reproductive life, fertility treatment, pregnancy, prenatal testing, contraception and fertility preservation options.

Fragile X protein in newborn dried blood spots.

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Adayev, Tatyana; LaFauci, Giuseppe; Dobkin, Carl; Caggana, Michele; Wiley, Veronica; Field, Michael; Wotton, Tiffany; Kascsak, Richard; Nolin, Sarah L; Glicksman, Anne; Hosmer, Nicole; Brown, W Ted

2014-10-28

The fragile X syndrome (FXS) results from mutation of the FMR1 gene that prevents expression of its gene product, FMRP. We previously characterized 215 dried blood spots (DBS) representing different FMR1 genotypes and ages with a Luminex-based immunoassay (qFMRP). We found variable FMRP levels in the normal samples and identified affected males by the drastic reduction of FMRP. Here, to establish the variability of expression of FMRP in a larger random population we quantified FMRP in 2,000 anonymous fresh newborn DBS. We also evaluated the effect of long term storage on qFMRP by retrospectively assaying 74 aged newborn DBS that had been stored for 7-84 months that included normal and full mutation individuals. These analyses were performed on 3 mm DBS disks. To identify the alleles associated with the lowest FMRP levels in the fresh DBS, we analyzed the DNA in the samples that were more than two standard deviations below the mean. Analysis of the fresh newborn DBS revealed a broad distribution of FMRP with a mean approximately 7-fold higher than that we previously reported for fresh DBS in normal adults and no samples whose FMRP level indicated FXS. DNA analysis of the lowest FMRP DBS showed that this was the low extreme of the normal range and included a female carrying a 165 CGG repeat premutation. In the retrospective study of aged newborn DBS, the FMRP mean of the normal samples was less than 30% of the mean of the fresh DBS. Despite the degraded signal from these aged DBS, qFMRP identified the FXS individuals. The assay showed that newborn DBS contain high levels of FMRP that will allow identification of males and potentially females, affected by FXS. The assay is also an effective screening tool for aged DBS stored for up to four years.

Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations.

Science.gov (United States)

Man, Limor; Lekovich, Jovana; Rosenwaks, Zev; Gerhardt, Jeannine

2017-01-01

Fragile X syndrome (FXS), is caused by a loss-of-function mutation in the FMR1 gene located on the X-chromosome, which leads to the most common cause of inherited intellectual disability in males and the leading single-gene defect associated with autism. A full mutation (FM) is represented by more than 200 CGG repeats within the FMR1 gene, resulting in FXS. A FM is inherited from women carrying a FM or a premutation (PM; 55-200 CGG repeats) allele. PM is associated with phenotypes distinct from those associated with FM. Some manifestations of the PM are unique; fragile-X-associated tremor/ataxia syndrome (FXTAS), and fragile-X-associated primary ovarian insufficiency (FXPOI), while others tend to be non-specific such as intellectual disability. In addition, women carrying a PM may suffer from subfertility or infertility. There is a need to elucidate whether the impairment of ovarian function found in PM carriers arises during the primordial germ cell (PGC) development stage, or due to a rapidly diminishing oocyte pool throughout life or even both. Due to the possibility of expansion into a FM in the next generation, and other ramifications, carrying a PM can have an enormous impact on one's life; therefore, preconception counseling for couples carrying the PM is of paramount importance. In this review, we will elaborate on the clinical manifestations in female PM carriers and propose the definition of fragile-X-associated diminished ovarian reserve (FXDOR), then we will review recent scientific findings regarding possible mechanisms leading to FXDOR and FXPOI. Lastly, we will discuss counseling, preventative measures and interventions available for women carrying a PM regarding different aspects of their reproductive life, fertility treatment, pregnancy, prenatal testing, contraception and fertility preservation options.

Observation of ferromagnetic resonance in strontium ruthenate (SrRuO3)

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Langner, Matthew C.; Kantner, Colleen L.S.; Chu, Y.H.; Martin, Lane M.; Yu, Pu; Ramesh, R.; Orenstein, Joe

2008-12-03

We report the observation of ferromagnetic resonance (FMR) in SrRuO3 using the time-resolved magnetooptical Kerr effect. The FMR oscillations in the time-domain appear in response to a sudden, optically induced change in the direction of easy-axis anistropy. The high FMR frequency, 250 GHz, and large Gilbert damping parameter, alpha ~;; 1, are consistent with strong spin-orbit coupling. We find that the parameters associated with the magnetization dynamics, including alpha, have a non-monotonic temperature dependence, suggestive of a link to the anomalous Hall effect.

Ferromagnetic resonance study of structure and relaxation of magnetization in NiFe/Ru superlattices

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Alayo, W., E-mail: willian.rodriguez@ufpel.edu.br [Depto. de Física, Univ. Federal de Pelotas, Campus Universitário, 96010-900, Pelotas, RS (Brazil); Landi Jr, S. [Instituto Federal Goiano, Rio Verde 75901-970 (Brazil); Pelegrini, F. [Instituto de Física, Universidade Federal de Goiás, Goiânia 74001-970 (Brazil); Baggio-Saitovitch, E. [Centro Brasileiro de Pesquisas Físicas, Rio de Janeiro 22290-180 (Brazil)

2014-01-15

The structural properties and relaxation processes of magnetization in [Ni{sub 81}Fe{sub 19}(t{sub 1})/Ru(t{sub 2})]{sub N} superlattices (N=number of bilayers) were analyzed by ferromagnetic resonance (FMR) with a fixed microwave frequency. One series of samples was deposited with constant NiFe layer thickness (t{sub 1}) and variable Ru layer thickness (t{sub 2}); the other series, with constant t{sub 2} and variable t{sub 1}. A single FMR mode was observed for t{sub 2}<15 Å and t{sub 1}>75 Å and it has been attributed to the resonance of the exchange-coupled NiFe layers across the Ru interlayers. For the other values of t{sub 1} and t{sub 2}, several FMR modes appeared and they were associated to non-coupled magnetic phases with different effective magnetization formed during the multilayer growth. The FMR linewidths were analyzed as a function of the magnetic layer thickness and a strong dependence on t{sub 1}{sup −2} was observed. It was attributed to the contribution of the two-magnon scattering mechanism for the linewidth. - Highlights: • We present a study of magnetic properties of NiFe/Ru superlattices by ferromagnetic resonance (FMR). • The FMR spectra show several modes for large Ru thicknesses and for low NiFe thicknesses. • The above behavior is correlated with the interlayer exchange coupling. • The two-magnon scattering mechanism is revealed by the dependence of the FMR linewidth on the NiFe thickness.

Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report.

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Saldarriaga, Wilmar; Ruiz, Fabian Andres; Tassone, Flora; Hagerman, Randi

2017-09-01

Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. Cytogenetic testing detected the presence of a complete trisomy 21. A combination of PCR and Southern blot analysis was utilized to document the presence of the FMR1 full mutation. The patient has physical characteristics and behavioural disturbances typical of both FXS and DS, which were confirmed by molecular testing. Her treatment plan included a trial of sertraline because of the severity of her shyness and lack of language. She had an excellent response to sertraline with improvement in shyness and social interactions, particularly with family members. In this study, we report the case of a woman with both FXS and DS, which is the fifth case of FXS and DS in the world's literature. The patient is from Ricaurte, a small town in Colombia, South America, where there is the world's highest prevalence for FXS. © 2016 John Wiley & Sons Ltd.

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice.

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Seese, Ronald R; Wang, Kathleen; Yao, Yue Qin; Lynch, Gary; Gall, Christine M

2014-11-25

Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.

Decreased surface expression of the δ subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome.

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Zhang, Nianhui; Peng, Zechun; Tong, Xiaoping; Lindemeyer, A Kerstin; Cetina, Yliana; Huang, Christine S; Olsen, Richard W; Otis, Thomas S; Houser, Carolyn R

2017-11-01

While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABA A receptors (GABA A Rs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the δ subunit of the GABA A R, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two δ subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that δ subunit-containing GABA A Rs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in δ subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the δ subunit led to studies of surface expression of the δ subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total δ subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the δ subunit in these mice. No significant changes were observed in total or surface expression of the α4 subunit protein, a major partner of the δ subunit in the forebrain. Postembedding immunogold labeling for the δ subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with

Summing the strokes: energy economy in northern elephant seals during large-scale foraging migrations.

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Maresh, J L; Adachi, T; Takahashi, A; Naito, Y; Crocker, D E; Horning, M; Williams, T M; Costa, D P

2015-01-01

The energy requirements of free-ranging marine mammals are challenging to measure due to cryptic and far-ranging feeding habits, but are important to quantify given the potential impacts of high-level predators on ecosystems. Given their large body size and carnivorous lifestyle, we would predict that northern elephant seals (Mirounga angustirostris) have elevated field metabolic rates (FMRs) that require high prey intake rates, especially during pregnancy. Disturbance associated with climate change or human activity is predicted to further elevate energy requirements due to an increase in locomotor costs required to accommodate a reduction in prey or time available to forage. In this study, we determined the FMRs, total energy requirements, and energy budgets of adult, female northern elephant seals. We also examined the impact of increased locomotor costs on foraging success in this species. Body size, time spent at sea and reproductive status strongly influenced FMR. During the short foraging migration, FMR averaged 90.1 (SE = 1.7) kJ kg(-1)d(-1) - only 36 % greater than predicted basal metabolic rate. During the long migration, when seals were pregnant, FMRs averaged 69.4 (±3.0) kJ kg(-1)d(-1) - values approaching those predicted to be necessary to support basal metabolism in mammals of this size. Low FMRs in pregnant seals were driven by hypometabolism coupled with a positive feedback loop between improving body condition and reduced flipper stroking frequency. In contrast, three additional seals carrying large, non-streamlined instrumentation saw a four-fold increase in energy partitioned toward locomotion, resulting in elevated FMRs and only half the mass gain of normally-swimming study animals. These results highlight the importance of keeping locomotion costs low for successful foraging in this species. In preparation for lactation and two fasting periods with high demands on energy reserves, migrating elephant seals utilize an economical foraging

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

OpenAIRE

Lim, Chae-Seok; Hoang, Elizabeth T.; Viar, Kenneth E.; Stornetta, Ruth L.; Scott, Michael M.; Zhu, J. Julius

2014-01-01

Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation. Lim et al. find that compounds activating serotonin (5HT) subtype 2B receptors or dopamine (DA) subtype 1-like receptors and those inhibiting 5HT2A-Rs or D2-Rs enhance Ras signaling, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Combining 5HT and DA compounds at low doses synergistically restored normal learning. This suggests that properly dosed an...

Modeling Fragile X Syndrome in Drosophila

Science.gov (United States)

Drozd, Małgorzata; Bardoni, Barbara; Capovilla, Maria

2018-01-01

Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5′-UTR of the gene. Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. This enables a much easier approach for FMR1 genetic studies. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. These studies have the potential to aid the discovery of pharmacological therapies for FXS. PMID:29713264

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

Science.gov (United States)

Lim, Chae-Seok; Hoang, Elizabeth T; Viar, Kenneth E; Stornetta, Ruth L; Scott, Michael M; Zhu, J Julius

2014-02-01

Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

The fragile x-associated tremor and ataxia syndrome (FXTAS A síndrome de tremor e ataxia associada ao X frágil (FXTAS

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Leonardo Pires Capelli

2010-10-01

Full Text Available FXTAS (Fragile X-associated tremor and ataxia syndrome is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS, the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.A FXTAS (síndrome de tremor e ataxia associada ao X frágil é uma doença neurodegenerativa de início tardio que afeta principalmente homens acima dos 50 anos de idade, portadores de pré-mutação do gene FMR1. A mutação completa desse gene é responsável pela síndrome do cromossomo X frágil (SXF, a causa mais comum de deficiência mental herdada. Indivíduos afetados pela FXTAS geralmente apresentam tremor de intenção e ataxia de marcha que podem estar associados a sinais radiológicos ou neuropatológicos específicos. Outras características comumente observadas são parkinsonismo, declínio cognitivo, neuropatia periférica e disfunções autonômicas. Quase uma década após sua caracterização clínica, a FXTAS é mal conhecida por médicos no Brasil. Esta revisão apresenta o conhecimento atual sobre os aspectos clínicos, genéticos e diagnósticos da síndrome.

Ferromagnetic resonance linewidth and two-magnon scattering in Fe1-xGdx thin films

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Sheng Jiang

2017-05-01

Full Text Available Magnetization dynamics of Fe1-xGdx thin films (0 ≤ x ≤ 22% has been investigated by ferromagnetic resonance (FMR. Out-of-plane magnetic field orientation dependence of resonance field and linewidth has been measured. Resonance field and FMR linewidth have been fitted by the free energy of our system and Landau-Lifshitz-Gilbert (LLG equation. It is found that FMR linewidth contains huge extrinsic components including two-magnon scattering contribution and inhomogeneous broadening for FeGd alloy thin films. In addition, the intrinsic linewidth and real damping constants have been obtained by extracting the extrinsic linewidth. The damping constant enhanced from 0.011 to 0.038 as Gd dopants increase from 0 to 22% which originates from the enhancement of L-S coupling in FeGd thin films. Besides, gyromagnetic ratio, Landé factor g and magnetic anisotropy of our films have also been determined.

Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats

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Yonglu Tian

2017-08-01

Full Text Available Fragile X syndrome (FXS is a neurodevelopmental disorder caused by mutations in the FMR1 gene that inactivate expression of the gene product, the fragile X mental retardation 1 protein (FMRP. In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR/CRISPR-associated protein 9 (Cas9 technology to generate Fmr1 knockout (KO rats by disruption of the fourth exon of the Fmr1 gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the Fmr1 KO rats (Fmr1exon4-KO. Electrophysiological analysis revealed that the theta-burst stimulation (TBS–induced long-term potentiation (LTP and the low-frequency stimulus (LFS–induced long-term depression (LTD were decreased in the hippocampal Schaffer collateral pathway of the Fmr1exon4-KO rats. Short-term plasticity, measured as the paired-pulse ratio, remained normal in the KO rats. The synaptic strength mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR was also impaired. Consistent with previous reports, the Fmr1exon4-KO rats demonstrated an enhanced 3,5-dihydroxyphenylglycine (DHPG–induced LTD in the present study, and this enhancement is insensitive to protein translation. In addition, the Fmr1exon4-KO rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the Fmr1 gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the Fmr1exon4-KO rats displayed impaired social interaction and macroorchidism, the results consistent with those observed in patients with FXS. Thus, Fmr1exon4-KO rats constitute a novel rat model of FXS that complements existing mouse models.

Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model.

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Cheng, Connie; Lau, Sally K M; Doering, Laurie C

2016-08-02

Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Defects in astrocyte signaling are implicated in neurodevelopmental disorders characterized by abnormal neural circuitry such as Fragile X syndrome (FXS). In animal models of FXS, the loss in expression of the Fragile X mental retardation 1 protein (FMRP) from astrocytes is associated with delayed dendrite maturation and improper synapse formation; however, the effect of astrocyte-derived factors on the development of neurons is not known. Thrombospondin-1 (TSP-1) is an important astrocyte-secreted protein that is involved in the regulation of spine development and synaptogenesis. In this study, we found that cultured astrocytes isolated from an Fmr1 knockout (Fmr1 KO) mouse model of FXS displayed a significant decrease in TSP-1 protein expression compared to the wildtype (WT) astrocytes. Correspondingly, Fmr1 KO hippocampal neurons exhibited morphological deficits in dendritic spines and alterations in excitatory synapse formation following long-term culture. All spine and synaptic abnormalities were prevented in the presence of either astrocyte-conditioned media or a feeder layer derived from FMRP-expressing astrocytes, or following the application of exogenous TSP-1. Importantly, this work demonstrates the integral role of astrocyte-secreted signals in the establishment of neuronal communication and identifies soluble TSP-1 as a potential therapeutic target for Fragile X syndrome.

Rare earth doped M-type hexaferrites; ferromagnetic resonance and magnetization dynamics

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Vipul Sharma

2018-05-01

Full Text Available M-type hexagonal barium ferrites come in the category of magnetic material that plays a key role in electromagnetic wave propagation in various microwave devices. Due to their large magnetic anisotropy and large magnetization, their operating frequency exceeds above 50 GHz. Doping is a way to vary its magnetic properties to such an extent that its ferromagnetic resonance (FMR response can be tuned over a broad frequency band. We have done a complete FMR study of rare earth elements neodymium (Nd and samarium (Sm, with cobalt (Co as base, doped hexaferrite nanoparticles (NPs. X-ray diffractometry, vibrating sample magnetometer (VSM, and ferromagnetic resonance (FMR techniques were used to characterize the microstructure and magnetic properties of doped hexaferrite nanoparticles. Using proper theoretical electromagnetic models, various parameters are extracted from FMR data which play important role in designing and fabricating high-frequency microwave devices.

Deficient Sleep in Mouse Models of Fragile X Syndrome

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R. Michelle Saré

2017-09-01

Full Text Available In patients with fragile X syndrome (FXS, sleep problems are commonly observed but are not well characterized. In animal models of FXS (dfmr1 and Fmr1 knockout (KO/Fxr2 heterozygote circadian rhythmicity is affected, but sleep per se has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in Fmr1 KO mice at different developmental stages. Fmr1 KOs at P21 do not differ from controls, but genotype × phase interactions in both adult (P70 and P180 groups are statistically significant indicating that sleep in Fmr1 KOs is reduced selectively in the light phase compared to controls. Our results show the emergence of abnormal sleep in Fmr1 KOs during the later stages of brain maturation. Treatment of adult Fmr1 KO mice with a GABAB agonist, R-baclofen, did not restore sleep duration in the light phase. In adult (P70 Fmr1 KO/Fxr2 heterozygote animals, total sleep time was further reduced, once again in the light phase. Our data highlight the importance of the fragile X genes (Fmr1 and Fxr2 in sleep physiology and confirm the utility of these mouse models in enhancing our understanding of sleep disorders in FXS.

High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

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Kaufmann, Markus; Schuffenhauer, Ansgar; Fruh, Isabelle; Klein, Jessica; Thiemeyer, Anke; Rigo, Pierre; Gomez-Mancilla, Baltazar; Heidinger-Millot, Valerie; Bouwmeester, Tewis; Schopfer, Ulrich; Mueller, Matthias; Fodor, Barna D; Cobos-Correa, Amanda

2015-10-01

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention. © 2015 Society for Laboratory Automation and Screening.

Ferromagnetic resonance studies on (Co40Fe40B20)x(SiO2)1-x granular magnetic films

International Nuclear Information System (INIS)

Yildiz, F.; Kazan, S.; Aktas, B.; Tarapov, S.I.; Tagirov, L.; Granovsky, B.

2006-01-01

Magnetic properties of granular (Co 40 Fe 40 B 20 ) x (SiO 2 ) 1-x thin films (x=0.37-0.53) have been studied by ferromagnetic resonance (FMR) technique. Samples have been prepared by ion-beam deposition of Co-Fe-B particles and SiO 2 on sitall ceramic substrate. The FMR measurements have been done for different orientations of DC magnetic field with respect to the sample plane. It was found that the deduced value of effective magnetization from FMR data of the thin granular film is reduced by the volume-filling factor of the bulk saturation magnetization. The overall magnetization changes from 152 to 515G depending on the ratio of the magnetic nanoparticles in the SiO 2 matrix. From angular measurements an induced in-plane uniaxial anisotropy has been obtained due to the preparation of the film conditions as well

Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome

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Rachel M. Saré

2018-01-01

Full Text Available Fragile X syndrome (FXS, the most common form of inherited intellectual disability, is also highly associated with autism spectrum disorders (ASD. It is caused by expansion of a CGG repeat sequence on the X chromosome resulting in silencing of the FMR1 gene. This is modeled in the mouse by deletion of Fmr1 (Fmr1 KO. Fmr1 KO mice recapitulate many of the behavioral features of the disorder including seizure susceptibility, hyperactivity, impaired social behavior, sleep problems, and learning and memory deficits. The mammalian target of rapamycin pathway (mTORC1 is upregulated in Fmr1 KO mice and is thought to be important for the pathogenesis of this disorder. We treated Fmr1 KO mice chronically with an mTORC1 inhibitor, rapamycin, to determine if rapamycin treatment could reverse behavioral phenotypes. We performed open field, zero maze, social behavior, sleep, passive avoidance, and audiogenic seizure testing. We found that pS6 was upregulated in Fmr1 KO mice and normalized by rapamycin treatment, but, except for an anxiogenic effect, it did not reverse any of the behavioral phenotypes examined. In fact, rapamycin treatment had an adverse effect on sleep and social behavior in both control and Fmr1 KO mice. These results suggest that targeting the mTOR pathway in FXS is not a good treatment strategy and that other pathways should be considered.

Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

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Eric W Fish

Full Text Available Fragile X syndrome (FXS is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y mice with intracranial self-stimulation (ICSS and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynylpyridine (MPEP, was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.

Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

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Fish, Eric W; Krouse, Michael C; Stringfield, Sierra J; Diberto, Jeffrey F; Robinson, J Elliott; Malanga, C J

2013-01-01

Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y)) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y) mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y) mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y) than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y) mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y) mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y) mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.

Live birth following serial vitrification of embryos and PGD for fragile X syndrome in a patient with the premutation and decreased ovarian reserve.

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Nayot, Dan; Chung, Jin Tae; Son, Weon-Young; Ao, Assangla; Hughes, Mark; Dahan, Michael H

2013-11-01

To present a live birth resulting from serial vitrification of embryos and pre-implantation genetic diagnosis (PGD). A 31-year-old with primary infertility, fragile-X premutation, and decreased ovarian reserve (DOR) (baseline FSH level 33 IU/L), presented after failing to stimulate to follicle diameters >10 mm with three cycles of invitro fertilization (IVF). After counseling, the couple opted for serial in-vitro maturation (IVM), embryo vitrification, and genetic testing using array comparative genomic hybridization (aCGH) and PGD. Embryos were vitrified 2 days after intra-cytoplasmic sperm injection (ICSI). Thawed embryos were biopsied on day-three and transferred on day-five. The couple underwent 20 cycles of assisted reproductive technology. A total of 23 in-vivo mature and five immature oocytes were retrieved, of which one matured in-vitro. Of 24 embryos, 17/24 (71 %) developed to day two and 11/24 (46 %) survived to blastocyst stage with a biopsy result available. Four blastocysts had normal PGD and aCGH results. Both single embryo transfers resulted in a successful implantation, one a blighted ovum and the other in a live birth. Young patients with DOR have potential for live birth as long as oocytes can be obtained and embryos created. Serial vitrification may be the mechanism of choice in these patients when PGD is needed.

A comprehensive study of ferromagnetic resonance and structural properties of iron-rich nickel ferrite (Ni{sub x}Fe{sub 3−x}O{sub 4}, x≤1) films grown by chemical vapor deposition

Energy Technology Data Exchange (ETDEWEB)

Pachauri, Neha; Khodadadi, Behrouz [Department of Physics and Astronomy, The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Center for Materials for Information Technology (MINT), The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Singh, Amit V. [Center for Materials for Information Technology (MINT), The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Mohammadi, Jamileh Beik [Department of Physics and Astronomy, The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Center for Materials for Information Technology (MINT), The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Martens, Richard L. [Central Analytical Facility (CAF), The University of Alabama, Tuscaloosa, Alabama 35487 (United States); LeClair, Patrick R.; Mewes, Claudia; Mewes, Tim [Department of Physics and Astronomy, The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Center for Materials for Information Technology (MINT), The University of Alabama, Tuscaloosa, Alabama 35487 (United States); Gupta, Arunava [Center for Materials for Information Technology (MINT), The University of Alabama, Tuscaloosa, Alabama 35487 (United States)

2016-11-01

We report a detailed study of the structural and ferromagnetic resonance properties of spinel nickel ferrite (NFO) films, grown on (100)-oriented cubic MgAl{sub 2}O{sub 4} substrates by direct liquid injection chemical vapor deposition (DLI-CVD) technique. Three different compositions of NFO films (Ni{sub x}Fe{sub 3−x}O{sub 4} where x=1, 0.8, 0.6) deposited at optimized growth temperature of 600 °C are characterized using X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Vibrating Sample Magnetometry (VSM), and broadband ferromagnetic resonance (FMR) techniques. XRD confirms the growth of epitaxial, single crystalline Ni{sub x}Fe{sub 3−x}O{sub 4} films. The out-of-plane lattice constant (c) obtained for Ni{sub 0.8}Fe{sub 2.2}O{sub 4} film is slightly higher than the bulk value (0.833 nm), indicating only partial strain relaxation whereas for the other two compositions (x=1 and x=0.6) films exhibit complete relaxation. The in-plane and out-of-plane FMR linewidths measurements at 10 GHz give the lowest values of 458 Oe and 98 Oe, respectively, for Ni{sub 0.8}Fe{sub 2.2}O{sub 4} film as compared to the other two compositions. A comprehensive frequency (5–40 GHz) and temperature (10–300 K) dependent FMR study of the Ni{sub 0.8}Fe{sub 2.2}O{sub 4} sample for both in-lane and out-of-plane configurations reveals two magnon scattering (TMS) as the dominant in-plane relaxation mechanism. It is observed that the TMS contribution to the FMR linewidth scales with the saturation magnetization M{sub s}. In-plane angle-dependent FMR measurements performed on the same sample show that the ferromagnetic resonance field (H{sub res}) and the FMR linewidth (ΔH) have a four-fold symmetry that is consistent with the crystal symmetry of the spinel. SEM measurements show formation of pyramid-like microstructures at the surface of the Ni{sub 0.8}Fe{sub 2.2}O{sub 4} sample, which can explain the observed four-fold symmetry of the FMR linewidth.

LBT/LUCIFER view of star-forming galaxies in the cluster 7C 1756+6520 at z ˜ 1.4

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Magrini, Laura; Sommariva, Veronica; Cresci, Giovanni; Sani, Eleonora; Galametz, Audrey; Mannucci, Filippo; Petropoulou, Vasiliki; Fumana, Marco

2012-10-01

Galaxy clusters are key places to study the contribution of nature (i.e. mass and morphology) and nurture (i.e. environment) in the formation and evolution of galaxies. Recently, a number of clusters at z > 1, i.e. corresponding to the first epochs of the cluster formation, have been discovered and confirmed spectroscopically. We present new observations obtained with the LBT Near Infrared Spectroscopic Utility with Camera and Integral Field Unit for Extragalactic Research (LUCIFER) spectrograph at Large Binocular Telescope (LBT) of a sample of star-forming galaxies associated with a large-scale structure around the radio galaxy 7C 1756+6520 at z = 1.42. Combining our spectroscopic data and the literature photometric data, we derived some of the properties of these galaxies: star formation rate, metallicity and stellar mass. With the aim of analysing the effect of the cluster environment on galaxy evolution, we have located the galaxies in the plane of the so-called fundamental metallicity relation (FMR), which is known not to evolve with redshift up to z = 2.5 for field galaxies, but it is still unexplored in rich environments at low and high redshifts. We found that the properties of the galaxies in the cluster 7C 1756+6520 are compatible with the FMR which suggests that the effect of the environment on galaxy metallicity at this early epoch of cluster formation is marginal. As a side study, we also report the spectroscopic analysis of a bright active galactic nucleus, belonging to the cluster, which shows a significant outflow of gas.

Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome

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Marko eUutela

2014-05-01

Full Text Available Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD, including Fragile X syndrome (FXS. The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO mice, a mouse model for FXS. We found that fluoxetine reduced anxiety-like behavior of both wild type and Fmr1 KO mice seen as shortened latency to enter the center area in the open field test. In Fmr1 KO mice, fluoxetine normalized locomotor hyperactivity but abnormally increased exploratory activity. Reduced Brain-derived neurotrophic factor (BDNF and increased TrkB receptor expression levels in the hippocampus of Fmr1 KO mice associated with inappropriate coping responses under stressful condition and abolished antidepressant activity of fluoxetine. Fluoxetine response in the cell proliferation was also missing in the hippocampus of Fmr1 KO mice when compared with wild type controls. The postnatal expression of serotonin transporter was reduced in the thalamic nuclei of Fmr1 KO mice during the time of transient innervation of somatosensory neurons suggesting that developmental changes of serotonin transporter (SERT expression were involved in the differential cellular and behavioral responses to fluoxetine in wild type and Fmr1 mice. The results indicate that changes of BDNF/TrkB signaling contribute to differential behavioral responses to fluoxetine among individuals with ASD.

Long-lasting Effects of Minocycline on Behavior in Young but not Adult Fragile X Mice

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Dansie, Lorraine E.; Phommahaxay, Kelly; Okusanya, Ayodeji G.; Uwadia, Jessica; Huang, Mike; Rotschafer, Sarah E.; Razak, Khaleel A.; Ethell, Douglas W.; Ethell, Iryna M.

2013-01-01

Fragile X Syndrome (FXS) is the most common single-gene inherited form of intellectual disability with behaviors characteristic of autism. People with FXS display childhood seizures, hyperactivity, anxiety, developmental delay, attention deficits, and visual-spatial memory impairment, as well as a propensity for obsessive-compulsive disorder (OCD). Several of these aberrant behaviors and FXS-associated synaptic irregularities also occur in “fragile X mental retardation gene” knock-out (Fmr1 KO) mice. We previously reported that minocycline promotes the maturation of dendritic spines - postsynaptic sites for excitatory synapses - in the developing hippocampus of Fmr1 KO mice, which may underlie the beneficial effects of minocycline on anxiolytic behavior in young Fmr1 KO mice. In this study, we compared the effectiveness of minocycline treatment in young and adult Fmr1 KO mice, and determined the dependence of behavioral improvements on short-term versus long-term minocycline administration. We found that 4 and 8 week long treatments significantly reduced locomotor activity in both young and adult Fmr1 KO mice. Some behavioral improvements persisted in young mice post-treatment, but in adults the beneficial effects were lost soon after minocycline treatment was stopped. We also show, for the first time, that minocycline treatment partially attenuates the number and severity of audiogenic seizures in Fmr1 KO mice. This report provides further evidence that minocycline treatment has immediate and long-lasting benefits on FXS-associated behaviors in the Fmr1 KO mouse model. PMID:23660195

Ferromagnetic resonance studies on (Co{sub 40}Fe{sub 40}B{sub 20}){sub x}(SiO{sub 2}){sub 1-x} granular magnetic films

Energy Technology Data Exchange (ETDEWEB)

Yildiz, F. [Department of Physics, Faculty of Sciences and Arts, Celal Bayar University, Muradiye/Manisa (Turkey) and Department of Physics, Electron Spin Science Center, Pohang University of Science and Technology, Pohang 790-784 (Korea, Republic of)]. E-mail: fyildiz@gyte.edu.tr; Kazan, S. [Gebze Institute of Technology, 41400 Gebze-Kocaeli (Turkey); Aktas, B. [Gebze Institute of Technology, 41400 Gebze-Kocaeli (Turkey); Tarapov, S.I. [Institute of Radiophysics and Electronics, National Academy of Sciences of Ukraine, Kharkov 61085 (Ukraine); Tagirov, L. [Gebze Institute of Technology, 41400 Gebze-Kocaeli (Turkey); Granovsky, B. [Moscow State University, 119992 Moscow (Russian Federation)

2006-10-15

Magnetic properties of granular (Co{sub 40}Fe{sub 40}B{sub 20}){sub x}(SiO{sub 2}){sub 1-x} thin films (x=0.37-0.53) have been studied by ferromagnetic resonance (FMR) technique. Samples have been prepared by ion-beam deposition of Co-Fe-B particles and SiO{sub 2} on sitall ceramic substrate. The FMR measurements have been done for different orientations of DC magnetic field with respect to the sample plane. It was found that the deduced value of effective magnetization from FMR data of the thin granular film is reduced by the volume-filling factor of the bulk saturation magnetization. The overall magnetization changes from 152 to 515G depending on the ratio of the magnetic nanoparticles in the SiO{sub 2} matrix. From angular measurements an induced in-plane uniaxial anisotropy has been obtained due to the preparation of the film conditions as well.

Lithium chloride ameliorates learning and memory ability and inhibits glycogen synthase kinase-3 beta activity in a mouse model of fragile X syndrome

Institute of Scientific and Technical Information of China (English)

Shengqiang Chen; Xuegang Luo; Quan Yang; Weiwen Sun; Kaiyi Cao; Xi Chen; Yueling Huang; Lijun Dai; Yonghong Yi

2011-01-01

In the present study, Fmr1 knockout mice (KO mice) were used as the model for fragile X syndrome. The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error counts, indicating a learning and memory disorder. After treatment with 30, 60, 90, 120, or 200 mg/kg lithium chloride, the learning and memory abilities of the Fmr1 KO mice were significantly ameliorated, in particular, the 200 mg/kg lithium chloride treatment had the most significant effect. Western blot analysis showed that lithium chloride significantly enhanced the expression of phosphorylated glycogen synthase kinase 3 beta, an inactive form of glycogen synthase kinase 3 beta, in the cerebral cortex and hippocampus of the Fmr1 KO mice. These results indicated that lithium chloride improved learning and memory in the Fmr1 KO mice, possibly by inhibiting glycogen synthase kinase 3 beta activity.

Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome.

Science.gov (United States)

Lovelace, Jonathan W; Wen, Teresa H; Reinhard, Sarah; Hsu, Mike S; Sidhu, Harpreet; Ethell, Iryna M; Binder, Devin K; Razak, Khaleel A

2016-05-01

Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS. Fragile X Syndrome (FXS) is the leading known genetic cause of autism spectrum disorders. Individuals with FXS show symptoms of auditory hypersensitivity. These symptoms may arise due to sustained neural responses to repeated sounds, but the underlying mechanisms remain unclear. For the first time, this study shows deficits

Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome

Science.gov (United States)

Dickson, Price E.; Corkill, Beau; McKimm, Eric; Miller, Mellessa M.; Calton, Michele A.; Goldowitz, Daniel; Blaha, Charles D.; Mittleman, Guy

2013-01-01

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non-salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task-dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load. PMID:23747611

Discrimination learning and attentional set formation in a mouse model of Fragile X.

Science.gov (United States)

Casten, Kimberly S; Gray, Annette C; Burwell, Rebecca D

2011-06-01

Fragile X Syndrome is the most prevalent genetic cause of mental retardation. Selective deficits in executive function, including inhibitory control and attention, are core features of the disorder. In humans, Fragile X results from a trinucleotide repeat in the Fmr1 gene that renders it functionally silent and has been modeled in mice by targeted deletion of the Fmr1 gene. Fmr1 knockout (KO) mice recapitulate many features of Fragile X syndrome, but evidence for deficits in executive function is inconsistent. To address this issue, we trained wild-type and Fmr1 KO mice on an experimental paradigm that assesses attentional set-shifting. Mice learned to discriminate between stimuli differing in two of three perceptual dimensions. Successful discrimination required attending only to the relevant dimension, while ignoring irrelevant dimensions. Mice were trained on three discriminations in the same perceptual dimension, each followed by a reversal. This procedure normally results in the formation of an attentional set to the relevant dimension. Mice were then required to shift attention and discriminate based on a previously irrelevant perceptual dimension. Wild-type mice exhibited the increase in trials to criterion expected when shifting attention from one perceptual dimension to another. In contrast, the Fmr1 KO group failed to show the expected increase, suggesting impairment in forming an attentional set. Fmr1 KO mice also exhibited a general impairment in learning discriminations and reversals. This is the first demonstration that Fmr1 KO mice show a deficit in attentional set formation.

A novel fragile X syndrome mutation reveals a conserved role for the carboxy-terminus in FMRP localization and function.

Science.gov (United States)

Okray, Zeynep; de Esch, Celine E F; Van Esch, Hilde; Devriendt, Koen; Claeys, Annelies; Yan, Jiekun; Verbeeck, Jelle; Froyen, Guy; Willemsen, Rob; de Vrij, Femke M S; Hassan, Bassem A

2015-04-01

Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5' untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR1 mutation and reveal an unexpected nuclear export function for the C-terminus of FMRP. We screened a cohort of patients with typical FXS symptoms who tested negative for CGG repeat expansion in the FMR1 locus. In one patient, we identified a guanine insertion in FMR1 exon 15. This mutation alters the open reading frame creating a short novel C-terminal sequence, followed by a stop codon. We find that this novel peptide encodes a functional nuclear localization signal (NLS) targeting the patient FMRP to the nucleolus in human cells. We also reveal an evolutionarily conserved nuclear export function associated with the endogenous C-terminus of FMRP. In vivo analyses in Drosophila demonstrate that a patient-mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

76 FR 60967 - Final Fair Market Rents for the Housing Choice Voucher Program and Moderate Rehabilitation Single...

Science.gov (United States)

2011-09-30

..., Houston-Baytown-Sugar Land, TX CT HMFA. HMFA. New Haven-Meriden, CT HMFA North Port-Bradenton-Sarasota, FL... than four bedrooms are calculated by adding 15 percent to the four- bedroom FMR for each extra bedroom...-bedroom FMR for each extra bedroom. For example, the FMR for a five-bedroom unit is 1.15 times the four...

Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

OpenAIRE

Qiu, Li-Feng; Lu, Ting-Jia; Hu, Xiao-Ling; Yi, Yong-Hong; Liao, Wei-Ping; Xiong, Zhi-Qi

2008-01-01

Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20?25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically acce...

Inactivation of the maternal fragile X gene results in sensitization of GABAB receptor function in the offspring

OpenAIRE

Zupan, Bojana; Toth, Miklos

2008-01-01

Fragile X syndrome is an X linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities and hyperactivity. Although Fragile X syndrome is considered a typical Mendelian disorder, we have recently reported that the environment, specifically the fmr-1+/− or fmr-1−/− (H or KO) maternal environment, elicits on its own a partial fragile X-like phenotype and can contribute to the overall phenotype of...

Elevated progranulin contributes to synaptic and learning deficit due to loss of fragile X mental retardation protein.

Science.gov (United States)

Zhang, Kun; Li, Yu-Jiao; Guo, Yanyan; Zheng, Kai-Yin; Yang, Qi; Yang, Le; Wang, Xin-Shang; Song, Qian; Chen, Tao; Zhuo, Min; Zhao, Ming-Gao

2017-12-01

Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Magnetization pinning in conducting films demonstrated using broadband ferromagnetic resonance

Science.gov (United States)

Kostylev, M.; Stashkevich, A. A.; Adeyeye, A. O.; Shakespeare, C.; Kostylev, N.; Ross, N.; Kennewell, K.; Magaraggia, R.; Roussigné, Y.; Stamps, R. L.

2010-11-01

The broadband microstrip ferromagnetic resonance (FMR), cavity FMR, and Brillouin light scattering spectroscopy techniques have been applied for detection and characterization of a magnetic inhomogeneity in a film sample. In the case of a 100 nm thick permalloy film, an additional magnetically depleted top sublayer has been detected due to pinning effect it produces on the magnetization in the bulk of the film. The pinning results in appearance of an exchange standing spin wave mode in the broadband FMR absorption spectrum, whose amplitudes are different depending on whether the film or the film substrate faces the microstrip transducer. Comparison of the experimental amplitudes for this mode with results of our theory for both film placements revealed that the depleted layer is located at the film surface facing away from the film substrate. Subsequent broadband FMR characterization of a large number of other presumably single-layer films with thicknesses in the range 30-100 nm showed the same result.

Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011-2012 Pilot European Sentinel Registry.

Science.gov (United States)

Nickenig, Georg; Estevez-Loureiro, Rodrigo; Franzen, Olaf; Tamburino, Corrado; Vanderheyden, Marc; Lüscher, Thomas F; Moat, Neil; Price, Susanna; Dall'Ara, Gianni; Winter, Reidar; Corti, Roberto; Grasso, Carmelo; Snow, Thomas M; Jeger, Raban; Blankenberg, Stefan; Settergren, Magnus; Tiroch, Klaus; Balzer, Jan; Petronio, Anna Sonia; Büttner, Heinz-Joachim; Ettori, Federica; Sievert, Horst; Fiorino, Maria Giovanna; Claeys, Marc; Ussia, Gian Paolo; Baumgartner, Helmut; Scandura, Salvatore; Alamgir, Farqad; Keshavarzi, Freidoon; Colombo, Antonio; Maisano, Francesco; Ebelt, Henning; Aruta, Patrizia; Lubos, Edith; Plicht, Björn; Schueler, Robert; Pighi, Michele; Di Mario, Carlo

2014-09-02

The use of transcatheter mitral valve repair (TMVR) has gained widespread acceptance in Europe, but data on immediate success, safety, and long-term echocardiographic follow-up in real-world patients are still limited. The aim of this multinational registry is to present a real-world overview of TMVR use in Europe. The Transcatheter Valve Treatment Sentinel Pilot Registry is a prospective, independent, consecutive collection of individual patient data. A total of 628 patients (mean age 74.2 ± 9.7 years, 63.1% men) underwent TMVR between January 2011 and December 2012 in 25 centers in 8 European countries. The prevalent pathogenesis was functional mitral regurgitation (FMR) (n = 452 [72.0%]). The majority of patients (85.5%) were highly symptomatic (New York Heart Association functional class III or higher), with a high logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (20.4 ± 16.7%). Acute procedural success was high (95.4%) and similar in FMR and degenerative mitral regurgitation (p = 0.662). One clip was implanted in 61.4% of patients. In-hospital mortality was low (2.9%), without significant differences between groups. The estimated 1-year mortality was 15.3%, which was similar for FMR and degenerative mitral regurgitation. The estimated 1-year rate of rehospitalization because of heart failure was 22.8%, significantly higher in the FMR group (25.8% vs. 12.0%, p[log-rank] = 0.009). Paired echocardiographic data from the 1-year follow-up, available for 368 consecutive patients in 15 centers, showed a persistent reduction in the degree of mitral regurgitation at 1 year (6.0% of patients with severe mitral regurgitation). This independent, contemporary registry shows that TMVR is associated with high immediate success, low complication rates, and sustained 1-year reduction of the severity of mitral regurgitation and improvement of clinical symptoms. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc

FMRP acts as a key messenger for dopamine modulation in the forebrain.

Science.gov (United States)

Wang, Hansen; Wu, Long-Jun; Kim, Susan S; Lee, Frank J S; Gong, Bo; Toyoda, Hiroki; Ren, Ming; Shang, Yu-Ze; Xu, Hui; Liu, Fang; Zhao, Ming-Gao; Zhuo, Min

2008-08-28

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that controls translational efficiency and regulates synaptic plasticity. Here, we report that FMRP is involved in dopamine (DA) modulation of synaptic potentiation. AMPA glutamate receptor subtype 1 (GluR1) surface expression and phosphorylation in response to D1 receptor stimulation were reduced in cultured Fmr1(-/-) prefrontal cortex (PFC) neurons. Furthermore, D1 receptor signaling was impaired, accompanied by D1 receptor hyperphosphorylation at serine sites and subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in both PFC and striatum of Fmr1(-/-) mice. FMRP interacted with GRK2, and pharmacological inhibition of GRK2 rescued D1 receptor signaling in Fmr1(-/-) neurons. Finally, D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1(-/-) mice. Our study has identified FMRP as a key messenger for DA modulation in the forebrain and may provide insights into the cellular and molecular mechanisms underlying fragile X syndrome.

The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

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Hongen Wei

Full Text Available Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs from Fmr1 knockout (KO mice, a mouse model for fragile X syndrome (FXS and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

Efficacy of fractionated microneedle radiofrequency with and without adding subcision for the treatment of atrophic facial acne scars: A randomized split-face clinical study.

Science.gov (United States)

Faghihi, Gita; Poostiyan, Nazila; Asilian, Ali; Abtahi-Naeini, Bahareh; Shahbazi, Masoom; Iraji, Fariba; Fatemi Naeini, Farahnaz; Nilforoushzadeh, Mohammad Ali

2017-06-01

There is no gold standard treatment for facial acne scars, and overall, little literature exists about the combination therapy for treatment of acne scar. The aim of this study was to evaluate the efficacy of fractionated microneedle radiofrequency (FMR) vs FMR combined with subcision for the treatment of atrophic acne scars. This was a randomized, split-face clinical study of 25 patients with II-IV Fitzpatrick skin types with moderate to severe facial atrophic acne scars. Initially, standard subcision by Nokor needle was performed on one side. Two weeks after subcision, FMR treatment was performed on both cheeks of each participant. Second and third FMR treatment sessions were performed within 4-week intervals. Two-blinded dermatologists performed clinical assessments using a quartile grading scale, and patients were also asked to judge their satisfaction using a visual analog scale (VAS) scoring system. The age of the patients varied from 24 to 40 years (mean: 30.08±4.94 years). Only nine patients (36%) were males. Clinical assessment by two-blinded dermatologists showed statistically significant improvement in the combination (FMR+subcision) group (P=.009). Patient satisfaction was statistically significantly better in the combination group (P=.001). A darkening of skin phototype was associated with a decrease in patient's satisfaction VAS score (P=.07). The combination of subcision and FMR is a safe and effective modality for mixed type acne scars. Additional randomized clinical study with long-term follow-up is necessary for further evaluation of FMR in combination with other procedures. The full trial protocol can be accessed in: http://www.irct.ir/searchresult.php?keyword=%20%20IRCT2016103130597N1&id=30597&number=1&field=a&prt=1&total=1&m=1. The clinical trial registration number is IRCT2016103130597N1. © 2017 Wiley Periodicals, Inc.

Thyroid hormones correlate with basal metabolic rate but not field metabolic rate in a wild bird species.

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Jorg Welcker

Full Text Available Thyroid hormones (TH are known to stimulate in vitro oxygen consumption of tissues in mammals and birds. Hence, in many laboratory studies a positive relationship between TH concentrations and basal metabolic rate (BMR has been demonstrated whereas evidence from species in the wild is scarce. Even though basal and field metabolic rates (FMR are often thought to be intrinsically linked it is still unknown whether a relationship between TH and FMR exists. Here we determine the relationship between the primary thyroid hormone triiodothyronine (T3 with both BMR and FMR in a wild bird species, the black-legged kittiwake (Rissa tridactyla. As predicted we found a strong and positive relationship between plasma concentrations of T3 and both BMR and mass-independent BMR with coefficients of determination ranging from 0.36 to 0.60. In contrast there was no association of T3 levels with either whole-body or mass-independent FMR (R(2 =0.06 and 0.02, respectively. In accordance with in vitro studies our data suggests that TH play an important role in modulating BMR and may serve as a proxy for basal metabolism in wild birds. However, the lack of a relationship between TH and FMR indicates that levels of physical activity in kittiwakes are largely independent of TH concentrations and support recent studies that cast doubt on a direct linkage between BMR and FMR.

Thyroid Hormones Correlate with Basal Metabolic Rate but Not Field Metabolic Rate in a Wild Bird Species

Science.gov (United States)

Welcker, Jorg; Chastel, Olivier; Gabrielsen, Geir W.; Guillaumin, Jerome; Kitaysky, Alexander S.; Speakman, John R.; Tremblay, Yann; Bech, Claus

2013-01-01

Thyroid hormones (TH) are known to stimulate in vitro oxygen consumption of tissues in mammals and birds. Hence, in many laboratory studies a positive relationship between TH concentrations and basal metabolic rate (BMR) has been demonstrated whereas evidence from species in the wild is scarce. Even though basal and field metabolic rates (FMR) are often thought to be intrinsically linked it is still unknown whether a relationship between TH and FMR exists. Here we determine the relationship between the primary thyroid hormone triiodothyronine (T3) with both BMR and FMR in a wild bird species, the black-legged kittiwake (Rissa tridactyla). As predicted we found a strong and positive relationship between plasma concentrations of T3 and both BMR and mass-independent BMR with coefficients of determination ranging from 0.36 to 0.60. In contrast there was no association of T3 levels with either whole-body or mass-independent FMR (R2 = 0.06 and 0.02, respectively). In accordance with in vitro studies our data suggests that TH play an important role in modulating BMR and may serve as a proxy for basal metabolism in wild birds. However, the lack of a relationship between TH and FMR indicates that levels of physical activity in kittiwakes are largely independent of TH concentrations and support recent studies that cast doubt on a direct linkage between BMR and FMR. PMID:23437096

Magnetic properties of permalloy-coated organic tubules

Science.gov (United States)

Krebs, J. J.; Rubinstein, M.; Lubitz, P.; Harford, M. Z.; Baral, S.; Shashidar, R.; Ho, Y. S.; Chow, G. M.; Qadri, S.

1991-11-01

An initial investigation is presented of the ferromagnetic properties of a novel type of magnetic composite, viz., permalloy-coated submicron diameter hollow cylinders or tubules. The tubules form spontaneously from an organic material, a diacetylenic phosopholipid, and were used as templates on which the ferromagnetic material was deposited by electroless deposition. The permalloy-coated tubules were dispersed in an epoxy matrix to measure the magnetization and ferromagnetic resonance (FMR) properties of individual tubules. The nature of the magnetic anisotropy and the FMR spectra observed confirmed that the tubules are well aligned by a magnetic field during the epoxy curing. The FMR spectra are interpreted in terms of a powder pattern distribution of thin-film spectra consistent with the large diameter-to-thickness ratio.

A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families.

Science.gov (United States)

Metsu, Sofie; Rainger, Jacqueline K; Debacker, Kim; Bernhard, Birgitta; Rooms, Liesbeth; Grafodatskaya, Daria; Weksberg, Rosanna; Fombonne, Eric; Taylor, Martin S; Scherer, Stephen W; Kooy, R Frank; FitzPatrick, David R

2014-11-01

We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed. © 2014 WILEY PERIODICALS, INC.

Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes

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Christos G. Gkogkas

2014-12-01

Full Text Available Summary: Fragile X syndrome (FXS is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1−/y, we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E, is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9 protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1−/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS. : Fragile X syndrome (FXS is caused by dysregulation of translation in the brain. Gkogkas et al. show that phosphorylation of eukaryotic translation initiation factor 4E (eIF4E is increased in FXS postmortem brains and Fmr1−/y mice. Downregulation of eIF4E phosphorylation in Fmr1−/y mice rescues defects in dendritic spine morphology, synaptic plasticity, and social interaction via normalization of MMP-9 expression.

GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism.

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Marjelo A Mines

Full Text Available BACKGROUND: Nearly 1% of children in the United States exhibit autism spectrum disorders, but causes and treatments remain to be identified. Mice with deletion of the fragile X mental retardation 1 (Fmr1 gene are used to model autism because loss of Fmr1 gene function causes Fragile X Syndrome (FXS and many people with FXS exhibit autistic-like behaviors. Glycogen synthase kinase-3 (GSK3 is hyperactive in brains of Fmr1 knockout mice, and inhibition of GSK3 by lithium administration ameliorates some behavioral impairment in these mice. We extended our studies of this association by testing whether GSK3 contributes to socialization behaviors. This used two mouse models with disrupted regulation of GSK3, Fmr1 knockout mice and GSK3 knockin mice, in which inhibitory serines of the two isoforms of GSK3, GSK3alpha and GSK3beta, are mutated to alanines, leaving GSK3 fully active. METHODOLOGY/PRINCIPAL FINDINGS: To assess sociability, test mice were introduced to a restrained stimulus mouse (S1 for 10 min, followed by introduction of a second restrained stimulus mouse (S2 for 10 min, which assesses social preference. Fmr1 knockout and GSK3 knockin mice displayed no deficit in sociability with the S1 mouse, but unlike wild-type mice neither demonstrated social preference for the novel S2 mouse. Fmr1 knockout mice displayed more anxiety-related behaviors during social interaction (grooming, rearing, and digging than wild-type mice, which was ameliorated by inhibition of GSK3 with chronic lithium treatment. CONCLUSIONS/SIGNIFICANCE: These results indicate that impaired inhibitory regulation of GSK3 in Fmr1 knockout mice may contribute to some socialization deficits and that lithium treatment can ameliorate certain socialization impairments. As discussed in the present work, these results suggest a role for GSK3 in social behaviors and implicate inhibition of GSK3 as a potential therapeutic.

Protein synthesis levels are increased in a subset of individuals with Fragile X syndrome

DEFF Research Database (Denmark)

Jacquemont, Sébastien; Pacini, Laura; Jønch, Aia E

2018-01-01

architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical...... severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS...... and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those...

Inactivation of the maternal fragile X gene results in sensitization of GABAB receptor function in the offspring.

Science.gov (United States)

Zupan, Bojana; Toth, Miklos

2008-12-01

Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR1 gene, with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Although fragile X syndrome is considered a typical Mendelian disorder, we have recently reported that the environment, specifically the fmr1(+/-) or fmr1(-/-) [H or knockout (KO)] maternal environment, elicits on its own a partial fragile X-like phenotype and can contribute to the overall phenotype of fmr1(-/0) (KO) male offspring. Genetically fmr1(+/0) (WT) males born to H females (H(maternal) > WT(offspring)), similar to KO male offspring born to H and KO mothers (H > KO and KO > KO), exhibit locomotor hyperactivity. These mice also showed reduced D(2) autoreceptor function, indicating a possible diminished feedback inhibition of dopamine (DA) release in the nigrostriatal and mesolimbic systems. The GABAergic system also regulates DA release, in part via presynaptic GABA(B) receptors (Rs) located on midbrain dopaminergic neurons. Here, we show that the locomotor inhibitory effect of the GABA(B)R agonist baclofen [4-amino-3-(4-chlorophenyl)-butanoic acid] is enhanced in all progeny of mutant mothers (H > WT, H > KO, and KO > KO) compared with WT > WT mice, irrespective of their own genotype. However, increased sensitivity to baclofen was selective and limited to the locomotor response because the muscle-relaxant and sedative effects of the drug were not altered by the maternal environment. These data show that GABA(B)R sensitization, traditionally induced pharmacologically, can also be elicited by the fmr1-deficient maternal environment.

Knockout mouse model for Fxr2: a model for mental retardation

NARCIS (Netherlands)

C.J.M. Bontekoe (Carola); L. Kirkpatrick; C.E. Bakker (Cathy); A.T. Hoogeveen (Andre); R. McAninch; M. Merriweather; B.A. Oostra (Ben); N.C. Cheng (Ngan Ching); K.L. McIlwain; I.M. Nieuwenhuizen (Ingeborg); L.A. Yuva-Paylor; R. Paylor; A. Nellis; R. Willemsen (Rob); Z. Fang; D. Nelson

2002-01-01

textabstractFragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Fmr1 knockout mice exhibit a phenotype with some similarities to humans, such as macro-orchidism and behavioral abnormalities. Two homologs of FMRP have been

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

Science.gov (United States)

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-02-15

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

An X-band Co2+ EPR study of Zn1-xCoxO (x=0.005-0.1) nanoparticles prepared by chemical hydrolysis methods using diethylene glycol and denaturated alcohol at 5 K

Science.gov (United States)

Misra, Sushil K.; Andronenko, S. I.; Srinivasa Rao, S.; Chess, Jordan; Punnoose, A.

2015-11-01

EPR investigations on two types of dilute magnetic semiconductor (DMS) ZnO nanoparticles doped with 0.5-10% Co2+ ions, prepared by two chemical hydrolysis methods, using: (i) diethylene glycol ((CH2CH2OH)2O) (NC-rod-like samples), and (ii) denatured ethanol (CH3CH2OH) solutions (QC-spherical samples), were carried out at X-band (9.5 GHz) at 5 K. The analysis of EPR data for NC samples revealed the presence of several types of EPR lines: (i) two types, intense and weak, of high-spin Co2+ ions in the samples with Co concentration >0.5%; (ii) surface oxygen vacancies, and (iii) a ferromagnetic resonance (FMR) line. QC samples exhibit an intense FMR line and an EPR line due to high-spin Co2+ ions. FMR line is more intense, than the corresponding line exhibited by NC samples. These EPR spectra varied for sample with different doping concentrations. The magnetic states of these samples as revealed by EPR spectra, as well as the origin of ferromagnetism DMS samples are discussed.

Ferromagnetic resonance linewidth and damping in perpendicular-anisotropy magnetic multilayers thin films

Science.gov (United States)

Beaujour, Jean-Marc

2010-03-01

Transition metal ferromagnetic films with perpendicular magnetic anisotropy (PMA) have ferromagnetic resonance (FMR) linewidths that are one order of magnitude larger than soft magnetic materials, such as pure iron (Fe) and permalloy (NiFe) thin films. We have conducted systematic studies of a variety of thin film materials with perpendicular magnetic anisotropy to investigate the origin of the enhanced FMR linewidths, including Ni/Co and CoFeB/Co/Ni multilayers. In Ni/Co multilayers the PMA was systematically reduced by irradiation with Helium ions, leading to a transition from out-of-plane to in-plane easy axis with increasing He ion fluence [1,2]. The FMR linewidth depends linearly on frequency for perpendicular applied fields and increases significantly when the magnetization is rotated into the film plane with an applied in-plane magnetic field. Irradiation of the film with Helium ions decreases the PMA and the distribution of PMA parameters, leading to a large reduction in the FMR linewidth for in-plane magnetization. These results suggest that fluctuations in the PMA lead to a large two magnon scattering contribution to the linewidth for in-plane magnetization and establish that the Gilbert damping is enhanced in such materials (α˜0.04, compared to α˜0.002 for pure Fe) [2]. We compare these results to those on CoFeB/Co/Ni and published results on other thin film materials with PMA [e.g., Ref. 3]. [1] D. Stanescu et al., J. Appl. Phys. 103, 07B529 (2008). [2] J-M. L. Beaujour, D. Ravelosona, I. Tudosa, E. Fullerton, and A. D. Kent, Phys. Rev. B RC 80, 180415 (2009). [3] N. Mo, J. Hohlfeld, M. ulIslam, C. S. Brown, E. Girt, P. Krivosik, W. Tong, A. Rebel, and C. E. Patton, Appl. Phys. Lett. 92, 022506 (2008). *Research done in collaboration with: A. D. Kent, New York University, D. Ravelosona, Institut d'Electronique Fondamentale, UMR CNRS 8622, Universit'e Paris Sud, E. E. Fullerton, Center for Magnetic Recording Research, UCSD, and supported by NSF

Comprehensive analysis of ultrasonic vocalizations in a mouse model of fragile X syndrome reveals limited, call type specific deficits.

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Snigdha Roy

Full Text Available Fragile X syndrome (FXS is a well-recognized form of inherited mental retardation, caused by a mutation in the fragile X mental retardation 1 (Fmr1 gene. The gene is located on the long arm of the X chromosome and encodes fragile X mental retardation protein (FMRP. Absence of FMRP in fragile X patients as well as in Fmr1 knockout (KO mice results, among other changes, in abnormal dendritic spine formation and altered synaptic plasticity in the neocortex and hippocampus. Clinical features of FXS include cognitive impairment, anxiety, abnormal social interaction, mental retardation, motor coordination and speech articulation deficits. Mouse pups generate ultrasonic vocalizations (USVs when isolated from their mothers. Whether those social ultrasonic vocalizations are deficient in mouse models of FXS is unknown. Here we compared isolation-induced USVs generated by pups of Fmr1-KO mice with those of their wild type (WT littermates. Though the total number of calls was not significantly different between genotypes, a detailed analysis of 10 different categories of calls revealed that loss of Fmr1 expression in mice causes limited and call-type specific deficits in ultrasonic vocalization: the carrier frequency of flat calls was higher, the percentage of downward calls was lower and that the frequency range of complex calls was wider in Fmr1-KO mice compared to their WT littermates.

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

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Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

2010-10-20

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

Comparison of field swept ferromagnetic resonance methods - A case study using Ni-Mn-Sn films

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Modak, R.; Samantaray, B.; Mandal, P.; Srinivasu, V. V.; Srinivasan, A.

2018-05-01

Ferromagnetic resonance spectroscopy is used to understand the magnetic behavior of Ni-Mn-Sn Heusler alloy film. Two popular experimental methods available for recording FMR spectra are presented here. In plane angular (φH) variation of magnetic relaxation is used to evaluate the in plane anisotropy (Ku) of the film. The out of plane (θH) variation of FMR spectra has been numerically analyzed to extract the Gilbert damping coefficient, effective magnetization and perpendicular magnetic anisotropy (K1). Magnetic homogeneity of the film had also been evaluated in terms of 2-magnon contribution from FMR linewidth. The advantage and limitations of these two popular FMR techniques are discussed on the basis of the results obtained in this comparative study.

Diagnostic, carrier and prenatal genetic testing for fragile X ...

African Journals Online (AJOL)

Background. 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 ...

Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders.

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Robertson, Erin E; Hall, Deborah A; McAsey, Andrew R; O'Keefe, Joan A

2016-08-01

The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS. By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis. Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.

Latent fingerprint wavelet transform image enhancement technique for optical coherence tomography

CSIR Research Space (South Africa)

Makinana, S

2016-09-01

Full Text Available (FMR) and Equal Error Rate (EER) were used. The results of these two measures gives the FMR of 3% and EER of 1.9% for denoised images which is better than non-denoised images where the EER is 8.7%....

Molecular Testing for Fragile X: Analysis of 5062 Tests from 1105 Fragile X Families—Performed in 12 Clinical Laboratories in Spain

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María-Isabel Tejada

2014-01-01

Full Text Available Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P<0.001. Furthermore, in mothers with intermediate alleles (45–54 repeats, there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55–59 repeats, there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.

77 FR 69651 - Final Fair Market Rents for the Housing Choice Voucher Program for Small Area Fair Market Rent...

Science.gov (United States)

2012-11-20

... the Housing Choice Voucher Program for Small Area Fair Market Rent Demonstration Program Participants... Authorities (PHAs) participating in the Small Area FMR Demonstration. SUMMARY: Section 8(c)(1) of the United... Housing Choice Voucher (HCV) Program for those PHAs selected to participate in the Small Area FMR...

An X-band Co{sup 2+} EPR study of Zn{sub 1−x}Co{sub x}O (x=0.005–0.1) nanoparticles prepared by chemical hydrolysis methods using diethylene glycol and denaturated alcohol at 5 K

Energy Technology Data Exchange (ETDEWEB)

Misra, Sushil K., E-mail: skmisra@alcor.concordia.ca [Physics Department, Concordia University, Montreal, QC, Canada H3G 1M8 (Canada); Andronenko, S.I. [Physics Institute, Kazan Federal University, Kazan 420008 (Russian Federation); Srinivasa Rao, S.; Chess, Jordan; Punnoose, A. [Department of Physics, Boise State University, Boise, ID 83725-1570 (United States)

2015-11-15

EPR investigations on two types of dilute magnetic semiconductor (DMS) ZnO nanoparticles doped with 0.5–10% Co{sup 2+} ions, prepared by two chemical hydrolysis methods, using: (i) diethylene glycol ((CH{sub 2}CH{sub 2}OH){sub 2}O) (NC-rod-like samples), and (ii) denatured ethanol (CH{sub 3}CH{sub 2}OH) solutions (QC-spherical samples), were carried out at X-band (9.5 GHz) at 5 K. The analysis of EPR data for NC samples revealed the presence of several types of EPR lines: (i) two types, intense and weak, of high-spin Co{sup 2+} ions in the samples with Co concentration >0.5%; (ii) surface oxygen vacancies, and (iii) a ferromagnetic resonance (FMR) line. QC samples exhibit an intense FMR line and an EPR line due to high-spin Co{sup 2+} ions. FMR line is more intense, than the corresponding line exhibited by NC samples. These EPR spectra varied for sample with different doping concentrations. The magnetic states of these samples as revealed by EPR spectra, as well as the origin of ferromagnetism DMS samples are discussed. - Highlights: • 5 K X band Co{sup 2+} EPR investigations on QC and NC ZnO dilute magnetic semiconductor nanoparticles. • NC and QC samples exhibited high-spin Co{sup 2+} EPR lines and ferromagnetic resonance line. • NC sample also exhibit line due surface oxygen vacancies. • FMR line is more intense in QC than that in NC samples. • Magnetic states and the origin of ferromagnetism are discussed.

A study of the magnetic resonance in a single-crystal Ni50.47Mn28.17Ga21.36 alloy

International Nuclear Information System (INIS)

Gavriljuk, V G; Dobrinsky, A; Shanina, B D; Kolesnik, S P

2006-01-01

The single-crystal non-stoichiometric magnetic shape memory alloy Ni 1-x-y Mn x Ga y with x = 0.2817, y = 0.2136 is studied using magnetic resonance spectroscopy: ferromagnetic resonance (FMR) and conduction electron spin resonance (CESR). The temperature dependence of the integral intensity, the resonance field and the line-width are measured across the wide temperature interval from 4.2 to 570 K. Three phase transformations are found in this alloy: paramagnetic ↔ ferromagnetic with a Curie temperature of 360 K, austenite-to-martensite (direct with T ms = 312 K and reverse with T as = 313 K), and a transformation at T = 45 K, suggestive of the spin-glass state. The angular dependence of the FMR signals is measured in the martensitic and austenitic states before and after the martensite-to-austenite transition. The experimental data are used for determination of the magnetization M m and anisotropy parameters K 1 and K 2 in the martensitic state. The obtained coefficient K 2 is determined to be not small and, moreover, it is comparable with K 1 . The temperature dependence of the resonance signals is also investigated at temperatures significantly higher than T C , where FMR was transformed to CESR. In the paramagnetic austenitic state (above T C ) the alloy reveals an extremely intensive signal of CESR, which suggests a high concentration of conduction electrons and correlates with the large value of the magnetic-field-induced strain observed in the alloys of such composition. The temperature dependence of the skin layer depth is found from the sharp decay of the CESR signal with temperature, which is related to the disappearing large magnetic resistance after transformation to the paramagnetic state

Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model

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Weirui Guo

2015-12-01

Full Text Available Abnormal metabotropic glutamate receptor 5 (mGluR5 function, as a result of disrupted scaffolding with its binding partner Homer, contributes to the pathophysiology of fragile X syndrome, a common inherited form of intellectual disability and autism caused by mutations in Fmr1. How loss of Fmr1 disrupts mGluR5-Homer scaffolds is unknown, and little is known about the dynamic regulation of mGluR5-Homer scaffolds in wild-type neurons. Here, we demonstrate that brief (minutes-long elevations in neural activity cause CaMKIIα-mediated phosphorylation of long Homer proteins and dissociation from mGluR5 at synapses. In Fmr1 knockout (KO cortex, Homers are hyperphosphorylated as a result of elevated CaMKIIα protein. Genetic or pharmacological inhibition of CaMKIIα or replacement of Homers with dephosphomimetics restores mGluR5-Homer scaffolds and multiple Fmr1 KO phenotypes, including circuit hyperexcitability and/or seizures. This work links translational control of an FMRP target mRNA, CaMKIIα, to the molecular-, cellular-, and circuit-level brain dysfunction in a complex neurodevelopmental disorder.

Impaired spatial processing in a mouse model of fragile X syndrome.

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Ghilan, Mohamed; Bettio, Luis E B; Noonan, Athena; Brocardo, Patricia S; Gil-Mohapel, Joana; Christie, Brian R

2018-05-17

Fragile X syndrome (FXS) is the most common form of inherited intellectual impairment. The Fmr1 -/y mouse model has been previously shown to have deficits in context discrimination tasks but not in the elevated plus-maze. To further characterize this FXS mouse model and determine whether hippocampal-mediated behaviours are affected in these mice, dentate gyrus (DG)-dependent spatial processing and Cornu ammonis 1 (CA1)-dependent temporal order discrimination tasks were evaluated. In agreement with previous findings of long-term potentiation deficits in the DG of this transgenic model of FXS, the results reported here demonstrate that Fmr1 -/y mice perform poorly in the DG-dependent metric change spatial processing task. However, Fmr1 -/y mice did not present deficits in the CA1-dependent temporal order discrimination task, and were able to remember the order in which objects were presented to them to the same extent as their wild-type littermate controls. These data suggest that the previously reported subregional-specific differences in hippocampal synaptic plasticity observed in the Fmr1 -/y mouse model may manifest as selective behavioural deficits in hippocampal-dependent tasks. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome.

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Zhao-hui Xu

Full Text Available Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP because of Fmr1 gene silencing. Serotonin (5-HT is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5-HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP in the anterior cingulate cortex (ACC of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca(2+ concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation.

Treatment of Fragile X Syndrome with a Neuroactive Steroid

Science.gov (United States)

2014-08-01

syndrome (FXTAS). Am J Med Genet A. 2012;158A(6):1304–1309. 8. Sullivan SD, Welt C, Sherman S. FMR1 and the continuum of primary ovarian insufficiency...differentiating between what behaviors may actually be changing as opposed to what the caregiver thinks should be changed. The large uproar from families with... Syndrome with a Neuroactive Steroid PRINCIPAL INVESTIGATOR: Randi Hagerman, M.D. CONTRACTING ORGANIZATION: University of California

Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome.

Science.gov (United States)

Hodges, Jennifer L; Yu, Xinzhu; Gilmore, Anthony; Bennett, Hannah; Tjia, Michelle; Perna, James F; Chen, Chia-Chien; Li, Xiang; Lu, Ju; Zuo, Yi

2017-07-15

Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. Taking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. We found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects. Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Combined Fractional Treatment of Acne Scars Involving Non-ablative 1,550-nm Erbium-glass Laser and Micro-needling Radiofrequency: A 16-week Prospective, Randomized Split-face Study

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Hyuck Hoon Kwon

2017-06-01

Full Text Available An optimized therapeutic regimen involving a non-ablative fractionated laser or radiofrequency therapy for acne scars has not yet been established. To evaluate whether the combination of a non-ablative fractional laser (NAF and fractional micro-needling radiofrequency (FMR has clinical advantages for the treatment of atrophic acne scars compared with NAF alone, a 16-week prospective, randomized split-face study was performed. Each facial side of a patient was treated with 3 sessions of either NAF with FMR or NAF alone, with a 4-week interval between each session. Although both sides demonstrated significant decreases in the échelle d’évaluation clinique des cicatrices d’acné (ECCA score, the facial side treated using the combination regimen demonstrated greater improvement in ECCA score regarding degree and onset time than the NAF-treated side. Histopathological and immunohistochemical results confirmed the clinical findings. This study demonstrated that a combination regimen involving NAF and FMR could be a viable option with satisfactory efficacy.

Treatment of fragile X-associated tremor ataxia syndrome (FXTAS and related neurological problems

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Randi J Hagerman

2008-06-01

Full Text Available Randi J Hagerman1,2, Deborah A Hall3, Sarah Coffey1,2, Maureen Leehey3, James Bourgeois4, John Gould5, Lin Zhang6, Andreea Seritan4, Elizabeth Berry-Kravis7–9, John Olichney6, Joshua W Miller10, Amy L Fong11, Randall Carpenter12, Cathy Bodine13, Louise W Gane1,2, Edgar Rainin1, Hillary Hagerman1, Paul J Hagerman141M.I.N.D. Institute, 2Department of Pediatrics, 4Department of Psychiatry & Behavioral Sciences, 5Department of Urology, 6Department of Neurology, 10Department of Pathology and Laboratory Medicine, 14Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA; 3Department of Neurology, University of Colorado, Denver, CO, USA; 7Department of Pediatrics, Neurology, and Biochemistry, 8Department of Neurological Sciences, 9Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; 11Physical Edge, Inc., Davis, CA, USA; 12Seaside Therapeutics, Cambridge, MA, USA; 13Department of Physical Medicine and Rehabilitation, University of Colorado Health Sciences Center, Denver, CO, USAAbstract: Fragile X-associated tremor/ataxia syndrome (FXTAS is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats of the fragile X (FMR1 gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently

Gender Difference in Body Fat for Healthy Chinese Children and Adolescents.

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Guo, Bin; Wu, Qiulian; Gong, Jian; Xiao, Zeyu; Tang, Yongjin; Shang, Jingjie; Cheng, Yong; Xu, Hao

2016-04-01

This study aimed to establish gender-related differences and the percentile curves for total body fat mass percentage (Total FM%), trunk/appendicular fat mass ratio (TrAppFMR), and fat mass ratio as % fat trunk/% fat lower limb (TrLLFMR) in Chinese children and adolescents using dual-energy X-ray absorptiometry (DXA). Children (n = 1541; 764 girls) and adolescents aged 5 to 19 years were recruited from southern China. Total FM% and regional FM were measured by DXA. TrAppFMR values were calculated as trunk FM divided by appendicular FM, and TrLLFMR values were calculated as the ratio between the percentage of trunk FM and the percentage of lower limb FM. Total FM% peaks for boys were at approximately age 11 years and continued to increase for girls throughout adolescence. Median Total FM% at the age of 19 years was 15.53% and 28.06% for boys and girls, respectively. Median TrAppFMR and TrLLFMR increases were 61% and 81% from 5 to 19 years of age in boys compared with those in girls, 31% and 54%. The curves for median TrAppFMR and TrLLFMR in girls were relatively flat, with TrAppFMR and TrLLFMR remaining near 1.0 after 16 years of age, whereas in boys, median TrAppFMR and TrLLFMR increased with age until approximately 19 years. Gender differences in the patterns of proportion and distribution of body fat were found. We present sex-specific percentile curves for Total FM%-age, TrAppFMR-age, and TrLLFMR-age relationships in this population.

Comparison of fractional microneedling radiofrequency and bipolar radiofrequency on acne and acne scar and investigation of mechanism: comparative randomized controlled clinical trial.

Science.gov (United States)

Min, Seonguk; Park, Seon Yong; Yoon, Ji Young; Suh, Dae Hun

2015-12-01

Fractional microneedling radiofrequency (FMR) is one of the promising methods in acne treatment. Moreover, bipolar radiofrequency (BR) generates heat thereby which induces neocollagenosis. FMR may have the potential to be a safe and effective treatment for the patients both with acne and acne scar. This study was performed to compare the efficacy and safety of FMR and BR in acne and acne scar treatment. Furthermore, mechanism of the FMR treatment was investigated through skin tissues obtained from subjects. Twenty subjects with mild-to-moderate acne and acne scars were treated in a split-face manner with FMR and BR. Two sessions of treatment was done 4 weeks apart in a total 12-week prospective single-blind, randomized clinical trial. Clinical assessment and sebum measurement were carried out for the evaluation of efficacy and safety. Skin tissues were acquired for investigation of molecular changes. FMR was more effective for acne scar especially in icepick and boxcar scar compared to BR. Both inflammatory and non-inflammatory acne lesions decreased by 80 and 65 % in the FMR-treated side at the final visit of 12 weeks, respectively. FMR treatment resulted in significant reduction of sebum excretion. Both treatments showed no severe adverse effects other than erythema. The FMR showed superior efficacy in acne and acne scar compared with BR. Increased expression of TGFβ and collagen I and decreased expression of NF-κB, IL-8 are suggested to involve in the improvement of acne scar and acne lesion by FMR.

Molecular diagnosis of Fragile X syndrome in subjects with intellectual disability of unknown origin: implications of its prevalence in regional Pakistan.

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Madiha Kanwal

Full Text Available Fragile-X syndrome (FXS is the most common form of inherited intellectual disability (ID and affects 0.7-3.0% of intellectually compromised population of unknown etiology worldwide. It is mostly caused by repeat expansion mutations in the FMR1 at chromosome Xq27.3. The present study aimed to develop molecular diagnostic tools for a better detection of FXS, to assess implementation of diagnostic protocols in a developing country and to estimate the prevalence of FXS in a cohort of intellectually disabled subjects from Pakistan. From a large pool of individuals with below normal IQ range, 395 subjects with intellectual disability of unknown etiology belonging to different regions of the country were recruited. Conventional-PCR, modified-PCR and Southern blot analysis methods were employed for the detection of CGG repeat polymorphisms in the FMR1 gene. Initial screening with conventional-PCR identified 13 suspected patients. Subsequent investigations through modified PCR and Southern blot analyses confirmed the presence of the FMR1 mutation, suggesting a prevalence of 3.5% and 2.8% (mean 3.3% among the male and female ID patients, respectively. These diagnostic methods were further customized with the in-house conditions to offer robust screening of referral patients/families for diagnostics and genetic counseling. Prescreening and early diagnosis are crucial for designing a prudent strategy for the management of subjects with ID. Outcome of the study recommends health practitioners for implementation of molecular based FXS diagnosis in routine clinical practice to give a better care for patients similar to the ones included in the study.

Field Metabolic Rate Is Dependent on Time-Activity Budget in Ring-Billed Gulls (Larus delawarensis Breeding in an Anthropogenic Environment.

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Sarah C Marteinson

Full Text Available Environmental and behavioral factors have long been assumed to affect variation in avian field metabolic rate (FMR. However, due to the difficulties in measuring continuous behavior of birds over prolonged periods of time, complete time-activity budgets have rarely been examined in relation to FMR. Our objective was to determine the effect of activity (measured by detailed time-activity budgets and a series of extrinsic and intrinsic factors on FMR of the omnivorous ring-billed gull (Larus delawarensis. The experiment was conducted during the incubation period when both members of the pair alternate between attending the nest-site and leaving the colony to forage in aquatic and anthropogenic environments (city, agricultural. FMR was determined using the doubly labeled water method. Time-activity budgets were extrapolated from spatio-temporal data (2-5 days obtained from bird-borne GPS data loggers. Gulls had low FMRs compared to those predicted by allometric equations based on recorded FMRs from several seabird species. Gulls proportioned their time mainly to nest-site attendance (71% of total tracking time, which reduced FMR/g body mass, and was the best variable explaining energy expenditure. The next best variable was the duration of foraging trips, which increased FMR/g; FMR/g was also elevated by the proportion of time spent foraging or flying (17% and 8% of tracking time respectively. Most environmental variables measured did not impact FMR/g, however, the percent of time birds were subjected to temperatures below their lower critical temperature increased FMR. Time-activity budgets varied between the sexes, and with temperature and capture date suggesting that these variables indirectly affected FMR/g. The gulls foraged preferentially in anthropogenic-related habitats, which may have contributed to their low FMR/g due to the high availability of protein- and lipid-rich foods. This study demonstrates that activities were the best

Study of anisotropy, magnetization reversal and damping in ultrathin Co films on MgO (0 0 1) substrate

Science.gov (United States)

Mallik, Srijani; Bedanta, Subhankar

2018-01-01

Ultrathin Co films of 3 nm thickness have been prepared on MgO (0 0 1) substrate in presence or absence of substrate pre-annealing. Uniaxial anisotropy is induced in the samples due to the deposition under oblique angle of incidence. Along with the oblique deposition induced anisotropy, another uniaxial anisotropy contribution has been observed due to pre-annealing. However, no cubic anisotropy has been observed here as compared to the thicker films. Angle dependent ferromagnetic resonance (FMR) measurement confirms the presence of two anisotropies in the pre-annealed sample with ∼18° misalignment with each other. The two anisotropy constants were calculated from both superconducting quantum interference device (SQUID) magnetometry and FMR spectroscopy. The magnetization reversal is governed by nucleation dominated aftereffect followed by domain wall motion for the pre-annealed sample. Branched domains are observed for the sample prepared without pre-annealing which indicates grain disorientation of Co. However, in the thicker (25 nm) Co films ripple domains were observed in contrary to ultrathin (3 nm) films.

Numerical simulations of N=(1,1) 1+1-dimensional super Yang-Mills theory with large supersymmetry breaking

International Nuclear Information System (INIS)

Filippov, I.; Pinsky, S.

2002-01-01

We consider the N=(1,1) super Yang-Mills (SYM) theory that is obtained by dimensionally reducing SYM theory in 2+1 dimensions to 1+1 dimensions and discuss soft supersymmetry breaking. We discuss the numerical simulation of this theory using supersymmetric discrete light-cone quantization when either the boson or the fermion has a large mass. We compare our result to the pure adjoint fermion theory and pure adjoint boson discrete light-cone quantization calculations of Klebanov, Demeterfi, Bhanot and Kutasov. With a large boson mass we find that it is necessary to add additional operators to the theory to obtain sensible results. When a large fermion mass is added to the theory we find that it is not necessary to add operators to obtain a sensible theory. The theory of the adjoint boson is a theory that has stringy bound states similar to the full SYM theory. We also discuss another theory of adjoint bosons with a spectrum similar to that obtained by Klebanov, Demeterfi, and Bhanot

Ferromagnetic resonance frequency increase and resonance line broadening of a ferromagnetic Fe–Co–Hf–N film with in-plane uniaxial anisotropy by high-frequency field perturbation

International Nuclear Information System (INIS)

Seemann, K.; Leiste, H.; Krüger, K.

2013-01-01

Soft ferromagnetic Fe-Co-Hf-N films, produced by reactive r.f. magnetron sputtering, are useful to study the ferromagnetic resonance (FMR) by means of frequency domain permeability measurements up to the GHz range. Films with the composition Fe 33 Co 43 Hf 10 N 14 exhibit a saturation polarisation J s of around 1.35 T. They are consequently considered as being uniformly magnetised due to an in-plane uniaxial anisotropy of approximately μ 0 H u ≈4.5 m T after annealing them, e.g., at 400 °C in a static magnetic field for 1 h. Being exposed to a high-frequency field, the precession of magnetic moments leads to a marked frequency-dependent permeability with a sharp Lorentzian shaped imaginary part at around 2.33 GHz (natural resonance peak), which is in a very good agreement with the modified Landau–Lifschitz–Gilbert (LLG) differential equation. A slightly increased FMR frequency and a clear increase in the resonance line broadening due to an increase of the exciting high-frequency power (1–25.1 mW), considered as an additional perturbation of the precessing system of magnetic moments, could be discovered. By solving the homogenous LLG differential equation with respect to the in-plane uniaxial anisotropy, it was revealed that the high-frequency field perturbation impacts the resonance peak position f FMR and resonance line broadening Δf FMR characterised by a completed damping parameter α=α eff +Δα. Adapted from this result, the increase in f FMR and decrease in lifetime of the excited level of magnetic moments associated with Δf FMR , similar to a spin-½ particle in a static magnetic field, was theoretically elaborated as well as compared with experimental data. - Highlights: • Impact on the resonance frequency and resonance line by the high-frequency power. • Theoretic approach by solving the LLG differential equation. • Experimental verification and magnon processes. • Theoretical and experimental determination of the resonance state

Distrofia miotônica tipo 1 em pacientes com catarata: diagnóstico molecular para triagem e aconselhamento genético Myotonic dystrophy type 1 in cataract patients: Molecular diagnosis for screening and genetic counseling

Directory of Open Access Journals (Sweden)

María Verónica Muñoz Rojas

2005-02-01

Full Text Available OBJETIVOS: Detectar novos pacientes portadores da mutação e pré-mutação da DM1, entre pacientes com catarata e realizar aconselhamento genético. MÉTODOS: Foi estudado o DNA de 60 pacientes, por meio da análise por reação em cadeia de polimerase. Este estudo foi realizado no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto e os pacientes foram selecionados a partir dos atendimentos realizados no Ambulatório de Catarata do Departamento de Oftalmologia, entre 01/01/1982 a 30/06/1995. Os critérios de seleção foram pacientes com menos de 55 anos, com catarata bilateral, sem fator causal que justificasse a lesão, exceto por diabete melito tipo 2 com ou sem sinais neuromusculares sugestivos de distrofia miotônica. RESULTADOS: Foram encontrados 3 pacientes com a mutação completa, correspondendo a 5% da amostra. Nenhum portador da pré-mutação foi encontrado. A partir dos pacientes diagnosticados, outros familiares afetados foram detectados. CONCLUSÕES: Este estudo enfatiza a importância da triagem de distrofia miotônica tipo 1 (DM1 entre pacientes com catarata, e mostra, também, a importância do aconselhamento genético destes pacientes.PURPOSE: To detect MD1 premutation and full mutation carriers among cataract patients and offer familial genetic counseling. METHODS: We studied the DNA of 60 selected cataract patients through polymerase chain reaction analysis. This study was performed at the "Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto" where selected patients had been examined at the Cataract Outpatient Clinic from 01/01/1982 to 30/06/1995. Selection criteria were age under 55 with no obvious precipitating factor, except diabetes mellitus type 2, with or without neuromuscular signs suggestive of myotonic dystrophy. RESULTS: Three patients were found to have a full mutation corresponding to 5% of the group. Additional affected individuals were found among patients' relatives. No

Promising Option for Treatment of Striae Alba: Fractionated Microneedle Radiofrequency in Combination with Fractional Carbon Dioxide Laser

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Farahnaz Fatemi Naeini

2016-01-01

Full Text Available Background. A consistent treatment has not been proposed for treatment of Striae Alba (SA. The present study was designed to compare the fractionated microneedle radiofrequency (FMR alone and in combination with fractional carbon dioxide laser (FMR + CO2 in the treatment of SA. Methods. Forty-eight pairs of SA from six patients were selected. Right or left SAs were randomly assigned to one of the treatment groups. The surface area of the SA before and after treatment and clinical improvement using a four-point scale were measured at the baseline, after one and three months. Results. The mean age of the patients was 30.17±5.19 years. The mean difference of the surface area between pre- and posttreatment in the FMR + CO2 group was significantly higher than that in the FMR group (p=0.003. Clinical improvement scales showed significantly higher improvement in the FMR + CO2 group than in the FMR group in the first and second follow-up (p=0.002 and 0.004, resp.. There were no major persistence side-effects in both groups. Conclusions. The results showed that FMR + CO2 laser was more effective than FMR alone in the treatment of SA.

Loss-of-function analyses of the fragile X-related and dopamine receptor genes by RNA interference in the cricket Gryllus bimaculatus.

Science.gov (United States)

Hamada, Aska; Miyawaki, Katsuyuki; Honda-sumi, Eri; Tomioka, Kenji; Mito, Taro; Ohuchi, Hideyo; Noji, Sumihare

2009-08-01

In order to explore a possibility that the cricket Gryllus bimaculatus would be a useful model to unveil molecular mechanisms of human diseases, we performed loss-of-function analyses of Gryllus genes homologous to human genes that are responsible for human disorders, fragile X mental retardation 1 (fmr1) and Dopamine receptor (DopR). We cloned cDNAs of their Gryllus homologues, Gb'fmr1, Gb'DopRI, and Gb'DopRII, and analyzed their functions with use of nymphal RNA interference (RNAi). For Gb'fmr1, three major phenotypes were observed: (1) abnormal wing postures, (2) abnormal calling song, and (3) loss of the circadian locomotor rhythm, while for Gb'DopRI, defects of wing posture and morphology were found. These results indicate that the cricket has the potential to become a novel model system to explore human neuronal pathogenic mechanisms and to screen therapeutic drugs by RNAi. Copyright (c) 2009 Wiley-Liss, Inc.

Field angle dependence of voltage-induced ferromagnetic resonance under DC bias voltage

International Nuclear Information System (INIS)

Shiota, Yoichi; Miwa, Shinji; Tamaru, Shingo; Nozaki, Takayuki; Kubota, Hitoshi; Fukushima, Akio; Suzuki, Yoshishige; Yuasa, Shinji

2016-01-01

We studied the rectification function of microwaves in CoFeB/MgO-based magnetic tunnel junctions using voltage-induced ferromagnetic resonance (FMR). Our findings reveal that the shape of the structure of the spectrum depends on the rotation angle of the external magnetic field, providing clear evidence that FMR dynamics are excited by voltage-induced magnetic anisotropy changes. Further, enhancement of the rectified voltage was demonstrated under a DC bias voltage. In our experiments, the highest microwave detection sensitivity obtained was 350 mV/mW, at an RF frequency of 1.0 GHz and field angle of θ_H=80°, ϕ_H=0°. The experimental results correlated with those obtained via simulation, and the calculated results revealed the magnetization dynamics at the resonance state. - Highlights: • Examined voltage-induced ferromagnetic resonance (FMR) under various field angles. • FMR dynamics are excited by voltage-induced magnetic anisotropy changes. • Microwave detection sensitivity depends on input RF and elevation angle. • Microwave detection sensitivity=350 mV/mW at RF=1.0 GHz, θ_H=80°, ϕ_H=0°.

Dissociation of social and nonsocial anxiety in a mouse model of fragile X syndrome

OpenAIRE

Liu, Zhong-Hua; Smith, Carolyn Beebe

2009-01-01

Anxiety is a common symptom in fragile X patients. However, an anxiety-prone phenotype in mouse models of fragile X syndrome is not clear. In most studies of fmr1 knockout mice, decreased anxiety-like responses in exploratory-based models are found, but mice also exhibit abnormal social interactions. We hypothesize the coexistence of elevated social anxiety and reduced nonsocial anxiety in fmr1 knockout mice. In the present study, we applied an automated three-chambered social approach method...

Ferromagnetic resonance features of degenerate GdN semiconductor

Energy Technology Data Exchange (ETDEWEB)

Vidyasagar, Reddithota, E-mail: dr.vidyasagar1979@gmail.com [Department of Electrical and Electronic Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Kobe 657-8501 (Japan); Kita, Takashi [Department of Electrical and Electronic Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai, Kobe 657-8501 (Japan); Sakurai, Takahiro; Shimokawa, Tokuro [Centre for Support to Research and Education Activities, Kobe University, 1-1 Rokkodai, Kobe 657-8501 (Japan); Ohta, Hitoshi [Molecular Photoscience Research Center and Graduate School of Science, Kobe University, 1-1 Rokkodai, Kobe 657-8501 (Japan)

2017-06-15

Using X-band Ferromagnetic Resonance (FMR) Spectroscopy, we demonstrate the microscopic ferromagnetic resonance features of degenerated GdN semiconductor. The FMR spectrum suggests a single resonance mode below 10 K; interestingly, this particular structure is found to exhibit a peculiar magnetic resonance (PMR) on the top of the uniform FMR while temperature increases from 12–36 K. The low-field PMR mode attributed to the differently magnetized part of the film with an easy in-plane axis. The narrow-field gap between PMR and uniform FMR suggests the strong coupling owning to the differently magnetized part with easy in-plane axis and the magnetized part with an out-of-plane axis. The saturation magnetization, cubic magnetocrystalline anisotropy, and uniaxial anisotropy of GdN epitaxial film have been evaluated by the angular-dependence FMR. - Highlights: • Observation of peculiar magnetic resonance (PMR) on the top of ferromagnetic resonance (FMR). • Newly evolving PMR manifests differently magnetized part of the film with an easy in-plane axis. • Narrow gap between PMR and FMR owing to the strong interaction between two spin–wave resonances. • Uniaxial anisotropy increases with GdN thickness decreases.

Electrical detection of ferromagnetic resonance in ferromagnet/n-GaAs heterostructures by tunneling anisotropic magnetoresistance

Energy Technology Data Exchange (ETDEWEB)

Liu, C.; Boyko, Y.; Geppert, C. C.; Christie, K. D.; Stecklein, G.; Crowell, P. A., E-mail: crowell@physics.umn.edu [School of Physics and Astronomy, University of Minnesota, Minneapolis, Minnesota 55455 (United States); Patel, S. J. [Department of Materials, University of California, Santa Barbara, California 93106 (United States); Palmstrøm, C. J. [Department of Materials, University of California, Santa Barbara, California 93106 (United States); Department of Electrical and Computer Engineering, University of California, Santa Barbara, California 93106 (United States)

2014-11-24

We observe a dc voltage peak at ferromagnetic resonance (FMR) in samples consisting of a single ferromagnetic (FM) layer grown epitaxially on the n-GaAs (001) surface. The FMR peak is detected as an interfacial voltage with a symmetric line shape and is present in samples based on various FM/n-GaAs heterostructures, including Co{sub 2}MnSi/n-GaAs, Co{sub 2}FeSi/n-GaAs, and Fe/n-GaAs. We show that the interface bias voltage dependence of the FMR signal is identical to that of the tunneling anisotropic magnetoresistance (TAMR) over most of the bias range. Furthermore, we show how the precessing magnetization yields a dc FMR signal through the TAMR effect and how the TAMR phenomenon can be used to predict the angular dependence of the FMR signal. This TAMR-induced FMR peak can be observed under conditions where no spin accumulation is present and no spin-polarized current flows in the semiconductor.

Flight-induced changes in gene expression in the Glanville fritillary butterfly.

Science.gov (United States)

Kvist, Jouni; Mattila, Anniina L K; Somervuo, Panu; Ahola, Virpi; Koskinen, Patrik; Paulin, Lars; Salmela, Leena; Fountain, Toby; Rastas, Pasi; Ruokolainen, Annukka; Taipale, Minna; Holm, Liisa; Auvinen, Petri; Lehtonen, Rainer; Frilander, Mikko J; Hanski, Ilkka

2015-10-01

Insect flight is one of the most energetically demanding activities in the animal kingdom, yet for many insects flight is necessary for reproduction and foraging. Moreover, dispersal by flight is essential for the viability of species living in fragmented landscapes. Here, working on the Glanville fritillary butterfly (Melitaea cinxia), we use transcriptome sequencing to investigate gene expression changes caused by 15 min of flight in two contrasting populations and the two sexes. Male butterflies and individuals from a large metapopulation had significantly higher peak flight metabolic rate (FMR) than female butterflies and those from a small inbred population. In the pooled data, FMR was significantly positively correlated with genome-wide heterozygosity, a surrogate of individual inbreeding. The flight experiment changed the expression level of 1513 genes, including genes related to major energy metabolism pathways, ribosome biogenesis and RNA processing, and stress and immune responses. Males and butterflies from the population with high FMR had higher basal expression of genes related to energy metabolism, whereas females and butterflies from the small population with low FMR had higher expression of genes related to ribosome/RNA processing and immune response. Following the flight treatment, genes related to energy metabolism were generally down-regulated, while genes related to ribosome/RNA processing and immune response were up-regulated. These results suggest that common molecular mechanisms respond to flight and can influence differences in flight metabolic capacity between populations and sexes. © 2015 John Wiley & Sons Ltd.

Low-relaxation spin waves in laser-molecular-beam epitaxy grown nanosized yttrium iron garnet films

Energy Technology Data Exchange (ETDEWEB)

Lutsev, L. V., E-mail: l-lutsev@mail.ru; Korovin, A. M.; Bursian, V. E.; Gastev, S. V.; Fedorov, V. V.; Suturin, S. M.; Sokolov, N. S. [Ioffe Physical-Technical Institute, Russian Academy of Sciences, 194021 St. Petersburg (Russian Federation)

2016-05-02

Synthesis of nanosized yttrium iron garnet (Y{sub 3}Fe{sub 5}O{sub 12}, YIG) films followed by the study of ferromagnetic resonance (FMR) and spin wave propagation in these films is reported. The YIG films were grown on gadolinium gallium garnet substrates by laser molecular beam epitaxy. It has been shown that spin waves propagating in YIG deposited at 700 °C have low damping. At the frequency of 3.29 GHz, the spin-wave damping parameter is less than 3.6 × 10{sup −5}. Magnetic inhomogeneities of the YIG films give the main contribution to the FMR linewidth. The contribution of the relaxation processes to the FMR linewidth is as low as 1.2%.

Comparison of ferromagnetic resonance between amorphous wires and microwires

International Nuclear Information System (INIS)

Raposo, V.; Zazo, M.; Iniguez, J.

2011-01-01

Measurements of magnetoimpedance in amorphous wires and microwires at the GHz region are presented here. The maxima observed in the magnetoimpedance of different samples in the high frequency range are attributed to the ferromagnetic resonance (FMR) that occurs when a sample is submitted to a longitudinal static magnetic field and an oscillating transversal field. While the appearance of a peak on the resistance and the drop of the inductance is explained by means of FMR, the dependence of the width of that resonance with different parameters (magnetic field, stress distribution, sample size, etc.) is not clearly understood, and therefore additional works to explain the value of the resonance width are needed. It is interesting to consider firstly, the influence of the diameter of the sample and thus the stress distribution on the FMR. The size and position of the FMR is found to be completely different for diameters ranging from 24 to 171 μm. The dependence of the frequency value at which the peak of the resistance is found can be explained by the different values of the anisotropy field in the sample. The width of the FMR changes drastically with the diameter of the sample and with the applied magnetic field and they will be discussed in this paper. - Research highlights: → Measurement of the FMR in wires and microwires → Comparison of the FMR width in both types of samples. → Correlation of the FMR to intrinsic properties as stress distribution.

Measuring the energy expenditure and water flux in free-ranging alpacas (Lama pacos) in the peruvian andes using the doubly labelled water technique.

Science.gov (United States)

Riek, Alexander; Van Der Sluijs, Leendert; Gerken, Martina

2007-12-01

Energy expenditure and water flux were measured in free-ranging alpacas Lama pacos, a South American camelid, on natural pastures of the Peruvian Andes (altitude: 4,400 m above sea level). Water influx rate (WIR) was estimated in 16 males (age 2 years, weight 48.5+/-8.6 kg) labelled with 2H. In addition, the field metabolic rate (FMR) was measured in four of these animals labelled with both an oxygen (18O) and a hydrogen (2H) isotope. The WIR averaged 3.62 L H2O/day and the mean total body water 33.1 kg, equal to 68.2% of body weight (BW). The FMR of the four doubly labelled animals was 14.05 MJ/day. New allometric equations were calculated describing the relationships between WIR or FMR and BW, respectively, including published data on ruminants and the present alpaca results. The regression equation indicates that daily WIR scales to a similar metabolic size (kilograms of BW(0.94)) in alpacas than in wild or domesticated ruminants and camelids originating from arid and semiarid habitats. The resulting regression equation for FMR explained over 99% of the variation and corresponded to the function FMR (kilojoules per day)=1079 (kilograms of BW0.668) (n=5, r2=0.995, Palpacas have similar energy expenditures on a metabolic weight basis as other wild ruminants living under harsh climatic conditions.

In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1 and Costello syndrome.

Directory of Open Access Journals (Sweden)

Tiantian eWang

2015-07-01

Full Text Available Defects in the rat sarcoma viral oncogene homolog (Ras/extracellular-signal-regulated kinase (ERK and the phosphatidylinositol 3-kinase (PI3K-mammalian target of rapamycin (mTOR signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB of the auditory brainstem, in mouse models of Tuberous sclerosis (TSC, Fragile X syndrome (FXS, Neurofibromatosis type 1 (NF1 and Costello syndrome (CS. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO mice showed increased volume and surface area compared to wild-type (WT controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to wild-type controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.

High-frequency permeability of electroplated CoNiFe and CoNiFe-C alloys

International Nuclear Information System (INIS)

Rhen, Fernando M.F.; McCloskey, Paul; O'Donnell, Terence; Roy, Saibal

2008-01-01

We have investigated CoNiFe and CoNiFe-C electrodeposited by pulse reverse plating (PRP) and direct current (DC) techniques. CoNiFe(PRP) films with composition Co 59.4 Fe 27.7 Ni 12.8 show coercivity of 95 A m -1 (1.2 Oe) and magnetization saturation flux (μ 0 M s ) of 1.8 T. Resistivity of CoNiFe (PRP) is about 24 μΩ cm and permeability remains almost constant μ r ' ∼475 up to 30 MHz with a quality factor (Q) larger than 10. Additionally, the permeability spectra analysis shows that CoNiFe exhibits a classical eddy current loss at zero bias field and ferromagnetic resonance (FMR) when biased with 0.05 T. Furthermore, a crossover between eddy current and FMR loss is observed for CoNiFe-PRP when baised with 0.05 T. DC and PRP plated CoNiFe-C, which have resistivity and permeability of 85, 38 μΩ cm, μ r '=165 and 35 with Q>10 up to 320 MHz, respectively, showed only ferromagnetic resonance losses. The ferromagnetic resonance peaks in CoNiFe and CoNiFe-C are broad and resembles a Gaussian distribution of FMR frequencies. The incorporation of C to CoNiFe reduces eddy current loss, but also reduces the FMR frequency

26 CFR 1.6655-4 - Large corporations.

Science.gov (United States)

2010-04-01

... Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Additions to the Tax, Additional Amounts, and Assessable Penalties § 1.6655-4 Large... not to be taken into account and the taxable income of a corporation for any taxable year during the...

Surface density: a new parameter in the fundamental metallicity relation of star-forming galaxies

Science.gov (United States)

Hashimoto, Tetsuya; Goto, Tomotsugu; Momose, Rieko

2018-04-01

Star-forming galaxies display a close relation among stellar mass, metallicity, and star formation rate (or molecular-gas mass). This is known as the fundamental metallicity relation (FMR) (or molecular-gas FMR), and it has a profound implication on models of galaxy evolution. However, there still remains a significant residual scatter around the FMR. We show here that a fourth parameter, the surface density of stellar mass, reduces the dispersion around the molecular-gas FMR. In a principal component analysis of 29 physical parameters of 41 338 star-forming galaxies, the surface density of stellar mass is found to be the fourth most important parameter. The new 4D fundamental relation forms a tighter hypersurface that reduces the metallicity dispersion to 50 per cent of that of the molecular-gas FMR. We suggest that future analyses and models of galaxy evolution should consider the FMR in a 4D space that includes surface density. The dilution time-scale of gas inflow and the star-formation efficiency could explain the observational dependence on surface density of stellar mass.

Neuronal mapping of the heart with 6-[18F]fluorometaraminol

International Nuclear Information System (INIS)

Wieland, D.M.; Rosenspire, K.C.; Hutchins, G.D.; Van Dort, M.; Rothley, J.M.; Mislankar, S.G.; Lee, H.T.; Massin, C.C.; Gildersleeve, D.L.; Sherman, P.S.

1990-01-01

The false neurotransmitter metaraminol labeled with fluorine-18 has been used to noninvasively assess regional adrenergic nerve density in the canine heart. Intravenous administration of 6-[ 18 F]fluorometaraminol (FMR) results in high, selective accumulation of radioactivity in the heart; drug blocking studies with desipramine and reserpine confirm the neuronal locus of FMR. Iodine-125 labeled metaraminol, however, shows no selective accumulation in the canine heart. Positron emission tomography (PET) analyses with FMR of closed-chest dogs bearing left ventricular neuronal defects clearly delineate the region of neuronal impairment; blood perfusion in the left ventricle wall was homogeneous as determined by [13N]NH3 tomograms. The accumulation of FMR in regionally denervated dog heart correlates closely (r = 0.88) with endogenous norepinephrine concentrations. PET-generated 18F time-activity curves demonstrate marked kinetic differences between normal and denervated myocardium. FMR/PET analysis could be used to assess the heterogeneity of sympathetic innervation in human heart disease contingent on the development of FMR with sufficiently high specific activity to clearly avoid pressor activity

High-output microwave detector using voltage-induced ferromagnetic resonance

International Nuclear Information System (INIS)

Shiota, Yoichi; Suzuki, Yoshishige; Miwa, Shinji; Tamaru, Shingo; Nozaki, Takayuki; Kubota, Hitoshi; Fukushima, Akio; Yuasa, Shinji

2014-01-01

We investigated the voltage-induced ferromagnetic resonance (FMR) with various DC bias voltage and input RF power in magnetic tunnel junctions. We found that the DC bias monotonically increases the homodyne detection voltage due to the nonlinear FMR originating in an asymmetric magnetization-potential in the free layer. In addition, the linear increase of an output voltage to the input RF power in the voltage-induced FMR is more robust than that in spin-torque FMR. These characteristics enable us to obtain an output voltage more than ten times than that of microwave detectors using spin-transfer torque

Discovery of Enhanced Magnetoelectric Coupling through Electric Field Control of Two-Magnon Scattering within Distorted Nanostructures.

Science.gov (United States)

Xue, Xu; Zhou, Ziyao; Dong, Guohua; Feng, Mengmeng; Zhang, Yijun; Zhao, Shishun; Hu, Zhongqiang; Ren, Wei; Ye, Zuo-Guang; Liu, Yaohua; Liu, Ming

2017-09-26

Electric field control of dynamic spin interactions is promising to break through the limitation of the magnetostatic interaction based magnetoelectric (ME) effect. In this work, electric field control of the two-magnon scattering (TMS) effect excited by in-plane lattice rotation has been demonstrated in a La 0.7 Sr 0.3 MnO 3 (LSMO)/Pb(Mn 2/3 Nb 1/3 )-PbTiO 3 (PMN-PT) (011) multiferroic heterostructure. Compared with the conventional strain-mediated ME effect, a giant enhancement of ME effect up to 950% at the TMS critical angle is precisely determined by angular resolution of the ferromagnetic resonance (FMR) measurement. Particularly, a large electric field modulation of magnetic anisotropy (464 Oe) and FMR line width (401 Oe) is achieved at 173 K. The electric-field-controllable TMS effect and its correlated ME effect have been explained by electric field modulation of the planar spin interactions triggered by spin-lattice coupling. The enhancement of the ME effect at various temperatures and spin dynamics control are promising paradigms for next-generation voltage-tunable spintronic devices.

Magnetic films for GHz applications (abstract)

International Nuclear Information System (INIS)

Korenivski, V.; van Dover, R.B.

1997-01-01

Tremendous growth of the communications industry and the increasingly high demand for low-cost light-weight/small-size products drive technology to designs with a high degree of integration. In particular, planar inductors used in integrated circuits with significantly improved inductance per unit area characteristics are needed for further miniaturization of cellular phones operating at 0.95 and 1.9 GHz. Little has been done, however, to use magnetic films to improve the performance and/or reduce size of planar magnetic flux devices. The successful thin-film material would have a high ferromagnetic resonance (FMR) frequency (well above the operating frequency of the device), large permaeability, and low magnetic loss, and very importantly be technologically attractive, i.e., be process compatible with IC technology and have as few preparation steps as possible. Here, we report on fabrication of metallic ferromagnetic films of CoNbZr, CoNbZr/AlN mulitilayered laminates, and exchange-biased structures suitable for GHz applications. Lamination of CoNbZr with thin insulating layers of AlN is shown to significantly improve the microstructure and dc magnetic properties of the films having thicknesses >0.2 μm, as well as to be effective in suppressing eddy current losses at frequencies up to 1 endash 2 GHz. We use exchange biasing to increase the FMR frequency of soft CoNbZr. In-plane unidirectional anisotropy fields of ∼50 Oe are achieved, which result in FMR frequencies >2 GHz. Permeability values of ∼200 with quality factors of ∼10 at 1 GHz are demonstrated. The films are deposited at room temperature and require no postdeposition processing. Application of these films in planar inductors is discussed.copyright 1997 American Institute of Physics

Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.

Science.gov (United States)

Thomson, Sophie R; Seo, Sang S; Barnes, Stephanie A; Louros, Susana R; Muscas, Melania; Dando, Owen; Kirby, Caoimhe; Wyllie, David J A; Hardingham, Giles E; Kind, Peter C; Osterweil, Emily K

2017-08-02

Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu 1/5 ) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1 -/y ) hippocampus, which exhibit exaggerated mGlu 1/5 -induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M 4 ) is excessively translated, and synthesis of M 4 downstream of mGlu 5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M 4 activity normalizes core phenotypes in the Fmr1 -/y , including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1 -/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Energetic consequences of sexual size dimorphism in nestling red-winged blackbirds

International Nuclear Information System (INIS)

Fiala, K.L.; Congdon, J.D.

1983-01-01

The energy budget of nestling Red-winged Blackbirds (Agelaius phoeniceus) was determined using doubly labeled water ( 3 HH 18 O) to measure field metabolic rate (FMR) and body component data to measure growth energy. Sex-specific measurements permitted the evaluation of the effects of this species' substantial sexual size dimorphism on FMR and total energetics. FMR averaged CO 2 release of 5.12 mL.g -1 .h -1 , or 0.129 kJ.g -1 .h -1 , with no significant differences between the sexes. Daytime FMRs of CO 2 production (5.34 mL.g -1 .h -1 ) were higher, but not significantly so, than nighttime FMRs (4.45 mL.g -1 .h -1 ). Water influx averaged 0.95 mL.g -1 .d -1 , with daytime rates (1.22 mL.g -1 .d -1 ) significantly higher than nighttime (0.40 mL.g -1 d -1 ) rates. Total assimilated energy from hatching to fledging was 1014 and 797 kJ for male and female nestlings, respectively. The sexual differences in total energetics reflected differences in body size of the nestlings and suggest that there is a greater cost to the parents in raising males than in raising females

Mutations of the resistance to 6-thioguanine after exposure of Chinese hamster cells at G1 phase to x-radiation and subsequent treatment with cytosine arabinoside combined with hydroxyurea

International Nuclear Information System (INIS)

Elisova, T.V.; Feoktistova, T.P.; Stavrakova, N.M.

1988-01-01

A study was made of the effect of two-hour treatment of Chinese hamster cells with cytosine arabinoside (AraC) combined with hydroxyurea (HU) at the G 1 phase of the cell cycle on lethal and mutagenic effects of X-radiation (50 to 400 cGy). The inhibitors were shown to increase a spontaneous mutation level of the resistance to 6-thioguanine: this increase augmented by 3 times as the time the treatment increased from 1-2 to 6 h. However, while shorply enhancing the inactivating effect of X-radiation (the enhancement coefficient was 2.6) Arac+HU caused an additive, or a somewhat lesser, effect as estimated by the yield of mutations. It is suggested that AraC combined with hydroxyurea fail to modify the radiation-induced premutation damages

Large hadron collider workshop. Proceedings. Vol. 1

International Nuclear Information System (INIS)

Jarlskog, G.; Rein, D.

1990-01-01

The aim of the LCH workshop at Aachen was to discuss the 'discovery potential' of a high-luminosity hadron collider (the Large Hadron Collider) and to define the requirements of the detectors. Of central interest was whether a Higgs particle with mass below 1 TeV could be seen using detectors potentially available within a few years from now. Other topics included supersymmetry, heavy quarks, excited gauge bosons, and exotica in proton-proton collisions, as well as physics to be observed in electron-proton and heavy-ion collisions. A large part of the workshop was devoted to the discussion of instrumental and detector concepts, including simulation, signal processing, data acquisition, tracking, calorimetry, lepton identification and radiation hardness. The workshop began with parallel sessions of working groups on physics and instrumentation and continued, in the second half, with plenary talks giving overviews of the LHC project and the SSC, RHIC, and HERA programmes, summaries of the working groups, presentations from industry, and conclusions. Vol. 1 of these proceedings contains the papers presented at the plenary sessions, Vol. 2 the individual contributions to the physics sessions, and Vol. 3 those to the instrumentation sessions. (orig.)

Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer

Energy Technology Data Exchange (ETDEWEB)

Yip, Connie [King' s College London, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); National Cancer Centre, Department of Radiation Oncology, Singapore (Singapore); Imaging 2, Level 1, Lambeth Wing, St Thomas' Hospital, London (United Kingdom); Goh, Vicky [King' s College London, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Department of Radiology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Davies, Andrew; Gossage, James; Mason, Robert [Guy' s and St Thomas' NHS Foundation Trust, Department of Upper Gastrointestinal and General Surgery, London (United Kingdom); Mitchell-Hay, Rosalind; Griffin, Nyree [Department of Radiology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Hynes, Orla [Department of Dietetics, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Maisey, Nick; Ross, Paul; Gaya, Andrew [Department of Oncology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Landau, David B. [King' s College London, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Department of Oncology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Cook, Gary J. [King' s College London, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom)

2014-05-15

Sarcopenia and changes in body composition following neoadjuvant chemotherapy (NAC) may affect clinical outcome. We assessed the associations between CT body composition changes following NAC and outcomes in oesophageal cancer. A total of 35 patients who received NAC followed by oesophagectomy, and underwent CT assessment pre- and post-NAC were included. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were derived from CT. Changes in FM, FFM, FMR, VA/SA and sarcopenia were correlated to chemotherapy dose reductions, postoperative complications, length of hospital stay (LOS), circumferential resection margin (CRM), pathological chemotherapy response, disease-free survival (DFS) and overall survival (OS). Nine (26 %) patients were sarcopenic before NAC and this increased to 15 (43 %) after NAC. Average weight loss was 3.7 % ± 6.4 (SD) in comparison to FM index (-1.2 ± 4.2), FFM index (-4.6 ± 6.8), FMR (-1.2 ± 24.3) and VA/SA (-62.3 ± 12.7). Changes in FM index (p = 0.022), FMR (p = 0.028), VA/SA (p = 0.024) and weight (p = 0.007) were significant univariable factors for CRM status. There was no significant association between changes in body composition and survival. Loss of FM, differential loss of VA/SA and skeletal muscle were associated with risk of CRM positivity. (orig.)

Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer

International Nuclear Information System (INIS)

Yip, Connie; Goh, Vicky; Davies, Andrew; Gossage, James; Mason, Robert; Mitchell-Hay, Rosalind; Griffin, Nyree; Hynes, Orla; Maisey, Nick; Ross, Paul; Gaya, Andrew; Landau, David B.; Cook, Gary J.

2014-01-01

Sarcopenia and changes in body composition following neoadjuvant chemotherapy (NAC) may affect clinical outcome. We assessed the associations between CT body composition changes following NAC and outcomes in oesophageal cancer. A total of 35 patients who received NAC followed by oesophagectomy, and underwent CT assessment pre- and post-NAC were included. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were derived from CT. Changes in FM, FFM, FMR, VA/SA and sarcopenia were correlated to chemotherapy dose reductions, postoperative complications, length of hospital stay (LOS), circumferential resection margin (CRM), pathological chemotherapy response, disease-free survival (DFS) and overall survival (OS). Nine (26 %) patients were sarcopenic before NAC and this increased to 15 (43 %) after NAC. Average weight loss was 3.7 % ± 6.4 (SD) in comparison to FM index (-1.2 ± 4.2), FFM index (-4.6 ± 6.8), FMR (-1.2 ± 24.3) and VA/SA (-62.3 ± 12.7). Changes in FM index (p = 0.022), FMR (p = 0.028), VA/SA (p = 0.024) and weight (p = 0.007) were significant univariable factors for CRM status. There was no significant association between changes in body composition and survival. Loss of FM, differential loss of VA/SA and skeletal muscle were associated with risk of CRM positivity. (orig.)

Probing VCMA in MTJs with in-plane magnetization

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M. Williamson

2017-11-01

Full Text Available Voltage controlled magnetic anisotropy (VCMA is a novel method to switch magnetizations in low-power and ultra-fast applications based on magnetic tunnel junctions (MTJs. Here we explore the ferromagnetic resonance (FMR technique to probe VCMA in situations where other methods cannot be applied. We quantify VCMA in CoFeB/MgO/CoFeB MTJ nanopillars with in-plane magnetizations where our FMR method is unique in providing direct information about VCMA. We observe a quadratic shift of the FMR resonance field when a voltage bias is applied across the MTJ. The VCMA energy corresponding to the quadratic shift varies with an energy factor of 8.2μJ/m2 for 1 V2/nm2. These results are important for understanding magnetodynamics in MTJ-based applications with in-plane magnetizations.

Large-angle Bhabha scattering at LEP 1

Science.gov (United States)

Beenakker, Wim; Passarino, Giampiero

1998-04-01

A critical assessment is given of the theoretical uncertainty in the predicted cross-sections for large-angle Bhabha scattering at LEP 1, with or without t-channel subtraction. To this end a detailed comparison is presented of the results obtained with the programs ALIBABA and TOPAZ0. Differences in the implementation of the radiative corrections and the effect of missing higher-order terms are critically discussed. © 1998

Magnetic properties and high frequency characteristics of FeCoN thin films

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Tae-Jong Hwang

2016-05-01

Full Text Available (Fe65Co35N soft magnetic thin films were prepared by reactive RF magnetron sputtering with the sputtering power of 100 W on thermally oxidized Si substrate in various nitrogen partial pressures (PN2. A strong uniaxial in-plane magnetic anisotropy with the easy-axis coercive field as low as 1∼2 Oe was observed in films grown at PN2 in the range from 3.3% to 5.5%. The saturation magnetizations for those films were about 20 KG. Outside this range, almost isotropic magnetization curves were observed. Vector network analyzer and grounded coplanar waveguide were used to measure the ferromagnetic resonance (FMR signals up to 25 GHz. The FMR signals were detected only in anisotropic films and their FMR frequencies were well fit to the Kittel formula. The obtained g-values and damping parameters at magnetic fields >20 kOe for films grown at PN2 of 3.3%, 4.8% and 5.5% were 1.96, 1.86, 1.92 and 0.0055, 0.0047, 0.0046, respectively. This low damping factor qualifies FeCoN thin films for high-frequency applications.

Echocardiographic evaluation of mitral geometry in functional mitral regurgitation

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Maleki Majid

2008-10-01

Full Text Available Abstract Objectives We sought to evaluate the geometric changes of the mitral leaflets, local and global LV remodeling in patients with left ventricular dysfunction and varying degrees of Functional mitral regurgitation (FMR. Background Functional mitral regurgitation (FMR occurs as a consequence of systolic left ventricular (LV dysfunction caused by ischemic or nonischemic cardiomyopathy. Mitral valve repair in ischemic MR is one of the most controversial topic in surgery and proper repairing requires an understanding of its mechanisms, as the exact mechanism of FMR are not well defined. Methods 136 consecutive patients mean age of 55 with systolic LV dysfunction and FMR underwent complete echocardiography and after assessing MR severity, LV volumes, Ejection Fraction, LV sphericity index, C-Septal distance, Mitral valve annulus, Interpapillary distance, Tenting distance and Tenting area were obtained. Results There was significant association between MR severity and echocardiogarphic indices (all p values Mitral annular dimensions and area, C-septal distance and sphericity index, although greater in patients with severe regurgitation, did not significantly contribute to FMR severity. Conclusion Degree of LV enlargement and dysfunction were not primary determinants of FMR severity, therefore local LV remodeling and mitral valve apparatus deformation are the strongest predictors of functional MR severity.

Ferromagnetic resonance of cobalt nanoparticles used as a catalyst for the carbon nanotubes synthesis

Energy Technology Data Exchange (ETDEWEB)

Duraia, El-Shazly M. [Suez Canal University, Faculty of Science, Physics Department, Ismailia (Egypt); Al-Farabi Kazakh National University, Almaty (Kazakhstan); Institute of Physics and Technology, Almaty (Kazakhstan)], E-mail: duraia_physics@yahoo.com; Abdullin, Kh.A. [Institute of Physics and Technology, Almaty (Kazakhstan)

2009-12-15

Catalyst is considered to be the most crucial parameter for the growth of carbon nanotubes. In this work we study the ferromagnetic resonance (FMR) spectra of the catalyst nanoclusters. Moreover we report for the first time the angle FMR studies of catalyst particles with and without CNT layer. The dependencies of the FMR spectra, X-ray diffraction (XRD) patterns, Raman spectra and morphology of the CNT layers on the growth conditions are discussed.

Ferromagnetic resonance and spin-wave resonances in GaMnAsP films

Science.gov (United States)

Liu, Xinyu; Li, Xiang; Bac, Seul-Ki; Zhang, Xucheng; Dong, Sining; Lee, Sanghoon; Dobrowolska, Margaret; Furdyna, Jacek K.

2018-05-01

A series of Ga1-xMnxAs1-yPy films grown by MBE on GaAs (100) substrates was systematically studied by ferromagnetic resonance (FMR). Magnetic anisotropy parameters were obtained by analyzing the angular dependence of the FMR data. The results clearly show that the easy axis of the films shifts from the in-plane [100] direction to the out-of-plane [001], indicating the emergence of a strong tensile-strain-induced perpendicular anisotropy when the P content exceeds y ≈ 0.07. Multiple resonances were observed in Ga1-xMnxAs1-yPy films with thicknesses over 48 nm, demonstrating the existence of exchange-dominated non-propagating spin-wave modes governed by surface anisotropy.

Quantitative ferromagnetic resonance analysis of CD 133 stem cells labeled with iron oxide nanoparticles

International Nuclear Information System (INIS)

Gamarra, L F; Pavon, L F; Marti, L C; Moreira-Filho, C A; Amaro, E Jr; Pontuschka, W M; Mamani, J B; Costa-Filho, A J; Vieira, E D

2008-01-01

The aim of this work is to provide a quantitative method for analysis of the concentration of superparamagnetic iron oxide nanoparticles (SPION), determined by means of ferromagnetic resonance (FMR), with the nanoparticles coupled to a specific antibody (AC 133), and thus to express the antigenic labeling evidence for the stem cells CD 133 + . The FMR efficiency and sensitivity were proven adequate for detecting and quantifying the low amounts of iron content in the CD 133 + cells (∼6.16 x 10 5 pg in the volume of 2 μl containing 4.5 x 10 11 SPION). The quantitative method led to the result of 1.70 x 10 -13 mol of Fe (9.5 pg), or 7.0 x 10 6 nanoparticles per cell. For the quantification analysis via the FMR technique it was necessary to carry out a preliminary quantitative visualization of iron oxide-labeled cells in order to ensure that the nanoparticles coupled to the antibodies are indeed tied to the antigen at the stem cell surface and that the cellular morphology was conserved, as proof of the validity of this method. The quantitative analysis by means of FMR is necessary for determining the signal intensity for the study of molecular imaging by means of magnetic resonance imaging (MRI)

Temperature dependence of electric field tunable ferromagnetic resonance lineshape in multiferroic heterostructure

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Fenglong Wang

2016-11-01

Full Text Available Herein, we experimentally investigate the effect of temperature on the electric field tunable ferromagnetic resonance (FMR in a ferroelectric/ferromagnetic heterostructure, and demonstrate the tuning of abnormal change in FMR using the polarization of the ferroelectric layer above 200 K. The FMR was found to be almost unchanged under different electric field strength at 100 K owing to frozen polarization, which causes extremely weak magnetoelectric coupling. More interestingly, negative effective linewidth was observed when an electric field greater than 10 kV/cm was applied above 220 K. The simultaneous electrical control of magnetization and its damping via FMR based on linear magnetoelectric coupling are directly relevant to use of composite multiferroics for a wide range of devices.

Treatment of primary axillary hyperhidrosis by fractional microneedle radiofrequency: Is it still effective after long-term follow-up?

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Bahareh Abtahi-Naeini

2016-01-01

Full Text Available Background: Primary axillary hyperhidrosis (PAH is a chronic idiopathic disorder causing major stress in patients. Among the common therapies for PAH, only surgical interventions have proven feasible as a permanent solution. Objective and Aim: The aim of this study was to evaluate the efficacy and safety of fractional microneedle radiofrequency (FMR as an alternative permanent treatment for PAH with long-term follow-up. Materials and Methods: This was a single-blind, sham-controlled comparative study. Twenty-five patients with severe PAH were provided three treatments of FMR at 3-week intervals (the treatment group, and a control group was provided the sham treatment. Clinical efficacy was evaluated using the hyperhidrosis disease severity scale (HDSS at baseline and the end of the study, as well as during the 1 year follow-up phase. Results: HDSS demonstrated significant improvement after treatment in the treatment group compared to the sham control. The mean (±standard deviation of HDSS in the group being treated with radiofrequency was 2.50 (±0.88 after 1 year follow-up, and that of the control group was 3.38 (±0.49; P < 0.001. Follow-up results show that there were 10 patients (41.6% with no relapse and 11 patients (45.9% with relapse after 1 year. There was a significant correlation between HDSS changes in relapse and body mass index (BMI (P = 0.03. Conclusion: Treatment of PAH with FMR is a safe and noninvasive procedure with a positive therapeutic effect on HDSS. It is recommended, however, that sessions of FMR be repeated after 1 year, particularly in overweight patients with high BMIs. Clinical Trial Registration: IRCT2013111915455N1. Level of Evidences: Level II-1.

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells.

Science.gov (United States)

Kumari, Daman; Swaroop, Manju; Southall, Noel; Huang, Wenwei; Zheng, Wei; Usdin, Karen

2015-07-01

: Fragile X syndrome (FXS), the most common form of inherited cognitive disability, is caused by a deficiency of the fragile X mental retardation protein (FMRP). In most patients, the absence of FMRP is due to an aberrant transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. FXS has no cure, and the available treatments only provide symptomatic relief. Given that FMR1 gene silencing in FXS patient cells can be partially reversed by treatment with compounds that target repressive epigenetic marks, restoring FMRP expression could be one approach for the treatment of FXS. We describe a homogeneous and highly sensitive time-resolved fluorescence resonance energy transfer assay for FMRP detection in a 1,536-well plate format. Using neural stem cells differentiated from an FXS patient-derived induced pluripotent stem cell (iPSC) line that does not express any FMRP, we screened a collection of approximately 5,000 known tool compounds and approved drugs using this FMRP assay and identified 6 compounds that modestly increase FMR1 gene expression in FXS patient cells. Although none of these compounds resulted in clinically relevant levels of FMR1 mRNA, our data provide proof of principle that this assay combined with FXS patient-derived neural stem cells can be used in a high-throughput format to identify better lead compounds for FXS drug development. In this study, a specific and sensitive fluorescence resonance energy transfer-based assay for fragile X mental retardation protein detection was developed and optimized for high-throughput screening (HTS) of compound libraries using fragile X syndrome (FXS) patient-derived neural stem cells. The data suggest that this HTS format will be useful for the identification of better lead compounds for developing new therapeutics for FXS. This assay can also be adapted for FMRP detection in clinical and research settings. ©AlphaMed Press.

Mutation induction in repair-deficient strains of Drosophila

International Nuclear Information System (INIS)

Wuergler, F.E.; Graf, U.

1980-01-01

Experimental evidence indicates a polygenic control of mutagenesis in Drosophila melanogaster. In oocytes chromosome aberrations detected as half-translocations or dominant lethals depend on a repair system which in a number of genetically nonrelated strains shows different repair capacities. Sister chromatid exchanges are easily studied as ring chromosome losses. They develop through a genotype controlled mechanism from, premutational lesions. Stocks with particular pairs of third chromosomes were discovered in which increased sensitivity of larvae to the toxic effects of a monofunctional alkylating agent correlates with high frequencies of x-ray induced SCE's. Sex-linked mutagen-sensitive mutants could be shown to control mutation fixation: pronounced maternal effects were found when sperm carrying particular types of premutational lesions were introduced into different types of mutant oocytes. The mutant mus(1)101D1 was found to be unable to process lesions induced by the crosslinking agent nitrogen mustard into point mutations. Alkylation damage leads to increased point mutation frequencies in the excision repair deficient mutant mei-9L1, but to reduced frequencies in the post-replication repair deficient mutant mei-41D5. It became clear that the study of maternal effects on mutagenized sperm represents an efficient tool to analyze the gentic control of mutagenesis in the eukaryotic genome of Drosophila melanogaster

Minimally invasive mitral valve annuloplasty confers a long-term survival benefit compared with state-of-the-art treatment in heart failure with functional mitral regurgitation.

Science.gov (United States)

Penicka, Martin; Kotrc, Martin; Ondrus, Tomas; Mo, Yujing; Casselman, Filip; Vanderheyden, Marc; Van Camp, Guy; Van Praet, Frank; Bartunek, Jozef

2017-10-01

Clinical impact of the minimally invasive surgical mitral valve annuloplasty (MVA) of functional mitral regurgitation (FMR) in systolic heart failure on top of the state-of-the-art standards of care remains controversial. Therefore, we aimed to compare clinical outcomes of isolated MVA using the mini-invasive videothoracoscopic approach versus the state-of-the-art (CON=conservative) treatment in patients with chronic systolic heart failure and symptomatic FMR. The study population consisted of 379 patients (age 68.9±11.0years, 62.8% males) with left ventricular (LV) systolic dysfunction, symptomatic FMR and previous heart failure hospitalization. A total of 167 patients underwent undersized MVA and 212 patients were treated conservatively. A concomitant MAZE was performed in 53 (31.7%) patients. In the MVA group, the periprocedural and the 30-day mortality were 1.2% and 4.8%, respectively. During the median follow-up of 7.1years (IQR 3.5-9.8years) a total of 74 (44.3%) and 138 (65.1%) died in the MVA and the CON group, respectively (pstate-of-the-art treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Soft magnetism, magnetostriction, and microwave properties of FeGaB thin films

International Nuclear Information System (INIS)

Lou, J.; Insignares, R. E.; Cai, Z.; Ziemer, K. S.; Liu, M.; Sun, N. X.

2007-01-01

A series of (Fe 100-y Ga y ) 1-x B x (x=0-21 and y=9-17) films were deposited; their microstructure, soft magnetism, magnetostrictive behavior, and microwave properties were investigated. The addition of B changes the FeGaB films from polycrystalline to amorphous phase and leads to excellent magnetic softness with coercivity s , self-biased ferromagnetic resonance (FMR) frequency of 1.85 GHz, narrow FMR linewidth (X band) of 16-20 Oe, and a high saturation magnetostriction constant of 70 ppm. The combination of these properties makes the FeGaB films potential candidates for tunable magnetoelectric microwave devices and other rf/microwave magnetic device applications

Repair and mutation induction in mouse germ cells: a summary and some thoughts

International Nuclear Information System (INIS)

Russell, L.B.

1979-01-01

The various lines of evidence for repair of premutational damage in mouse germ cells are reviewed with the implications for future experiment planning. Relation between mutagenicity and carcinogenicity are discussed

Fragile X Syndrome in a Colombian Family

Directory of Open Access Journals (Sweden)

Saldarriaga Gil, Wilmar

2018-01-01

Full Text Available A study was performed on a family from Cali, Colombia in which nine patients were evaluated, three of which presented with intellectual disability with no previous etiological diagnosis. The proband was diagnosed with Fragile X syndrome by DNA molecular testing and, cascade testing, performed on all available family members, identifying two additional individuals with the full mutation and four carriers of a premutation allele. With this report we seek to contribute to Colombian epidemiology of the syndrome and emphasize the importance of diagnosis to provide a comprehensive and specific treatment to those affected. Further we seek to identify premutation carriers in their families or women with a full mutation without the classic phenotype for genetic counseling and education about potential associated pathologies.

Fragile X syndrome in females - a familial case report and review of the literature.

Science.gov (United States)

Stembalska, Agnieszka; Łaczmańska, Izabela; Gil, Justyna; Pesz, Karolina A

2016-01-01

Fragile X syndrome (FXS), one of the manifestations of FMR1-related disorders, is one of the most frequent genetic causes of intellectual disability. In over 99% of all cases it results from the expansion of CGG repeats in the 5'-untranslated region of the FMR1 gene and presents in males and in about 50% of the females with an FMR1 full mutation, usually with a milder phenotype. Although the morphologic and behavioral phenotype in males is a well-recognized entity, the presentation in females is variable and not as specific. The objective of this paper is to present a family with quite a severe expression of the disorder in two sisters with a full mutation. We report on a two-generation family where both males and females were found to be affected by FXS. We also present the diagnostic pathway and methods that led to the diagnosis of fragile X syndrome in the two sisters, as well as the method that explained the normal phenotype in their mother. The CGG repeats analysis in the FMR1 gene showed one normal allele and one allele with a full mutation in both sisters (probands) and their mother. A full mutation was also found in three male cousins of the probands. The analysis of the X-chromosome methylation status has shown a random X inactivation in proband 1 and 2 and a non-random one in the proband's mother, with the normal allele predominantly active. The reasons for different clinical presentations are discussed; moreover a review of the literature on females with FXS is presented. We hope that this paper will facilitate the future diagnosis of fragile X syndromes in females.

Electric-field tunable spin waves in PMN-PT/NiFe heterostructure: Experiment and micromagnetic simulations

Energy Technology Data Exchange (ETDEWEB)

Ziȩtek, Slawomir, E-mail: zietek@agh.edu.pl [AGH University of Science and Technology, Department of Electronics, Al. Mickiewicza 30, 30-059 Kraków (Poland); Chȩciński, Jakub [AGH University of Science and Technology, Department of Electronics, Al. Mickiewicza 30, 30-059 Kraków (Poland); AGH University of Science and Technology, Faculty of Physics and Applied Computer Science, Al. Mickiewicza 30, 30-059 Kraków (Poland); Frankowski, Marek; Skowroński, Witold; Stobiecki, Tomasz [AGH University of Science and Technology, Department of Electronics, Al. Mickiewicza 30, 30-059 Kraków (Poland)

2017-04-15

We present a comprehensive theoretical and experimental study of voltage-controlled standing spin waves resonance (SSWR) in PMN-PT/NiFe multiferroic heterostructures patterned into microstrips. A spin-diode technique was used to observe ferromagnetic resonance (FMR) mode and SSWR in NiFe strip mechanically coupled with a piezoelectric substrate. Application of an electric field to a PMN-PT creates a strain in permalloy and thus shifts the FMR and SSWR fields due to the magnetostriction effect. The experimental results are compared with micromagnetic simulations and a good agreement between them is found for dynamics of FMR and SSWR with and without electric field. Moreover, micromagnetic simulations enable us to discuss the amplitude and phase spatial distributions of FMR and SSWR modes, which are not directly observable by means of spin diode detection technique.

Ferromagnetic resonance of a YIG film in the low frequency regime

Energy Technology Data Exchange (ETDEWEB)

Lee, Seongjae [Department of Physics, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791 (Korea, Republic of); Grudichak, Scott; Sklenar, Joseph; Ketterson, John B. [Department of Physics and Astronomy, Northwestern University, Evanston, Illinois 60208 (United States); Tsai, C. C. [Department of Engineering and Management of Advanced Technology, Chang Jung Christian University, Tainan 71101, Taiwan (China); Jang, Moongyu [Department of Materials Science and Engineering, Hallym University, Chuncheon 200-702 (Korea, Republic of); Yang, Qinghui; Zhang, Huaiwu [State Key Laboratory of Electronic Films and Integrated Devices, University of Electronic Science and Technology, Chengdu, Sichuan 610054 (China)

2016-07-21

An improved method for characterizing the magnetic anisotropy of films with cubic symmetry is described and is applied to an yttrium iron garnet (111) film. Analysis of the ferromagnetic resonance (FMR) spectra performed both in-plane and out-of-plane from 0.7 to 8 GHz yielded the magnetic anisotropy constants as well as the saturation magnetization. The field at which FMR is observed turns out to be quite sensitive to anisotropy constants (by more than a factor ten) in the low frequency (<2 GHz) regime, and when the orientation of the magnetic field is nearly normal to the sample plane; the restoring force on the magnetization arising from the magnetocrystalline anisotropy fields is then comparable to that from the external field, thereby allowing the anisotropy constants to be determined with greater accuracy. In this region, unusual dynamical behaviors are observed such as multiple resonances and a switching of FMR resonance with only a 1° change in field orientation at 0.7 GHz.

Thickness-dependent enhancement of damping in C o2FeAl /β -Ta thin films

Science.gov (United States)

Akansel, Serkan; Kumar, Ankit; Behera, Nilamani; Husain, Sajid; Brucas, Rimantas; Chaudhary, Sujeet; Svedlindh, Peter

2018-04-01

In the present work C o2FeAl (CFA) thin films were deposited by ion beam sputtering on Si (100) substrates at the optimized deposition temperature of 300 °C. A series of CFA films with different thicknesses (tCFA), 8, 10, 12, 14, 16, 18, and 20 nm, were prepared and all samples were capped with a 5-nm-thick β-Ta layer. The thickness-dependent static and dynamic properties of the films were studied by SQUID magnetometry, in-plane as well as out-of-plane broadband vector network analyzer-ferromagnetic resonance (FMR) measurements, and angle-dependent cavity FMR measurements. The saturation magnetization and the coercive field were found to be weakly thickness dependent and lie in the range 900-950 kA/m and 0.53-0.87 kA/m, respectively. The effective damping parameter (αeff) extracted from in-plane and out-of-plane FMR results reveals a 1/tCFA dependence, the values for the in-plane αeff being larger due to two-magnon scattering (TMS). The origin of the αeff thickness dependence is spin pumping into the nonmagnetic β-Ta layer and in the case of the in-plane αeff, also a thickness-dependent TMS contribution. From the out-of-plane FMR results, it was possible to disentangle the different contributions to αeff and to the extract values for the intrinsic Gilbert damping (αG) and the effective spin-mixing conductance (geff↑↓) of the CFA/ β-Ta interface, yielding αG=(1.1 ±0.2 ) ×10-3 and geff↑↓=(2.90 ±0.10 ) ×1019m-2 .

Premature ovarian failure (POF in Brazilian fragile X carriers

Directory of Open Access Journals (Sweden)

Angela M. Vianna-Morgante

1999-12-01

Full Text Available The gynecological and reproductive histories of 193 women from fragile X families were surveyed. Among the 101 carriers of the premutation, 14 experienced premature menopause, contrarily to their 37 fully mutated and 55 noncarrier female relatives. Although premature menopause showed a tendency to cluster in certain fragile X families, as a group, the premutated women experienced menopause earlier than noncarriers. This suggests that premature menopause may be the extreme effect of a spectrum of ovarian anomalies associated with the fragile X premutation.Entrevistamos 193 mulheres de famílias com afetados pela síndrome do cromossomo X frágil, quanto a sua história ginecológica e reprodutiva. Entre as 101 portadoras da pré-mutação, 14 tiveram menopausa precoce, mas nenhuma das 37 portadoras da mutação completa ou das 55 não portadoras apresentaram esta anomalia. Observamos uma tendência para a concentração da menopausa precoce em certas famílias, o que poderia significar uma peculiariedade de certas pré-mutações. Entretanto, o fato de as mulheres pré-mutadas tenderem a entrar em menopausa mais cedo do que as não portadoras sugere que a menopausa precoce seja o extremo do espectro de efeitos ovarianos da pré-mutação.

Large-Scale Environment Properties of Narrow-Line Seyfert 1 Galaxies at z < 0.4

Energy Technology Data Exchange (ETDEWEB)

Järvelä, Emilia [Metsähovi Radio Observatory, Aalto University, Espoo (Finland); Department of Electronics and Nanoengineering, Aalto University, Espoo (Finland); Lähteenmäki, A. [Metsähovi Radio Observatory, Aalto University, Espoo (Finland); Department of Electronics and Nanoengineering, Aalto University, Espoo (Finland); Tartu Observatory, Tõravere (Estonia); Lietzen, H., E-mail: emilia.jarvela@aalto.fi [Tartu Observatory, Tõravere (Estonia)

2017-11-30

The large-scale environment is believed to affect the evolution and intrinsic properties of galaxies. It offers a new perspective on narrow-line Seyfert 1 galaxies (NLS1) which have not been extensively studied in this context before. We study a large and diverse sample of 960 NLS1 galaxies using a luminosity-density field constructed using Sloan Digital Sky Survey. We investigate how the large-scale environment is connected to the properties of NLS1 galaxies, especially their radio loudness. Furthermore, we compare the large-scale environment properties of NLS1 galaxies with other active galactic nuclei (AGN) classes, for example, other jetted AGN and broad-line Seyfert 1 (BLS1) galaxies, to shed light on their possible relations. In general NLS1 galaxies reside in less dense large-scale environments than any of our comparison samples, thus supporting their young age. The average luminosity-density and distribution to different luminosity-density regions of NLS1 sources is significantly different compared to BLS1 galaxies. This contradicts the simple orientation-based unification of NLS1 and BLS1 galaxies, and weakens the hypothesis that BLS1 galaxies are the parent population of NLS1 galaxies. The large-scale environment density also has an impact on the intrinsic properties of NLS1 galaxies; the radio loudness increases with the increasing luminosity-density. However, our results suggest that the NLS1 population is indeed heterogeneous, and that a considerable fraction of them are misclassified. We support a suggested description that the traditional classification based on the radio loudness should be replaced with the division to jetted and non-jetted sources.

Quantitative ferromagnetic resonance analysis of CD 133 stem cells labeled with iron oxide nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Gamarra, L F; Pavon, L F; Marti, L C; Moreira-Filho, C A; Amaro, E Jr [Instituto Israelita de Ensino e Pesquisa Albert Einstein, IIEPAE, Sao Paulo 05651-901 (Brazil); Pontuschka, W M; Mamani, J B [Instituto de Fisica, Universidade de Sao Paulo, Sao Paulo 05315-970 (Brazil); Costa-Filho, A J; Vieira, E D [Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo, Sao Carlos 13560-970 (Brazil)], E-mail: lgamarra@einstein.br

2008-05-21

The aim of this work is to provide a quantitative method for analysis of the concentration of superparamagnetic iron oxide nanoparticles (SPION), determined by means of ferromagnetic resonance (FMR), with the nanoparticles coupled to a specific antibody (AC 133), and thus to express the antigenic labeling evidence for the stem cells CD 133{sup +}. The FMR efficiency and sensitivity were proven adequate for detecting and quantifying the low amounts of iron content in the CD 133{sup +} cells ({approx}6.16 x 10{sup 5} pg in the volume of 2 {mu}l containing 4.5 x 10{sup 11} SPION). The quantitative method led to the result of 1.70 x 10{sup -13} mol of Fe (9.5 pg), or 7.0 x 10{sup 6} nanoparticles per cell. For the quantification analysis via the FMR technique it was necessary to carry out a preliminary quantitative visualization of iron oxide-labeled cells in order to ensure that the nanoparticles coupled to the antibodies are indeed tied to the antigen at the stem cell surface and that the cellular morphology was conserved, as proof of the validity of this method. The quantitative analysis by means of FMR is necessary for determining the signal intensity for the study of molecular imaging by means of magnetic resonance imaging (MRI)

78 FR 61667 - Final Fair Market Rents for the Housing Choice Voucher Program and Moderate Rehabilitation Single...

Science.gov (United States)

2013-10-03

... Metro FMR Area 2016 Area. Las Vegas-Paradise, NV MSA 2015 New Haven-Meriden, CT HUD Metro FMR 2016 Area...) in the Low-Income Housing Tax Credit program is outside of the scope of this notice. However, HUD...

A mouse model of the human Fragile X syndrome I304N mutation.

Directory of Open Access Journals (Sweden)

Julie B Zang

2009-12-01

Full Text Available The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1 in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder.

Investigating spin-transfer torques induced by thermal gradients in magnetic tunnel junctions by using micro-cavity ferromagnetic resonance

Science.gov (United States)

Cansever, H.; Narkowicz, R.; Lenz, K.; Fowley, C.; Ramasubramanian, L.; Yildirim, O.; Niesen, A.; Huebner, T.; Reiss, G.; Lindner, J.; Fassbender, J.; Deac, A. M.

2018-06-01

Similar to electrical currents flowing through magnetic multilayers, thermal gradients applied across the barrier of a magnetic tunnel junction may induce pure spin-currents and generate ‘thermal’ spin-transfer torques large enough to induce magnetization dynamics in the free layer. In this study, we describe a novel experimental approach to observe spin-transfer torques induced by thermal gradients in magnetic multilayers by studying their ferromagnetic resonance response in microwave cavities. Utilizing this approach allows for measuring the magnetization dynamics on micron/nano-sized samples in open-circuit conditions, i.e. without the need of electrical contacts. We performed first experiments on magnetic tunnel junctions patterned into 6  ×  9 µm2 ellipses from Co2FeAl/MgO/CoFeB stacks. We conducted microresonator ferromagnetic resonance (FMR) under focused laser illumination to induce thermal gradients in the layer stack and compared them to measurements in which the sample was globally heated from the backside of the substrate. Moreover, we carried out broadband FMR measurements under global heating conditions on the same extended films the microstructures were later on prepared from. The results clearly demonstrate the effect of thermal spin-torque on the FMR response and thus show that the microresonator approach is well suited to investigate thermal spin-transfer-driven processes for small temperatures gradients, far below the gradients required for magnetic switching.

Critical behavior in dome D = 1 large-N matrix models

International Nuclear Information System (INIS)

Das, S.R.; Dhar, A.; Sengupta, A.M.; Wadia, D.R.

1990-01-01

The authors study the critical behavior in D = 1 large-N matrix models. The authors also look at the subleading terms in susceptibility in order to find out the dimensions of some of the operators in the theory

Disease: H01731 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available H01731 Fragile X tremor/ataxia syndrome (FXTAS) Fragile X tremor/ataxia syndrome (...0) in the fragile X mental retardation 1 (FMR1) gene. Common manifestations of FXTAS are progressive intention tremor

Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark

DEFF Research Database (Denmark)

Thomassen, Mads; Gerdes, Anne-Marie; Cruger, Dorthe

2006-01-01

Germline mutations in BRCA1 and BRCA2 predispose female carriers to breast and ovarian cancer. The majority of mutations identified are small deletions or insertions or are nonsense mutations. Large genomic rearrangements in BRCA1 are found with varying frequencies in different populations......, but BRCA2 rearrangements have not been investigated thoroughly. The objective in this study was to determine the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large group of Danish families with increased risk of breast and ovarian cancer. A total of 617 families previously tested...... negative for mutations involving few bases were screened with multiplex ligation-dependent probe amplification (MLPA). Two deletions in BRCA1 were identified in three families; no large rearrangements were detected in BRCA2. The large deletions constitute 3.8% of the BRCA1 mutations identified, which...

Thickness dependence of dynamic and static magnetic properties of pulsed laser deposited La{sub 0.7}Sr{sub 0.3}MnO{sub 3} films on SrTiO{sub 3}(001)

Energy Technology Data Exchange (ETDEWEB)

Monsen, Åsmund [Department of Physics, NTNU, 7491 Trondheim (Norway); Boschker, Jos E. [Department of Electronics and Telecommunications, NTNU, 7491 Trondheim (Norway); Macià, Ferran [Department of Physics, New York University, 4 Washington Place, New York, NY 10003 (United States); Wells, Justin W. [Department of Physics, NTNU, 7491 Trondheim (Norway); Nordblad, Per [Department of Engineering Sciences, Uppsala University, Box 534, SE-751 21 Uppsala (Sweden); Kent, Andrew D. [Department of Physics, New York University, 4 Washington Place, New York, NY 10003 (United States); Mathieu, Roland [Department of Engineering Sciences, Uppsala University, Box 534, SE-751 21 Uppsala (Sweden); Tybell, Thomas [Department of Electronics and Telecommunications, NTNU, 7491 Trondheim (Norway); Wahlström, Erik, E-mail: erik.wahlstrom@ntnu.no [Department of Physics, NTNU, 7491 Trondheim (Norway)

2014-11-15

We present a comprehensive study of the thickness dependence of static and magneto-dynamic magnetic properties of La{sub 0.7}Sr{sub 0.3}MnO{sub 3}. Epitaxial pulsed laser deposited La{sub 0.7}Sr{sub 0.3}MnO{sub 3}/SrTiO{sub 3}(001) thin films in the range from 3 unit cell (uc) to 40 uc (1.2–16 nm) have been investigated through ferromagnetic resonance (FMR) spectroscopy and SQUID magnetometry at variable temperature. Magnetodynamically, three different thickness, d, regimes are identified: 20 uc ≲d uc where the system is bulk like, a transition region 8 uc ≤d≲20 uc where the FMR linewidth and the position depend on thickness and d=6 uc which displays significantly altered magnetodynamic properties, while still displaying bulk magnetization. Magnetization and FMR measurements are consistent with a nonmagnetic volume corresponding to ∼4 uc. We observe a reduction of Curie temperature (T{sub C}) with decreasing thickness, which is coherent with a mean field model description. The reduced ordering temperature also accounts for the thickness dependence of the magnetic anisotropy constants and resonance fields. The damping of the system is strongly thickness dependent, and is for thin films dominated by thickness dependent anisotropies, yielding both a strong two-magnon scattering close to T{sub c} and a low temperature broadening. For the bulk like samples a large part of the broadening can be linked to spread in magnetic anisotropies attributed to crystal imperfections/domain boundaries of the bulk like film. - Highlights: • Thickness dependent magnetodynamic anisotropy constants and line-widths have been measured. • For thicknesses >8nm the films are bulk-like. • Thin film line-widths are dominated by surface/interface imperfections. • Thick film line-widths are dominated by crystal imperfections/domain boundaries.

Selective electronalysis of peracetic acid in the presence of a large excess of H2O2 at Au(1 1 1)-like gold electrode

International Nuclear Information System (INIS)

Awad, M.I.

2012-01-01

Highlights: ► Analysis of peracetic acid in the presence of a large excess of H 2 O 2 is introduced. ► Au(1 1 1)-like gold electrode serves as an ideal for this purpose. ► The analysis is characterized by high selectivity and sensitivity. - Abstract: Peracetic acid (PAA) has been selectively electroanalyzed in the presence of a large excess of hydrogen peroxide (H 2 O 2 ), about 500 fold that of PAA, using Au (1 1 1)-like gold electrode in acetate buffer solutions of pH 5.4. Au(1 1 1)-like gold electrode was prepared by a controlled reductive desorption of a previously assembled thiol, typically cysteine, monolayer onto the polycrystalline gold (poly-Au) electrode. Cysteine molecules were selectively removed from the Au(1 1 1) facets of the poly-Au electrode, keeping the other two facets (i.e., Au(1 1 0) and Au(1 0 0)) under the protection of the adsorbed cysteine. It has been found that Au(1 1 1)-like gold electrode positively shifts the reduction peak of PAA, while, fortunately, shifts the reduction peak of H 2 O 2 negatively, achieving a large potential separation (around 750 mV) between the two reduction peaks as compared with that (around 450 mV) obtained at the poly-Au electrode. This large potential separation between the two reduction peaks enabled the analysis of PAA in the presence of a large excess of H 2 O 2 . In addition, the positive shift of the reduction peak of PAA gives the present method a high immunity against the interference of the dissolved oxygen.

Large-scale functional purification of recombinant HIV-1 capsid.

Directory of Open Access Journals (Sweden)

Magdeleine Hung

Full Text Available During human immunodeficiency virus type-1 (HIV-1 virion maturation, capsid proteins undergo a major rearrangement to form a conical core that protects the viral nucleoprotein complexes. Mutations in the capsid sequence that alter the stability of the capsid core are deleterious to viral infectivity and replication. Recently, capsid assembly has become an attractive target for the development of a new generation of anti-retroviral agents. Drug screening efforts and subsequent structural and mechanistic studies require gram quantities of active, homogeneous and pure protein. Conventional means of laboratory purification of Escherichia coli expressed recombinant capsid protein rely on column chromatography steps that are not amenable to large-scale production. Here we present a function-based purification of wild-type and quadruple mutant capsid proteins, which relies on the inherent propensity of capsid protein to polymerize and depolymerize. This method does not require the packing of sizable chromatography columns and can generate double-digit gram quantities of functionally and biochemically well-behaved proteins with greater than 98% purity. We have used the purified capsid protein to characterize two known assembly inhibitors in our in-house developed polymerization assay and to measure their binding affinities. Our capsid purification procedure provides a robust method for purifying large quantities of a key protein in the HIV-1 life cycle, facilitating identification of the next generation anti-HIV agents.

Ferromagnetic resonance studies of lunar core stratigraphy

Science.gov (United States)

Housley, R. M.; Cirlin, E. H.; Goldberg, I. B.; Crowe, H.

1976-01-01

We first review the evidence which links the characteristic ferromagnetic resonance observed in lunar fines samples with agglutinatic glass produced primarily by micrometeorite impacts and present new results on Apollo 15, 16, and 17 breccias which support this link by showing that only regolith breccias contribute significantly to the characteristic FMR intensity. We then provide a calibration of the amount of Fe metal in the form of uniformly magnetized spheres required to give our observed FMR intensities and discuss the theoretical magnetic behavior to be expected of Fe spheres as a function of size. Finally, we present FMR results on samples from every 5 mm interval in the core segments 60003, 60009, and 70009. These results lead us to suggest: (1) that secondary mixing may generally be extensive during regolith deposition so that buried regolith surfaces are hard to recognize or define; and (2) that local grinding of rocks and pebbles during deposition may lead to short scale fluctuations in grain size, composition, and apparent exposure age of samples.

The c.IVS1+1G>A mutation inthe GJB2 gene is prevalent and large ...

Indian Academy of Sciences (India)

IVS1+1G>A mutation inthe GJB2 gene is prevalent and large deletions involving the GJB6 gene are not present in the Turkish population. ASLI SIRMACI, DUYGU AKCAYOZ-DUMAN and MUSTAFA TEKIN∗. Division of Pediatric Molecular Genetics, Ankara University School of Medicine, Ankara 06100, Turkey. Introduction.

Genetic pathways to Neurodegeneration Models and mechanisms ...

Indian Academy of Sciences (India)

Paige Rudich

Models and mechanisms of repeat expansion disorders: a worm's eye view ..... retardation 1 gene FMR1 gives rise to a spectrum of neurological disorders (Saul and Tarleton ... autism. Shorter repeat expansion lengths from 55-200 cause the.

Vector network analyzer ferromagnetic resonance spectrometer with field differential detection

Science.gov (United States)

Tamaru, S.; Tsunegi, S.; Kubota, H.; Yuasa, S.

2018-05-01

This work presents a vector network analyzer ferromagnetic resonance (VNA-FMR) spectrometer with field differential detection. This technique differentiates the S-parameter by applying a small binary modulation field in addition to the DC bias field to the sample. By setting the modulation frequency sufficiently high, slow sensitivity fluctuations of the VNA, i.e., low-frequency components of the trace noise, which limit the signal-to-noise ratio of the conventional VNA-FMR spectrometer, can be effectively removed, resulting in a very clean FMR signal. This paper presents the details of the hardware implementation and measurement sequence as well as the data processing and analysis algorithms tailored for the FMR spectrum obtained with this technique. Because the VNA measures a complex S-parameter, it is possible to estimate the Gilbert damping parameter from the slope of the phase variation of the S-parameter with respect to the bias field. We show that this algorithm is more robust against noise than the conventional algorithm based on the linewidth.

Nonlinear dynamics of three-magnon process driven by ferromagnetic resonance in yttrium iron garnet

Energy Technology Data Exchange (ETDEWEB)

Cunha, R. O. [Departamento de Física, Universidade Federal de Pernambuco, 50670-901 Recife, PE (Brazil); Centro Interdisciplinar de Ciências da Natureza, Universidade Federal da Integração Latino-Americana, 85867-970 Foz do Iguaçu, PR (Brazil); Holanda, J.; Azevedo, A.; Rezende, S. M., E-mail: rezende@df.ufpe.br [Departamento de Física, Universidade Federal de Pernambuco, 50670-901 Recife, PE (Brazil); Vilela-Leão, L. H. [Departamento de Física, Universidade Federal de Pernambuco, 50670-901 Recife, PE (Brazil); Centro Acadêmico do Agreste, Universidade Federal de Pernambuco, 55002-970 Caruaru, PE (Brazil); Rodríguez-Suárez, R. L. [Facultad de Física, Pontificia Universidad Católica de Chile, Casilla 306, Santiago (Chile)

2015-05-11

We report an investigation of the dynamics of the three-magnon splitting process associated with the ferromagnetic resonance (FMR) in films of the insulating ferrimagnet yttrium iron garnet (YIG). The experiments are performed with a 6 μm thick YIG film close to a microstrip line fed by a microwave generator operating in the 2–6 GHz range. The magnetization precession is driven by the microwave rf magnetic field perpendicular to the static magnetic field, and its dynamics is observed by monitoring the amplitude of the FMR absorption peak. The time evolution of the amplitude reveals that if the frequency is lowered below a critical value of 3.3 GHz, the FMR mode pumps two magnons with opposite wave vectors that react back on the FMR, resulting in a nonlinear dynamics of the magnetization. The results are explained by a model with coupled nonlinear equations describing the time evolution of the magnon modes.

Doping the 1 kton Large Volume Detector with Gd

International Nuclear Information System (INIS)

Bruno, Gianmarco; Fulgione, Walter; Porta, Amanda; Machado, Ana Amelia Bergamini; Mal'gin, Alexei; Molinario, Andrea; Vigorito, Carlo

2011-01-01

The Large Volume Detector (LVD) in the INFN Gran Sasso National Laboratory (LNGS), Italy, is a ν observatory which has been monitoring the Galaxy since June 1992 to study neutrinos from core collapse supernovae. The experiment in the present configuration is made by 840 scintillator detectors, for a total active mass of 1000 tons. The detector sensitivity to neutrino bursts due to a core collapse supernova has been already discussed in term of maximum detectable distance. In this paper we evaluate the improvements that LVD could obtain if all its active scintillator mass was doped with a small amount (0.14% in weight) of Gadolinium. We simulated neutron captures following ν-bar e inverse beta decay reactions in one LVD counter (1.2 ton) with Gd doped liquid scintillator obtaining an efficiency for the detection of this process of η n | Gd = 80% and a mean capture time τ = 25μs, in good agreement with the results obtained by the measures. This implies a gain of a factor ∼ 20 in the signal to noise ratio for neutron capture detection with respect to the undoped liquid scintillator. We discuss how the captures of neutrons from rock radioactivity on Gd modify the background conditions of the detector and we calculate the curves expressing the sensitivity to a ν-bar e burst from core collapse supernovae depending on the distance of the collapsing star. It results that doping the 1 kton Large Volume Detector with Gd would assure a 90% detection efficiency at the distance of the Large Magellanic Cloud (50 kpc), an achievement which is equivalent to that obtained by doubling the number of counters in LVD

Electric field-induced ferromagnetic resonance in a CoFeB/MgO magnetic tunnel junction under dc bias voltages

Science.gov (United States)

Kanai, Shun; Gajek, Martin; Worledge, D. C.; Matsukura, Fumihiro; Ohno, Hideo

2014-12-01

We measure homodyne-detected ferromagnetic resonance (FMR) induced by the electric-field effect in a CoFeB/MgO/CoFeB magnetic tunnel junction (MTJ) with perpendicular magnetic easy axis under dc bias voltages up to 0.1 V. From the bias dependence of the resonant frequency, we find that the first order perpendicular magnetic anisotropy is modulated by the applied electric field, whereas the second order component is virtually independent of the electric field. The lineshapes of the FMR spectra are bias dependent, which are explained by the combination of electric-field effect and reflection of the bias voltage from the MTJ.

Magnetic anisotropy of Ni/Cr multilayers

International Nuclear Information System (INIS)

Kang, S.; Xia, H.

1997-01-01

The magnetic anisotropy of Ni/Cr multilayers has been investigated by using vibrating sample magnetometer (VSM) and ferromagnetic resonance techniques (FMR). The FMR spectra are obtained as a function of the orientation of the applied magnetic field from in-plane to out-of-plane. The results are fitted theoretically to determine the magnetic anisotropy. From VSM and FMR, a positive value for Ni/Cr interface anisotropy is obtained, which favours a perpendicular easy axis. The possible mechanism for the perpendicular anisotropy has been discussed and it may be attributed to the magnetostriction, caused by intrinsic stress due to lattice mismatch. (orig.). With 005 figs., 001 tabs

Deconvolution of ferromagnetic resonance in devitrification process of Co-based amorphous alloys

International Nuclear Information System (INIS)

Montiel, H.; Alvarez, G.; Betancourt, I.; Zamorano, R.; Valenzuela, R.

2006-01-01

Ferromagnetic resonance (FMR) measurements were carried out on soft magnetic amorphous ribbons of composition Co 66 Fe 4 B 12 Si 13 Nb 4 Cu prepared by melt spinning. In the as-cast sample, a simple FMR spectrum was apparent. For treatment times of 5-20 min a complex resonant absorption at lower fields was detected; deconvolution calculations were carried out on the FMR spectra and it was possible to separate two contributions. These results can be interpreted as the combination of two different magnetic phases, corresponding to the amorphous matrix and nanocrystallites. The parameters of resonant absorptions can be associated with the evolution of nanocrystallization during the annealing

Self-induced inverse spin-Hall effect in an iron and a cobalt single-layer films themselves under the ferromagnetic resonance

Science.gov (United States)

Kanagawa, Kazunari; Teki, Yoshio; Shikoh, Eiji

2018-05-01

The inverse spin-Hall effect (ISHE) is produced even in a "single-layer" ferromagnetic material film. Previously, the self-induced ISHE in a Ni80Fe20 film under the ferromagnetic resonance (FMR) was discovered. In this study, we observed an electromotive force (EMF) in an iron (Fe) and a cobalt (Co) single-layer films themselves under the FMR. As origins of the EMFs in the films themselves, the ISHE was main for Fe and dominant for Co, respectively 2 and 18 times larger than the anomalous Hall effect. Thus, we demonstrated the self-induced ISHE in an Fe and a Co single-layer films themselves under the FMR.

Doping the 1 kton Large Volume Detector with Gd

Energy Technology Data Exchange (ETDEWEB)

Bruno, Gianmarco [University of L' Aquila, Via Vetoio snc, 67100 Coppito (AQ) Italy (Italy); Fulgione, Walter; Porta, Amanda [Istituto di Fisica dello Spazio Interplanetario, INAF, Corso Fiume 4, Torino (Italy); Machado, Ana Amelia Bergamini [Laboratori Nazionali del Gran Sasso, INFN, s.s. 17bis Km 18-10, Assergi (AQ) (Italy); Mal' gin, Alexei [Institute for Nuclear Research, Russian Academy of Sciences, pr. Shestidesyatiletiya Oktyabrya 7a, Moscow, 117312 (Russian Federation); Molinario, Andrea; Vigorito, Carlo, E-mail: bruno@to.infn.it, E-mail: fulgione@to.infn.it, E-mail: ana.machado@lngs.infn.it, E-mail: malgin@lngs.infn.it, E-mail: amolinar@to.infn.it, E-mail: Amanda.Porta@subatech.in2p3.fr, E-mail: vigorito@to.infn.it [INFN, Via Pietro Giuria 1, Torino (Italy)

2011-06-01

The Large Volume Detector (LVD) in the INFN Gran Sasso National Laboratory (LNGS), Italy, is a ν observatory which has been monitoring the Galaxy since June 1992 to study neutrinos from core collapse supernovae. The experiment in the present configuration is made by 840 scintillator detectors, for a total active mass of 1000 tons. The detector sensitivity to neutrino bursts due to a core collapse supernova has been already discussed in term of maximum detectable distance. In this paper we evaluate the improvements that LVD could obtain if all its active scintillator mass was doped with a small amount (0.14% in weight) of Gadolinium. We simulated neutron captures following ν-bar {sub e} inverse beta decay reactions in one LVD counter (1.2 ton) with Gd doped liquid scintillator obtaining an efficiency for the detection of this process of η{sub n}|{sub Gd} = 80% and a mean capture time τ = 25μs, in good agreement with the results obtained by the measures. This implies a gain of a factor ∼ 20 in the signal to noise ratio for neutron capture detection with respect to the undoped liquid scintillator. We discuss how the captures of neutrons from rock radioactivity on Gd modify the background conditions of the detector and we calculate the curves expressing the sensitivity to a ν-bar {sub e} burst from core collapse supernovae depending on the distance of the collapsing star. It results that doping the 1 kton Large Volume Detector with Gd would assure a 90% detection efficiency at the distance of the Large Magellanic Cloud (50 kpc), an achievement which is equivalent to that obtained by doubling the number of counters in LVD.

Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

Directory of Open Access Journals (Sweden)

Karen Kelley

2012-01-01

Full Text Available The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs such as fragile X syndrome (FXS. After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed by Dicer endoribonuclases to form microRNA (miRNA-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of the FMR1 5′-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptional FMR1 gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, while FMR1 inactivation augments metabotropic glutamate receptor (mGluR-activated long-term depression (LTD, leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability

Science.gov (United States)

Lima-Cabello, Elena; Garcia-Guirado, Francisco; Calvo-Medina, Rocio; el Bekay, Rajaa; Perez-Costillas, Lucia; Quintero-Navarro, Carolina; Sanchez-Salido, Lourdes

2016-01-01

Background. Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. Methods. This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. Results. Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. Conclusions. These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome. PMID:26788253

Three Faces of Fragile X.

Science.gov (United States)

Lieb-Lundell, Cornelia C E

2016-11-01

Fragile X syndrome (FXS) is the first of 3 syndromes identified as a health condition related to fragile X mental retardation (FMR1) gene dysfunction. The other 2 syndromes are fragile X-associated primary ovarian insufficiency syndrome (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which together are referred to as fragile X-associated disorders (FXDs). Collectively, this group comprises the 3 faces of fragile X. Even though the 3 conditions share a common genetic defect, each one is a separate health condition that results in a variety of body function impairments such as motor delay, musculoskeletal issues related to low muscle tone, coordination limitations, ataxia, tremor, undefined muscle aches and pains, and, for FXTAS, a late-onset neurodegeneration. Although each FXD condition may benefit from physical therapy intervention, available evidence as to the efficacy of intervention appropriate to FXDs is lacking. This perspective article will discuss the genetic basis of FMR1 gene dysfunction and describe health conditions related to this mutation, which have a range of expressions within a family. Physical therapy concerns and possible assessment and intervention strategies will be introduced. Understanding the intergenerational effect of the FMR1 mutation with potential life-span expression is a key component to identifying and treating the health conditions related to this specific genetic condition. © 2016 American Physical Therapy Association.

An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability

Directory of Open Access Journals (Sweden)

Elena Lima-Cabello

2016-01-01

Full Text Available Background. Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. Methods. This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. Results. Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. Conclusions. These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome.

Similar star formation rate and metallicity variability time-scales drive the fundamental metallicity relation

Science.gov (United States)

Torrey, Paul; Vogelsberger, Mark; Hernquist, Lars; McKinnon, Ryan; Marinacci, Federico; Simcoe, Robert A.; Springel, Volker; Pillepich, Annalisa; Naiman, Jill; Pakmor, Rüdiger; Weinberger, Rainer; Nelson, Dylan; Genel, Shy

2018-06-01

The fundamental metallicity relation (FMR) is a postulated correlation between galaxy stellar mass, star formation rate (SFR), and gas-phase metallicity. At its core, this relation posits that offsets from the mass-metallicity relation (MZR) at a fixed stellar mass are correlated with galactic SFR. In this Letter, we use hydrodynamical simulations to quantify the time-scales over which populations of galaxies oscillate about the average SFR and metallicity values at fixed stellar mass. We find that Illustris and IllustrisTNG predict that galaxy offsets from the star formation main sequence and MZR oscillate over similar time-scales, are often anticorrelated in their evolution, evolve with the halo dynamical time, and produce a pronounced FMR. Our models indicate that galaxies oscillate about equilibrium SFR and metallicity values - set by the galaxy's stellar mass - and that SFR and metallicity offsets evolve in an anticorrelated fashion. This anticorrelated variability of the metallicity and SFR offsets drives the existence of the FMR in our models. In contrast to Illustris and IllustrisTNG, we speculate that the SFR and metallicity evolution tracks may become decoupled in galaxy formation models dominated by feedback-driven globally bursty SFR histories, which could weaken the FMR residual correlation strength. This opens the possibility of discriminating between bursty and non-bursty feedback models based on the strength and persistence of the FMR - especially at high redshift.

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome.

Science.gov (United States)

Nomura, Toshihiro; Musial, Timothy F; Marshall, John J; Zhu, Yiwen; Remmers, Christine L; Xu, Jian; Nicholson, Daniel A; Contractor, Anis

2017-11-22

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS. SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin

The mass-metallicity and fundamental metallicity relations at z > 2 using very large telescope and Subaru near-infrared spectroscopy of zCOSMOS galaxies

Energy Technology Data Exchange (ETDEWEB)

Maier, C.; Ziegler, B. L. [Department of Astrophysics, University of Vienna, Türkenschanzstrasse 17, A-1180 Vienna (Austria); Lilly, S. J.; Peng, Y. [Institute of Astronomy, ETH Zurich, Wolfgang-Pauli-Strasse 27, CH-8093 Zurich (Switzerland); Contini, T. [Institut de Recherche en Astrophysique et Planétologie, CNRS, 14 avenue Édouard Belin, F-31400 Toulouse (France); Pérez Montero, E. [Instituto de Astrofísica de Andalucia, CSIC, Apartado de Correos 3004, E-18080 Granada (Spain); Balestra, I., E-mail: christian.maier@univie.ac.at [Max-Planck-Institut für Extraterrestrische Physik, Postfach 1312, Giessenbachstrasse, D-85741 Garching b. München (Germany)

2014-09-01

In the local universe, there is good evidence that, at a given stellar mass M, the gas-phase metallicity Z is anti-correlated with the star formation rate (SFR) of the galaxies. It has also been claimed that the resulting Z(M, SFR) relation is invariant with redshift—the so-called 'fundamental metallicity relation' (FMR). Given a number of difficulties in determining metallicities, especially at higher redshifts, the form of the Z(M, SFR) relation and whether it is really independent of redshift is still very controversial. To explore this issue at z > 2, we used VLT-SINFONI and Subaru-MOIRCS near-infrared spectroscopy of 20 zCOSMOS-deep galaxies at 2.1 < z < 2.5 to measure the strengths of up to five emission lines: [O II] λ3727, Hβ, [O III] λ5007, Hα, and [N II] λ6584. This near-infrared spectroscopy enables us to derive O/H metallicities, and also SFRs from extinction corrected Hα measurements. We find that the mass-metallicity relation (MZR) of these star-forming galaxies at z ≈ 2.3 is lower than the local Sloan Digital Sky Survey (SDSS) MZR by a factor of three to five, a larger change than found by Erb et al. using [N II]/Hα-based metallicities from stacked spectra. We discuss how the different selections of the samples and metallicity calibrations used may be responsible for this discrepancy. The galaxies show direct evidence that the SFR is still a second parameter in the MZR at these redshifts. However, determining whether the Z(M, SFR) relation is invariant with epoch depends on the choice of extrapolation used from local samples, because z > 2 galaxies of a given mass have much higher SFRs than the local SDSS galaxies. We find that the zCOSMOS galaxies are consistent with a non-evolving FMR if we use the physically motivated formulation of the Z(M, SFR) relation from Lilly et al., but not if we use the empirical formulation of Mannucci et al.

Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma

DEFF Research Database (Denmark)

Xia, Yi; Xu-Monette, Z Y; Tzankov, A

2017-01-01

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBC...

Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer.

Science.gov (United States)

Yip, Connie; Goh, Vicky; Davies, Andrew; Gossage, James; Mitchell-Hay, Rosalind; Hynes, Orla; Maisey, Nick; Ross, Paul; Gaya, Andrew; Landau, David B; Cook, Gary J; Griffin, Nyree; Mason, Robert

2014-05-01

Sarcopenia and changes in body composition following neoadjuvant chemotherapy (NAC) may affect clinical outcome. We assessed the associations between CT body composition changes following NAC and outcomes in oesophageal cancer. A total of 35 patients who received NAC followed by oesophagectomy, and underwent CT assessment pre- and post-NAC were included. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were derived from CT. Changes in FM, FFM, FMR, VA/SA and sarcopenia were correlated to chemotherapy dose reductions, postoperative complications, length of hospital stay (LOS), circumferential resection margin (CRM), pathological chemotherapy response, disease-free survival (DFS) and overall survival (OS). Nine (26 %) patients were sarcopenic before NAC and this increased to 15 (43 %) after NAC. Average weight loss was 3.7 % ± 6.4 (SD) in comparison to FM index (-1.2 ± 4.2), FFM index (-4.6 ± 6.8), FMR (-1.2 ± 24.3) and VA/SA (-62.3 ± 12.7). Changes in FM index (p = 0.022), FMR (p = 0.028), VA/SA (p = 0.024) and weight (p = 0.007) were significant univariable factors for CRM status. There was no significant association between changes in body composition and survival. Loss of FM, differential loss of VA/SA and skeletal muscle were associated with risk of CRM positivity. • Changes in CT body composition occur after neoadjuvant chemotherapy in oesophageal cancer. • Sarcopenia was more prevalent after neoadjuvant chemotherapy. • Fat mass, fat-free mass and weight decreased after neoadjuvant chemotherapy. • Changes in body composition were associated with CRM positivity. • Changes in body composition did not affect perioperative complications and survival.

Changes in insulin-like growth factor signaling alter phenotypes in Fragile X Mice.

Science.gov (United States)

Wise, T L

2017-02-01

Fragile X syndrome (FXS) is an inherited form of intellectual disability that is usually caused by expansion of a polymorphic CGG repeat in the 5' untranslated region of the X-linked FMR1 gene, which leads to hypermethylation and transcriptional silencing. Two non-neurological phenotypes of FXS are enlarged testes and connective tissue dysplasia, which could be caused by alterations in a growth factor signaling pathway. FXS patients also frequently have autistic-like symptoms, suggesting that the signaling pathways affected in FXS may overlap with those affected in autism. Identifying these pathways is important for both understanding the effects of FMR1 inactivation and developing treatments for both FXS and autism. Here we show that decreasing the levels of the insulin-like growth factor (Igf) receptor 1 corrects a number of phenotypes in the mouse model of FXS, including macro-orchidism, and that increasing the levels of IGF2 exacerbates the seizure susceptibility phenotype. These results suggest that the pathways altered by the loss of the FMR1-encoded protein (FMRP) may overlap with the pathways affected by changes in Igf signaling or that one or more of the proteins that play a role in Igf signaling could interact with FMRP. They also indicate a new set of potential targets for drug treatment of FXS and autism spectrum disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Perinatal mortality in twin pregnancy: an analysis of birth weight-specific mortality rates and adjusted mortality rates for birth weight distributions.

Science.gov (United States)

Fabre, E; González de Agüero, R; de Agustin, J L; Pérez-Hiraldo, M P; Bescos, J L

1988-01-01

The objective of this study is to compare the fetal mortality rate (FMR), early neonatal mortality rate (ENMR) and perinatal mortality rate (PMR) of twin and single births. It is based on a survey which was carried out in 22 Hospital Centers in Spain in 1980, and covered 1,956 twins born and 110,734 singletons born. The FMR in twins was 36.3/1000 and 8.8/1000 for singletons. The ENMR in twins was 36.1/1000 and 5.7/1000 for singletons. The PMR in twins was 71.1/1000 and 14.4/1000 for singletons. When birthweight-specific PMR in twin and singletons births are compared, there were no differences between the rates for groups 500-999 g and 1000-1499 g. For birthweight groups of 1500-1999 g (124.4 vs 283.8/1000) and 2000-2999 g (29.6 vs 73.2/1000) the rates for twins were about twice lower than those for single births. The PMR for 2500 g and over birthweight was about twice higher in twins than in singletons (12.5 vs 5.5/1000). After we adjusted for birthweight there was a difference in the FMR (12.6 vs 9.8/1000) and the PMR (19.1 vs 16.0/1000, and no difference in the ENMR between twins and singletons (5.9 vs 6.4/1000), indicating that most of the differences among crude rates are due to differences in distribution of birthweight.

Fragile X mental retardation protein expression in Alzheimer’s disease

Directory of Open Access Journals (Sweden)

Abigail J Renoux

2014-10-01

Full Text Available The FMR1 protein product, FMRP, is an mRNA binding protein associated with translational inhibition of target transcripts. One FMRP target is the amyloid precursor protein (APP mRNA, and APP levels are elevated in Fmr1 KO mice. Given that elevated APP protein expression can elicit Alzheimer’s disease (AD in patients and model systems, we evaluated whether FMRP expression might be altered in Alzheimer’s autopsy brain samples and mouse models compared to controls. In a double transgenic mouse model of AD (APP/PS1, we found no difference in FMRP expression in aged AD model mice compared to littermate controls. FMRP expression was also similar in AD and control patient frontal cortex and cerebellum samples. Fragile X-associated tremor/ataxia syndrome (FXTAS is an age related neurodegenerative disorder caused by expanded CGG repeats in the 5’UTR of the FMR1 gene. Patients experience cognitive impairment and dementia in addition to motor symptoms. In parallel studies, we measured FMRP expression in cortex and cerebellum from three FXTAS patients and found reduced expression compared to both controls and Alzheimer’s patient brains, consistent with animal models. We also find increased APP levels in cerebellar, but not cortical, samples of FXTAS patients compared to controls. Taken together, these data suggest that a decrease in FMRP expression is unlikely to be a primary contributor to Alzheimer’s disease pathogenesis.

Estimating energetics in cetaceans from respiratory frequency: why we need to understand physiology

Directory of Open Access Journals (Sweden)

A. Fahlman

2016-04-01

Full Text Available The accurate estimation of field metabolic rates (FMR in wild animals is a key component of bioenergetic models, and is important for understanding the routine limitations for survival as well as individual responses to disturbances or environmental changes. Several methods have been used to estimate FMR, including accelerometer-derived activity budgets, isotope dilution techniques, and proxies from heart rate. Counting the number of breaths is another method used to assess FMR in cetaceans, which is attractive in its simplicity and the ability to measure respiration frequency from visual cues or data loggers. This method hinges on the assumption that over time a constant tidal volume (VT and O2 exchange fraction (ΔO2 can be used to predict FMR. To test whether this method of estimating FMR is valid, we measured breath-by-breath tidal volumes and expired O2 levels of bottlenose dolphins, and computed the O2 consumption rate (V̇O2 before and after a pre-determined duration of exercise. The measured V̇O2 was compared with three methods to estimate FMR. Each method to estimate V̇O2 included variable VT and/or ΔO2. Two assumption-based methods overestimated V̇O2 by 216-501%. Once the temporal changes in cardio-respiratory physiology, such as variation in VT and ΔO2, were taken into account, pre-exercise resting V̇O2 was predicted to within 2%, and post-exercise V̇O2 was overestimated by 12%. Our data show that a better understanding of cardiorespiratory physiology significantly improves the ability to estimate metabolic rate from respiratory frequency, and further emphasizes the importance of eco-physiology for conservation management efforts.

Passive high-frequency devices based on superlattice ferromagnetic nanowires

International Nuclear Information System (INIS)

Ye, B.; Li, F.; Cimpoesu, D.; Wiley, J.B.; Jung, J.-S.; Stancu, A.; Spinu, L.

2007-01-01

In this paper we propose to tailor the bandwidth of a microwave filter by exploitation of shape anisotropy of nanowires. In order to achieve this control of shape anisotropy, we considered superlattice wires containing varying-sized ferromagnetic regions separated by nonferromagnetic regions. Superlattice wires of Ni and Au with a nominal diameter of 200 nm were grown using standard electrodeposition techniques. The microwave properties were probed using X-band (9.8 GHz) ferromagnetic resonance (FMR) experiments performed at room temperature. In order to investigate the effectiveness of the shape anisotropy on the superlattice nanowire based filter the FMR spectrum of superlattice structure is compared to the FMR spectra of nanowires samples with constant length

Thin Co films with tunable ferromagnetic resonance frequency

International Nuclear Information System (INIS)

Maklakov, Sergey S.; Maklakov, Sergey A.; Ryzhikov, Ilya A.; Rozanov, Konstantin N.; Osipov, Alexey V.

2012-01-01

The tailored production of thin Co films of 50 nm thick with ferromagnetic resonance frequency in a range from 2.9 to 7.3 GHz using the DC magnetron sputtering is reported. The ferromagnetic resonance frequency, coercivity, effective magnetic field and nanocrystalline structure parameters are shown to be governed by the Co deposition rate. For this investigation, FMR, VSM and TEM techniques were used. - Highlights: ► Thin Co films with FMR frequency in a range from 2.9 to 7.3 GHz are obtained. ► The films' properties are governed by the deposition rate during DC magnetron sputtering. ► FMR, VSM and TEM techniques were used during the study.

HIDE-AND-SEEK WITH THE FUNDAMENTAL METALLICITY RELATION

Energy Technology Data Exchange (ETDEWEB)

Kashino, D. [Division of Particle and Astrophysical Science, Graduate School of Science, Nagoya University, Nagoya, 464-8602 (Japan); Renzini, A. [INAF Osservatorio Astronomico di Padova, vicolo dell’Osservatorio 5, I-35122 Padova (Italy); Silverman, J. D. [Kavli Institute for the Physics and Mathematics of the Universe (WPI), Todai Institutes for Advanced Study, the University of Tokyo, Kashiwanoha, Kashiwa, 277-8583 (Japan); Daddi, E., E-mail: daichi@nagoya-u.jp [Laboratoire AIM-Paris-Saclay, CEA/DSM-CNRS-Université Paris Diderot, Irfu/CEA-Saclay, Service d’Astrophysique, F-91191 Gif-sur-Yvette (France)

2016-06-01

We use ∼83,000 star-forming galaxies at 0.04 < z < 0.3 from the Sloan Digital Sky Survey to study the so-called fundamental metallicity relation (FMR) and report on the disappearance of its anti-correlation between metallicity and star formation rate (SFR) when using the new metallicity indicator recently proposed by Dopita et al. In this calibration, metallicity is primarily sensitive to the emission line ratio [N ii] λ 6584/[S ii] λλ 6717, 6731 that is insensitive to dilution by pristine infalling gas that may drive the FMR anti-correlation with SFR. Therefore, we conclude that the apparent disappearance of the FMR (using this new metallicity indicator) does not rule out its existence.

Selective electronalysis of peracetic acid in the presence of a large excess of H{sub 2}O{sub 2} at Au(1 1 1)-like gold electrode

Energy Technology Data Exchange (ETDEWEB)

Awad, M.I., E-mail: mawad70@yahoo.com [Department of Chemistry, Faculty of Science, Cairo University (Egypt)

2012-06-12

Highlights: Black-Right-Pointing-Pointer Analysis of peracetic acid in the presence of a large excess of H{sub 2}O{sub 2} is introduced. Black-Right-Pointing-Pointer Au(1 1 1)-like gold electrode serves as an ideal for this purpose. Black-Right-Pointing-Pointer The analysis is characterized by high selectivity and sensitivity. - Abstract: Peracetic acid (PAA) has been selectively electroanalyzed in the presence of a large excess of hydrogen peroxide (H{sub 2}O{sub 2}), about 500 fold that of PAA, using Au (1 1 1)-like gold electrode in acetate buffer solutions of pH 5.4. Au(1 1 1)-like gold electrode was prepared by a controlled reductive desorption of a previously assembled thiol, typically cysteine, monolayer onto the polycrystalline gold (poly-Au) electrode. Cysteine molecules were selectively removed from the Au(1 1 1) facets of the poly-Au electrode, keeping the other two facets (i.e., Au(1 1 0) and Au(1 0 0)) under the protection of the adsorbed cysteine. It has been found that Au(1 1 1)-like gold electrode positively shifts the reduction peak of PAA, while, fortunately, shifts the reduction peak of H{sub 2}O{sub 2} negatively, achieving a large potential separation (around 750 mV) between the two reduction peaks as compared with that (around 450 mV) obtained at the poly-Au electrode. This large potential separation between the two reduction peaks enabled the analysis of PAA in the presence of a large excess of H{sub 2}O{sub 2}. In addition, the positive shift of the reduction peak of PAA gives the present method a high immunity against the interference of the dissolved oxygen.

Inelastic energy loss in large angle scattering of Ar9+ ions from Au(1 1 1) crystal

International Nuclear Information System (INIS)

Pesic, Z.D.; Anton, J.; Bremer, J.H.; Hoffmann, V.; Stolterfoht, N.; Vikor, Gy.; Schuch, R.

2003-01-01

The azimuthal angle dependence of the energy loss in large-angle scattering of slow (v∼0.06 a.u.) Ar 9+ ions from a Au(1 1 1) single crystal was investigated. Regarding the kinematics of quasi-single collisions, the smallest energy loss is expected for the azimuthal orientations which correspond to the closest packed atomic row of the crystal. This agrees with the prediction of a trajectory simulation (Marlowe code), but the experimental results don't show such dependence. Thus, we discuss possible inelastic processes as image charge energy gain, electronic energy loss in close collision and the electronic energy loss in the interaction with the electron gas. The observed azimuthal dependence is explained by the change of the electronic stopping power due to the variation of effective electron density sampled by the projectile

Achondroplasia in sibs of normal parents.

OpenAIRE

Philip, N; Auger, M; Mattei, J F; Giraud, F

1988-01-01

A new case of recurrent achondroplasia in sibs of normal parents is reported. Two sisters and a half sister were affected. Various mechanisms can be postulated to account for unexpected recurrence of achondroplasia in the same sibship. Germinal mosaicism and unstable premutation are discussed here.

Assessment of TRAC-PF1/MOD1 code for large break LOCA in PWR

International Nuclear Information System (INIS)

Akimoto, Hajime; Ohnuki, Akira; Murao, Yoshio; Abe, Yutaka.

1993-03-01

As the first step of the REFLA/TRAC code development, the TRAC/PF1/MOD1 code has been assessed for various experiments that simulate postulated large-break loss-of-coolant accident (LBLOCA) in PWR to understand the predictive capability and to identify the problem areas of the code. The assessment calculations were performed for separate effect tests for critical flow, counter current flow, condensation at cold leg and reflood as well as integral tests to understand predictability for individual phenomena. This report summarizes results from the assessment calculations of the TRAC-PF1/MOD1 code for LBLOCA in PWR. The assessment calculations made clear the predictive capability and problem areas of the TRAC-PF1/MOD1 code for LBLOCA in PWR. The areas, listed below, should be improved for more realistic and effective simulation of LBLOCA in PWR: (1) core heat transfer model during blowdown, (2) ECC bypass model at downcomer during refill, (3) condensation model during accumulator injection, and (4) core thermal hydraulic model during reflood. (author) 57 refs

Post-test analysis of semiscale large-break test S-06-3 using TRAC-PF1

International Nuclear Information System (INIS)

Boyack, B.E.

1982-01-01

The Transient Reactor Analysis Code (TRAC) is an advanced systems code for light-water-reactor accident analysis. The code was developed originally to analyze large-break loss-of-coolant accidents (LOCAs) and running time was not a primary development criterion. TRAC-PF1 was developed because increased application of the code to long transients such as small-break LOCAs required a faster-running code version. Although developed for long transients, its performance on large-break transients is still important. This paper assesses the ability of TRAC-PF1 to predict large-break-LOCA Test S-06-3 conducted in the Semiscale Mod-1 facility

Damping constant of Co/Pt multilayer thin-film media

International Nuclear Information System (INIS)

Fujita, N.; Inaba, N.; Kirino, F.; Igarashi, S.; Koike, K.; Kato, H.

2008-01-01

Gilbert's damping constants, α, of Co(t Co )/Pt (1.4 nm) multilayer thin films are investigated by Q-band FMR analysis. α is calculated from the resonance width of the FMR spectrum. With decreasing t Co , the α value decreases from 0.034 (t Co =8.7 nm) to 0.023 (t Co =1.8 nm), and then increases to 0.037 (t Co =1.0 nm). The decrease of α with t Co >1.8 nm is probably due to the eddy current loss effects. The increase of α with t Co <1.8 nm would be caused by the increase of the distortion between the Co and the Pt layers at the interface. When the magnetic field direction was changed from θ=90 deg. (parallel to the specimen) to θ=0 deg. (perpendicular to the specimen), the α of all the specimens increased, and a sharp step in α was observed around θ=40 deg., where the α has the maximum value

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

Science.gov (United States)

Guo, Weirui; Molinaro, Gemma; Collins, Katie A; Hays, Seth A; Paylor, Richard; Worley, Paul F; Szumlinski, Karen K; Huber, Kimberly M

2016-02-17

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and

Development of large-capacity refrigeration at 1.8 K for the Large Hadron Collider at CERN

CERN Document Server

Lebrun, P; Claudet, G

1996-01-01

CERN, the European Laboratory for Particle Physics, is working towards the construction of the Large Hadron Collider (LHC), a high-energy, high-luminosity particle accelerator and collider [1] of 26.7 km circumference, due to start producing frontier physics, by bringing into collision intense proton and ion beams with centre-of-mass energies in the TeV-per-constituent range, at the beginning of the next century. The key technology for achieving this ambitious scientific goal at economically acceptable cost is the use of high-field superconducting magnets using Nb-Ti conductor operating in superfluid helium [2]. To maintain the some 25 km of bending and focusing magnets at their operating temperature of 1.9 K, the LHC cryogenic system will have to produce an unprecedented total refrigeration capacity of about 20 kW at 1.8 K, in eight cryogenic plants distributed around the machine circumference [3]. This has requested the undertaking of an industrial development programme, in the form of a collaboration betwe...

A Possible 1.8 K Refrigeration Cycle for the Large Hadron Collider

CERN Document Server

Millet, F; Tavian, L; Wagner, U

1998-01-01

The Large Hadron Collider (LHC) under construction at the European Laboratory for Particle Physics, CERN, will make use of superconducting magnets operating below 2.0 K. This requires, for each of the eight future cryogenic installations, an isothermal cooling capacity of up to 2.4 kW obtained by vaporisation of helium II at 1.6 kPa and 1.8 K. The process design for this cooling duty has to satisfy several demands. It has to be adapted to four already existing as well as to four new refrigerators. It must cover a dynamic range of one to three, and it must to allow continuous pump-down from 4.5 K to 1.8 K. A possible solution, as presented in this paper, includes a combination of cold centrifugal and warm volumetric compressors. It is characterised by a low thermal load on the refrigerator, and a large range of adaptability to different operation modes. The expected power factor for 1.8 K cooling is given, and the proposed control strategy is explained.

Structural Characterization of the Putative Cholinergic Binding Region alpha(179-201) of the Nicotinic Acetylcholine Receptor. Part 1. Review and Experimental Design.

Science.gov (United States)

1993-04-01

SUBJCT TERMS .. 15. NUMBER OF PAGES Nicotinic acetylcholine receptor FTIR 21 Vibrational spectroscopy Cholinergic 16. PRICE COOE Resonance raman 17...Wilson et al 1955). FMR spectroscopy measures the absorbance of infra-red rad iation, where as Raman spectroscopy measures inelastic scattering of...frequency is domrunated by that chromophore, then Raman scattering involving vibrations localized in that chromophore will be sharply enhanced(Cantor and

Pet measurements of presynaptic sympathetic nerve terminals in the heart

International Nuclear Information System (INIS)

Schwaiger, M.; Hutchins, G.D.; Wieland, D.M.

1991-01-01

[ 18 F]Metaraminol (FMR) and [ 11 C]hydroxyephedrine (HED) are catecholamine analogues that have been developed at the University of Michigan for the noninvasive characterization of the sympathetic nervous system of the heart using positron emission tomography (PET). Pharmacological studies employing neurotoxins and uptake inhibitors have demonstrated that both FMR and HED specifically trace the uptake and storage of catecholamines in sympathetic nerve terminals with little nonspecific tracer accumulation. These compounds exhibit excellent qualitative imaging characteristics with heart-to-blood ratios exceeding 6:1 as early as 15 min after intravenous injection in both animals (HED and FMR) and humans (HED). Tracer kinetic modeling techniques have been employed for the quantitative assessment of neuronal catecholamine uptake and storage. Indices of neuronal function, such as the volume of tracer distribution derived from the kinetic models, have been employed in preliminary human studies. Comparison of the tissue distribution volume of HED between normal (control subjects) and denervated (recent transplant patients) cardiac tissue demonstrates a dynamic range of approximately 5:1. This distribution volume is reduced by 60% from normal in patients with dilated cardiomyopathy, indicating dysfunction of the sympathetic system. These results show that HED used in combination with PET provides a sophisticated quantitative approach for studying the sympathetic nervous system of the normal and diseased human heart

Effect of small in-plane anisotropy in the large-D phase systems based on Ni{sup 2+} (S=1) ions in Heisenberg antiferromagnetic chains

Energy Technology Data Exchange (ETDEWEB)

Rudowicz, Czesław, E-mail: crudowicz@zut.edu.pl

2014-03-01

Heisenberg antiferromagnetic chains based on Ni{sup 2+} ions with integer spin S=1 exhibit intriguing behavior, e.g. the Haldane gap phase and the large-D phase. The predicted transitions between the two phases and the Neel phase has generated search for real candidate systems. Crucial to this search is the interplay between the ‘in-plane anisotropy’, i.e. the rhombic zero-field splitting (ZFS) E-term, and the ‘planar anisotropy’, i.e. the axial ZFS D-term. This paper clarifies intricate properties of orthorhombic ZFS Hamiltonians (H{sub ZFS}) and inconsistencies revealed by critical survey of pertinent studies. Reporting the non-standard (D, E) sets with λ=E/D out of the standard range (0, 1/3) alongside the standard sets with λ∝(0, 1/3) indicates that these properties are not recognized. We show that direct comparisons of the non-standard and standard sets are meaningless and lead to incorrect conclusions on the strength of the ‘in-plane anisotropy’ (E) as compared with the ‘planar anisotropy’ (D). To remedy such problems, the ZFSP sets reported for the large-D phase candidate systems are reanalyzed using orthorhombic standardization. The six physically equivalent ZFSP sets are determined in the conventional (D, E) and Stevens (b{sub 2}{sup 0}, b{sub 2}{sup 2}) notation. These considerations help understanding intricacies inherent in orthorhombic H{sub ZFS} and provide consistent data for future modeling of ZFS parameters in the large-D phase and Haldane gap systems.

Effects of iron deficiency on anisotropy and ferromagnetic resonance linewidth in Bi-doped LiZn ferrite

Directory of Open Access Journals (Sweden)

Xiaona Jiang

2017-05-01

Full Text Available Bi-doped LiZn ferrites with different iron deficiencies were fabricated by a conventional ceramic method. Anisotropy constant (K1 was calculated and ferromagnetic resonance (FMR linewidth (ΔH was investigated. Crystalline anisotropy broadening linewidth (ΔHa and porosity broadening linewidth (ΔHp were derived by an approximate calculation based on dipolar narrowing theory, which play a significant role in contributions to FMR linewidth and occupy more than 90 % of ΔH. Physical and static magnetic properties of LiZn ferrite with iron deficiency are presented, which supports a decline in linewidths with increasing iron deficiency. Iron deficiency makes K1, ΔHa and ΔHp reduce. The results also show that ΔHp is the majority of contributions to ΔH in Bi-doped LiZn ferrite and densification is an effective method to decrease ΔH.

Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma

DEFF Research Database (Denmark)

Møller, Michael Boe; Kania, P W; Ino, Y

2000-01-01

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data fr...

Ferromagnetic resonance response of electron-beam patterned arrays of ferromagnetic nanoparticles

Science.gov (United States)

Jung, Sukkoo; Watkins, Byron; Feller, Jeffrey; Ketterson, John; Chandrasekhar, Venkat

2001-03-01

We report on the fabrication and the dynamic magnetic properties of periodic permalloy dot arrays. Electron-beam lithography and e-gun evaporation have been used to make the arrays with the aspect ratio of 2 (dot diameter : 40 nm, height : 80 nm) and periods of 100 - 200 nm. The magnetic properties of the arrays and their interactions have been investigated by ferromagnetic resonance (FMR), magnetic force microscopy (MFM), and SQUID magnetometry. The measured FMR data show that the position and magnitude of resonant absorption peaks strongly depend on the angle between magnetic field and the lattice structure. The results of dot arrays with various kinds of structural parameters will be presented. Supported by Army Research Office, DAAD19-99-1-0334/P001

Clinical and Histologic Effects of Fractional Microneedling Radiofrequency Treatment on Rosacea.

Science.gov (United States)

Park, Seon Yong; Kwon, Hyuck Hoon; Yoon, Ji Young; Min, Seonguk; Suh, Dae Hun

2016-12-01

Fractional microneedling radiofrequency (FMR) is an emerging treatment modality, but its effect on rosacea has not been studied yet. To investigate the potential impact of FMR treatment on clinical improvement and histologic changes in rosacea patients. A 12-week, prospective, randomized, split-face clinical trial was conducted. Two sessions of FMR were performed on one side of the cheeks with 4-week interval and the other side remained untreated. Erythema index from DermaSpectrometer and a* value from Spectrophotometer CM-2002 were measured at each visit for the objective measurement of erythema. Histologic analysis of skin samples was also carried out. Clinical evaluation and photometric measurement revealed the reduction of redness in the treated side compared with untreated side and baseline. Erythema index decreased 13.6% and a* value decreased 6.8% at Week 12 compared with baseline. Reduced expression of markers related to inflammation, innate immunity, and angiogenesis was observed in immunohistochemical staining of tissue obtained after FMR treatment. Fractional microneedling radiofrequency treatment showed modest clinical and histologic improvement of rosacea, and it might be used as an alternative or in combination with other treatment methods.

CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.

Directory of Open Access Journals (Sweden)

Abhishek Nag

Full Text Available Tourette syndrome (TS is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179 have a significant excess (P = 0.006 of large CNV (>500 kb calls compared to controls (N = 234. Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.

Science.gov (United States)

Nag, Abhishek; Bochukova, Elena G; Kremeyer, Barbara; Campbell, Desmond D; Muller, Heike; Valencia-Duarte, Ana V; Cardona, Julio; Rivas, Isabel C; Mesa, Sandra C; Cuartas, Mauricio; Garcia, Jharley; Bedoya, Gabriel; Cornejo, William; Herrera, Luis D; Romero, Roxana; Fournier, Eduardo; Reus, Victor I; Lowe, Thomas L; Farooqi, I Sadaf; Mathews, Carol A; McGrath, Lauren M; Yu, Dongmei; Cook, Ed; Wang, Kai; Scharf, Jeremiah M; Pauls, David L; Freimer, Nelson B; Plagnol, Vincent; Ruiz-Linares, Andrés

2013-01-01

Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.

Bolometric detection of ferromagnetic resonance in amorphous microwires

Czech Academy of Sciences Publication Activity Database

Kraus, Luděk

2015-01-01

Roč. 51, č. 1 (2015), s. 6100104 ISSN 0018-9464 R&D Projects: GA ČR GAP102/12/2177 Institutional support: RVO:68378271 Keywords : amorphous microwires * anisotropic magnetoresistance (AMR) * bolometric effect * ferromagnetic resonance (FMR) Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 1.277, year: 2015

Molecular characterization of X chromosome fragility in idiopathic ...

African Journals Online (AJOL)

Background: Fragile X syndrome (FXS) is the most common form of inherited mental retardation. Frequency of fragile X syndrome among male siblings and relatives of mentally retarded patients is relatively high. Cytogenetic diagnosis of FXS is unreliable since it is ineffective for the diagnosis of premutated males or ...

Achondroplasia in sibs of normal parents.

Science.gov (United States)

Philip, N; Auger, M; Mattei, J F; Giraud, F

1988-01-01

A new case of recurrent achondroplasia in sibs of normal parents is reported. Two sisters and a half sister were affected. Various mechanisms can be postulated to account for unexpected recurrence of achondroplasia in the same sibship. Germinal mosaicism and unstable premutation are discussed here. Images PMID:3236371

75 FR 51392 - Federal Management Regulation; Transportation Management

Science.gov (United States)

2010-08-20

...; Docket Number 2010-0011, sequence 1] RIN 3090-AJ03 Federal Management Regulation; Transportation Management AGENCY: Office of Governmentwide Policy, General Services Administration (GSA). ACTION: Final rule. SUMMARY: The General Services Administration (GSA) is amending the Federal Management Regulation (FMR) by...

The Power of Flash Mob Research: Conducting a Nationwide Observational Clinical Study on Capillary Refill Time in a Single Day.

Science.gov (United States)

Alsma, Jelmer; van Saase, Jan L C M; Nanayakkara, Prabath W B; Schouten, W E M Ineke; Baten, Anique; Bauer, Martijn P; Holleman, Frits; Ligtenberg, Jack J M; Stassen, Patricia M; Kaasjager, Karin H A H; Haak, Harm R; Bosch, Frank H; Schuit, Stephanie C E

2017-05-01

Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients; various methods are available to assess CRT. Conventional clinical research often demands large numbers of patients, making it costly, labor-intensive, and time-consuming. We studied the interobserver agreement on CRT in a nationwide study by using a novel method of research called flash mob research (FMR). Physicians in the Netherlands were recruited by using word-of-mouth referrals, conventional media, and social media to participate in a nationwide, single-day, "nine-to-five," multicenter, cross-sectional, observational study to evaluate CRT. Patients aged ≥ 18 years presenting to the ED or who were hospitalized were eligible for inclusion. CRT was measured independently (by two investigators) at the patient's sternum and distal phalanx after application of pressure for 5 s (5s) and 15 s (15s). On October 29, 2014, a total of 458 investigators in 38 Dutch hospitals enrolled 1,734 patients. The mean CRT measured at the distal phalanx were 2.3 s (5s, SD 1.1) and 2.4 s (15s, SD 1.3). The mean CRT measured at the sternum was 2.6 s (5s, SD 1.1) and 2.7 s (15s, SD 1.1). Interobserver agreement was higher for the distal phalanx (κ value, 0.40) than for the sternum (κ value, 0.30). Interobserver agreement on CRT is, at best, moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared with sternal CRT measurements. FMR proved a valuable instrument to investigate a relatively simple clinical question in an inexpensive, quick, and reliable manner. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Are We Ready for Fragile X Newborn Screening Testing?—Lessons Learnt from a Feasibility Study

Directory of Open Access Journals (Sweden)

Tiffany Wotton

2018-02-01

Full Text Available Fragile X syndrome (FXS is the most prevalent heritable cause of cognitive impairment but is not yet included in a newborn screening (NBS program within Australia. This paper aims to assess the feasibility and reliability of population screening for FXS using a pilot study in one hospital. A total of 1971 mothers consented for 2000 newborns to be tested using routine NBS dried blood spot samples. DNA was extracted and a modified PCR assay with a chimeric CGG primer was used to detect fragile X alleles in both males and females in the normal, premutation, and full mutation ranges. A routine PCR-based fragile X assay was run in parallel to validate the chimeric primer assay. Babies with CGG repeat number ≥59 were referred for family studies. One thousand nine hundred and ninety NBS samples had a CGG repeat number less than 55 (1986 < 50; 10 had premutation alleles >54 CGG repeats (1/123 females and 1/507 males. There was complete concordance between the two PCR-based assays. A recent review revealed no clinically identified cases in the cohort up to 5 years later. The cost per test was $AUD19. Fragile X status can be determined on routine NBS samples using the chimeric primer assay. However, whilst this assay may not be considered cost-effective for population screening, it could be considered as a second-tier assay to a developed immunoassay for fragile X mental retardation protein (FMRP.

Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

DEFF Research Database (Denmark)

Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders

2009-01-01

BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovaria...

Diphoton excess from hidden U(1 gauge symmetry with large kinetic mixing

Directory of Open Access Journals (Sweden)

Fuminobu Takahashi

2016-09-01

Full Text Available We show that the 750 GeV diphoton excess can be explained by introducing vector-like quarks and hidden fermions charged under a hidden U(1 gauge symmetry, which has a relatively large coupling constant as well as a significant kinetic mixing with U(1Y. With the large kinetic mixing, the standard model gauge couplings unify around 1017 GeV, suggesting the grand unified theory without too rapid proton decay. Our scenario predicts events with a photon and missing transverse momentum, and its cross section is related to that for the diphoton excess through the kinetic mixing. We also discuss other possible collider signatures and cosmology, including various ways to evade constraints on exotic stable charged particles. In some cases where the 750 GeV diphoton excess is due to diaxion decays, our scenario also predicts triphoton and tetraphoton signals.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders.

Science.gov (United States)

O'Donnell, Cian; Gonçalves, J Tiago; Portera-Cailliau, Carlos; Sejnowski, Terrence J

2017-10-11

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca 2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits.

Molecular approach of the fragile chromosomal region Xq31-34 in cattle (Bos taurus by microdissection and DOP-PCR Aproximação molecular da região cromossômica frágil Xq31-34 em bovinos (Bos taurus utilizando microdissecação cromossômica e DOP-PCR

Directory of Open Access Journals (Sweden)

S. Llambí

2008-08-01

Full Text Available Fragile sites (FS are chromosomal regions where the normal compactation of chromatine is not observed. FRAXA (Fra Xq27.3, X sexual chromosome is one of the most studied FS in humans. FRAXA is an expansion of the trinucleotide CGG located in the gene FMR-1. In cattle, sites of chromosomal fragility were reported in BTAX, associated with different pathologies and fertility impairment. Chromosomal microdissection has became a valuable tool for isolating chromatine fragments. In this work, it was combined the chromosomal microdissection technique with DOP-PCR in order to carry out a molecular analysis of the fragile chromosomal region BTAXq31-34. In that region, polymorphic DNA-RAPD sequences (GC rich are present and sequences of the gene FMR-1 are missing. The results showed the usefulness of the microdissection-DOP-PCR technique for molecular characterization of fragile chromosomal sites in cattle.Os sítios frágeis (FS são regiões de cromossomo onde a compactação normal da cromatina não é realizada. O FRAXA (Fra Xq27.3, cromossomo sexual X é um dos FS mais estudados em seres humanos. O FRAXA apresenta expansão do trinucleotídeo CGG localizado no gene FMR-1. Em bovinos, existem estudos informando sobre fragilidade cromossômica em BTAX associada com diversas patologias e alterações na fertilidade. A microdissecação cromossômica é uma valiosa técnica para isolar fragmentos de cromatina. Neste trabalho, combinou-se a técnica de microdissecação de cromossomo com DOP-PCR para executar a análise molecular da região do sitio frágil cromossômico BTAXq31-34. Naquela região estão presentes seqüências do polimorfo DNA-RAPD (rico em GC, em que as seqüências do gene FMR-1 estão ausentes. Os resultados mostram a utilidade da técnica de microdissecação-DOP-PCR para a caracterização molecular de sítios frágeis cromossômicos em bovinos.

Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group

NARCIS (Netherlands)

B.B.A. de Vries (Bert); B.A. Oostra (Ben); M.F. Niermeijer (Martinus); A. Tibben (Arend); A.M.W. van den Ouweland (Ans); S. Mohkamsing; H.J. Duivenvoorden (Hugo); E. Mol; K. Gelsema; M. van Rijn; D.J.J. Halley (Dicky); L.A. Sandkuijl (Lodewijk)

1997-01-01

textabstractThe fragile X syndrome is an X-linked mental retardation disorder caused by an expanded CGG repeat in the first exon of the fragile X mental retardation (FMR1) gene. Its frequency, X-linked inheritance, and consequences for relatives all prompt for

Fragile X syndrome in two siblings with major congenital malformations

Energy Technology Data Exchange (ETDEWEB)

Giampietro, P.F.; Haas, B.R.; Lipper, E. [Cornell Univ. Medical Center, New York, NY (United States)] [and others

1996-05-17

We report on 2 brothers with both fragile X and VACTERL-H syndrome. The first sibling, age 5, had bilateral cleft lip and palate, ventricular septal defect, and a hypoplastic thumb. The second sibling, age 2{1/2}, had a trachesophageal fistula, esophageal atresia, and vertebral abnormality. High-resolution chromosome analysis showed a 46,XY chromosome constitution in both siblings. By PCR and Southern blot analysis, the siblings were found to have large triplet repeat expansions in the fragile X gene (FMR 1) and both had methylation mosaicism. Enzyme kinetic studies of iduronate sulfatase demonstrated a two-fold increase in activity in the first sib as compared to the second. Possible mechanisms through which the fragile X mutation can cause down-regulation of adjacent loci are discussed. 24 refs., 4 figs.

Are we adequately preparing the next generation of physicians to prescribe exercise as prevention and treatment? Residents express the desire for more training in exercise prescription

OpenAIRE

Solmundson, Kara; Koehle, Michael; McKenzie, Donald

2016-01-01

Background: Physical activity (PA) is a key intervention for chronic disease, yet few physicians provide exercise prescription (EP). EP is an important component in larger strategies of reducing non-communicable disease (NCD). Our objective was to assess Family Medicine Residents (FMR) knowledge, competence, and perspectives of EP to help inform future curriculum development. Methods: A 49-item cross-sectional survey was administered to 396 University of British Columbia FMR. Residents’ EP...

26 CFR 1.585-5 - Denial of bad debt reserves for large banks.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Denial of bad debt reserves for large banks. 1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Banking Institutions § 1.585-5 Denial of bad debt... other section for an addition to a reserve for bad debts. However, for these years, except as provided...

Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model.

Science.gov (United States)

Zeidler, Shimriet; Pop, Andreea S; Jaafar, Israa A; de Boer, Helen; Buijsen, Ronald A M; de Esch, Celine E F; Nieuwenhuizen-Bakker, Ingeborg; Hukema, Renate K; Willemsen, Rob

2018-06-01

Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABA B agonists. As FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABA B agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three-chamber sociability test. Unexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild-type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice. Altogether, the disappointing results of recent clinical trials with the R-baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Damping constant of Co/Pt multilayer thin-film media

Energy Technology Data Exchange (ETDEWEB)

Fujita, N. [Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510 (Japan); Inaba, N. [Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510 (Japan)], E-mail: inaba@yz.yamagata-u.ac.jp; Kirino, F. [National University of Fine Arts and Music, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8577 (Japan); Igarashi, S.; Koike, K.; Kato, H. [Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510 (Japan)

2008-11-15

Gilbert's damping constants, {alpha}, of Co(t{sub Co})/Pt (1.4 nm) multilayer thin films are investigated by Q-band FMR analysis. {alpha} is calculated from the resonance width of the FMR spectrum. With decreasing t{sub Co}, the {alpha} value decreases from 0.034 (t{sub Co}=8.7 nm) to 0.023 (t{sub Co}=1.8 nm), and then increases to 0.037 (t{sub Co}=1.0 nm). The decrease of {alpha} with t{sub Co}>1.8 nm is probably due to the eddy current loss effects. The increase of {alpha} with t{sub Co}<1.8 nm would be caused by the increase of the distortion between the Co and the Pt layers at the interface. When the magnetic field direction was changed from {theta}=90 deg. (parallel to the specimen) to {theta}=0 deg. (perpendicular to the specimen), the {alpha} of all the specimens increased, and a sharp step in {alpha} was observed around {theta}=40 deg., where the {alpha} has the maximum value.

Fe/Ni thin films temperature investigation with MgO and SiO2 interfaces by ferromagnetic resonance

International Nuclear Information System (INIS)

Zyubin, A; Orlova, A; Astashonok, A; Kupriyanova, G; Nevolin, V

2011-01-01

In this work the temperature study of magnetic – resonance properties of the structures such as Fe/MgO/Ni, Fe/SiO2/Ni differing thickness of spacer and of method of preparation was carried out by FMR. These systems are investigated to estimate their applicability in model creation experiments for a spintronics devices research [1–4]. The special attention was given to the temperature dependence research of three layer films linewidths. The out-of-plane temperature dependences of FMR signal position and line widths have been measured for Fe/Ni samples with MgO and Si/SiO2 interfaces in static position of 0 and 90 degrees rotation angle to the external static magnetic field. The extracted magnetic parameters such as linewidths and resonance field position were studied.

Executive Functioning Mediates the Effect of Behavioral Problems on Depression in Mothers of Children with Developmental Disabilities

Science.gov (United States)

Chan, Wai; Smith, Leann E.; Greenberg, Jan S.; Hong, Jinkuk; Mailick, Marsha R.

2017-01-01

The present investigation explored long-term relationships of behavioral symptoms of adolescents and adults with developmental disabilities with the mental health of their mothers. Fragile X premutation carrier mothers of an adolescent or adult child with fragile X syndrome (n = 95), and mothers of a grown child with autism (n = 213) were…

Repair in fertilized eggs of mice and its role in the production of chromosomal aberrations

International Nuclear Information System (INIS)

Generoso, W.M.

1979-01-01

The fertilized egg may influence the yield of dominant-lethal mutations produced from chemical treatment of male postmeiotic germ cells to a small or large extent depending upon the mutagen used and the competence of the egg to repair the premutational lesions induced. The strain of females has small influence on the yield of dominant-lethal mutations induced by TEM or EMS in spermatids and spermatozoa. On the contrary, it has large influence in the case of IMS. In addition to this difference, TEM and EMS induce high levels of heritable translocations at these germ cell stages while IMS is practically ineffective even though doses of these chemicals used produced comparable levels of dominant-lethal mutations. These differences between EMS and TEM on one hand and IMS on the other, were explained as a function of the types of chromosomal lesions present at the time of repair activity and whether or not chromosomal aberrations are already fixed at the time of postfertilization pronuclear DNA synthesis

Variation in allocation of time, water and energy in Hoopoe Larks from the Arabian Desert

NARCIS (Netherlands)

Tieleman, BI; Williams, JB; Visser, GH

2003-01-01

1. Patterns of resource allocation in different times of the year can provide insights into the effects of simultaneous environmental constraints on reproduction and survival of desert birds. Field metabolic rate (FMR), water influx rate (WIR) and patterns of time allocation of Hoopoe Larks (Alaemon

Assessment of intratumor hypoxia by integrated 18F-FDG PET / perfusion CT in a liver tumor model.

Directory of Open Access Journals (Sweden)

Yong Wang

Full Text Available Hypoxia in solid tumors occurs when metabolic demands in tumor cells surpass the delivery of oxygenated blood. We hypothesize that the 18F-fluorodeoxyglucose (18F-FDG metabolism and tumor blood flow mismatch would correlate with tumor hypoxia.Liver perfusion computed tomography (CT and 18F-FDG positron emission tomography (PET imaging were performed in twelve rabbit livers implanted with VX2 carcinoma. Under CT guidance, a fiber optic probe was inserted into the tumor to measure the partial pressure of oxygen (pO2. Tumor blood flow (BF and standardized uptake value (SUV were measured to calculate flow-metabolism ratio (FMR. Tumor hypoxia was further identified using pimonidazole immunohistochemical staining. Pearson correlation analysis was performed to determine the correlation between the imaging parameters and pO2 and pimonidazole staining.Weak correlations were found between blood volume (BV and pO2 level (r = 0.425, P = 0.004, SUV and pO2 (r = -0.394, P = 0.007, FMR and pimonidazole staining score (r = -0.388, P = 0.031. However, there was stronger correlation between tumor FMR and pO2 level (r = 0.557, P < 0.001.FMR correlated with tumor oxygenation and pimonidazole staining suggesting it may be a potential hypoxic imaging marker in liver tumor.

Adapted to change: Low energy requirements in a low and unpredictable productivity environment, the case of the Galapagos sea lion

Science.gov (United States)

Villegas-Amtmann, Stella; McDonald, Birgitte I.; Páez-Rosas, Diego; Aurioles-Gamboa, David; Costa, Daniel P.

2017-06-01

The rate of energy expenditure and acquisition are fundamental components of an animals' life history. Within mammals, the otariids (sea lions and fur seals) exhibit energetically expensive life styles, which can be challenging in equatorial regions where resources are particularly limited and unpredictable. To better understand how this energetically expensive life history pattern functions in an energetically challenging equatorial system, we concurrently measured the field metabolic rate (FMR) and foraging behavior of lactating Galapagos sea lions (GSL) rearing pups and yearlings. Females with pups tended to forage to the north, diving deeper, epi and mesopelagically compared to females with yearlings, which foraged to the west and performed dives to the sea bed that were shallower. FMR did not differ between females with pups or yearlings but, increased significantly with % time spent at-sea. Females with yearlings had higher water influx, suggesting greater food intake, but had lower body condition. The FMR (4.08±0.6 W/kg) of GSL is the lowest measured for any otariid, but is consistent with Galapagos fur seals which also exhibit low FMR. The observation that these two otariids have reduced energy requirements is consistent with an adaptation to the reduced prey availability of the Galapagos marine environment compared to other more productive marine systems.

Large magnetic entropy change in melt-spun LaFe11.5Si1.5 ribbons

International Nuclear Information System (INIS)

Xie Kun; Song Xiaoping; Zhu Yaoming; Lv Weipeng; Sun Zhanbo

2004-01-01

The microstructure transformation and the magnetic entropy change of LaFe 11.5 Si 1.5 melt-spun ribbons were investigated. The melt-spun ribbons show a homogeneous distribution of elements, and the homogeneity develops further after 5 h annealing. XRD results show that the ribbons are composed of NaZn 13 -type LaFe 11.5 Si 1.5 compounds and an α-Fe phase. After annealing, the ribbons crystallize well in the NaZn 13 -type structure and exhibit a very large magnetic entropy change. A first-order magnetic transition is observed in the annealed ribbons, and this is believed to be the origin of the large magnetic entropy. These results suggest that NaZn 13 -type LaFe 11.5 Si 1.5 compounds with a large magnetic entropy change can be produced by melt-spinning, the annealing time can be shortened significantly and the production cost of the magnetic refrigerant will be cut down accordingly

Experimental determination of magnetocrystalline anisotropy constants and saturation magnetostriction constants of NiZn and NiZnCo ferrites intended to be used for antennas miniaturization

International Nuclear Information System (INIS)

Mattei, Jean-Luc; Le Guen, Emmanuel; Chevalier, Alexis; Tarot, Anne-Claude

2015-01-01

This study investigates the magnetocrystalline anisotropy constants (K 1 ) and the saturation magnetostriction constants (λ S ) of Ni 1−x Zn x Fe 2 O 4 (NiZn) and Ni 0.8−x Zn x Co 0.2 Fe 1.98 O 4−δ (NiZnCo) ferrites intended to be used for antenna downsizing. Composite materials constituted of soft ferrite nanosized particles (NiZn or NiZnCo ferrites) embedded in an epoxy matrix are realized. Measurements of their magnetic permeability in the frequency range of 200 MHz–6 GHz are performed. The influence of compressive stress (in the range of 32–96 MPa) on their Ferrimagnetic Resonance (FMR) is demonstrated. An analytical modeling of stress-induced FMR changes is proposed that allows simultaneous determinations of the Natural Ferrimagnetic Resonance (NFMR, F 0 ), K 1 and λ S of Ni 1−x Zn x Fe 2 O 4 and Ni 0.8−x Zn x Co 0.2 Fe 1.98 O 4−δ ferrites. The obtained results for NiZn ferrites are in agreement with literature data, validating both the experimental process and the proposed modeling of the stress-induced FMR changes. Regarding NiZnCo ferrites, extended data on K 1 and λ S are presented for the first time. Increasing zinc content (x) induces a spin disorder that reduces in a same time K 1 and the magnetization at saturation M S . The rapid variation of K 1 (x) is related to that of the magnetization M S (x) through a power law. The single-ion anisotropy model allows a satisfactory interpretation of K 1 dependence on zinc content. The unexpected low values of λ S got for NiZnCo ferrites, compared to those got for NiZn ferrites, are also discussed. Application of compressive stress lowers noticeably magnetic losses of Ni 0.6 Zn 0.2 Co 0.2 Fe 1.98 O 4−δ at given frequency, thereby enhancing the ability of this spinel ferrite to be used as a substrate in the aim of antenna miniaturization. - Highlights: • We measure permeability of ferrite-based composites from 0.1 GHz to 6 GHz. • The influence of compressive stress on the FMR of

76 FR 31545 - Federal Management Regulation; Motor Vehicle Management

Science.gov (United States)

2011-06-01

...; Sequence 1] RIN 3090-AJ14 Federal Management Regulation; Motor Vehicle Management AGENCY: Office of... Services Administration is proposing to amend the Federal Management Regulation (FMR) by revising current....C. 553(a)(2) because it applies to agency management. However, this proposed rule is being published...

Anlægsbærere for fragilt X-syndrom kan udvise et bredt spektrum af kliniske manifestationer

DEFF Research Database (Denmark)

Jønch, Aia Elise; Grønskov, Karen; Lunding, Jytte

2014-01-01

Fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are three clinically distinct disorders caused by expansions of a CGG repeat sequence in the non-coding part of the FMR1. FXTAS and FXPOI are seen in carriers...

Acute Effects of Positive Airway Pressure on Functional Mitral Regurgitation in Patients with Systolic Heart Failure

Directory of Open Access Journals (Sweden)

Takao Kato

2017-11-01

Full Text Available Background: Acute effects of positive airway pressure (PAP [including continuous PAP (CPAP and adaptive servo-ventilation, an advanced form of bi-level PAP] on functional mitral regurgitation (fMR in patients with heart failure (HF with left ventricular (LV systolic dysfunction remain unclear. Thus, whether PAP therapy reduces fMR in such patients with HF was investigated.Methods and Results: Twenty patients with HF and LV systolic dysfunction defined as LV ejection fraction (LVEF <50% (14 men; mean LVEF, 35.0 ± 11.5% with fMR underwent echocardiography during 10-min CPAP (4 and 8 cm H2O and adaptive servo-ventilation. For fMR assessment, MR jet area fraction, defined as the ratio of MR jet on color Doppler to the left atrial area, was measured. The forward stroke volume (SV index (fSVI was calculated from the time-velocity integral, cross-sectional area of the aortic annulus, and body surface area. fMR significantly reduced on CPAP at 8 cm H2O (0.30 ± 0.12 and adaptive servo-ventilation (0.29 ± 0.12, compared with the baseline phase (0.37 ± 0.12 and CPAP at 4 cm H2O (0.34 ± 0.12 (P < 0.001. The fSVI did not change in any of the PAP sessions (P = 0.888. However, significant differences in fSVI responses to PAP were found between sexes (P for interaction, 0.006, with a significant reduction in fSVI in women (P = 0.041 and between patients with baseline fSVI ≥ and < the median value (27.8 ml/m2, P for interaction, 0.018, with a significant fSVI reduction in patients with high baseline fSVI (P = 0.028. In addition, significant differences were found in fSVI responses to PAP between patients with LV end-systolic volume (LVESV index ≥ and < the median value (62.0 ml/m2, P for interaction, 0.034, with a significant fSVI increase in patients with a high LVESV index (P = 0.023.Conclusion: In patients with HF, LV systolic dysfunction, and fMR, PAP can alleviate fMR without any overall changes in forward SV. However, MR alleviation due to PAP

Of Men and Mice: Modeling the Fragile X Syndrome

Science.gov (United States)

Dahlhaus, Regina

2018-01-01

The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research. PMID:29599705

Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

International Nuclear Information System (INIS)

Silva, Amanda Gonçalves; Achatz, Maria Isabel W; Rosenberg, Carla; Krepischi, Ana C V; Ewald, Ingrid Petroni; Sapienza, Marina; Pinheiro, Manuela; Peixoto, Ana; Nóbrega, Amanda França de; Carraro, Dirce M; Teixeira, Manuel R; Ashton-Prolla, Patricia

2012-01-01

Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility

Search for large extra dimensions in final states containing one photon or jet and large missing transverse energy produced in pp collisions at square root[s]=1.96 TeV.

Science.gov (United States)

Aaltonen, T; Adelman, J; Akimoto, T; Albrow, M G; Alvarez González, B; Amerio, S; Amidei, D; Anastassov, A; Annovi, A; Antos, J; Apollinari, G; Apresyan, A; Arisawa, T; Artikov, A; Ashmanskas, W; Attal, A; Aurisano, A; Azfar, F; Azzurri, P; Badgett, W; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Bartsch, V; Bauer, G; Beauchemin, P-H; Bedeschi, F; Bednar, P; Beecher, D; Behari, S; Bellettini, G; Bellinger, J; Benjamin, D; Beretvas, A; Beringer, J; Bhatti, A; Binkley, M; Bisello, D; Bizjak, I; Blair, R E; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bolla, G; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Bridgeman, A; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Budd, S; Burkett, K; Busetto, G; Bussey, P; Buzatu, A; Byrum, K L; Cabrera, S; Calancha, C; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carlsmith, D; Carosi, R; Carrillo, S; Carron, S; Casal, B; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavaliere, V; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, S H; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, K; Chokheli, D; Chou, J P; Choudalakis, G; Chuang, S H; Chung, K; Chung, W H; Chung, Y S; Ciobanu, C I; Ciocci, M A; Clark, A; Clark, D; Compostella, G; Convery, M E; Conway, J; Copic, K; Cordelli, M; Cortiana, G; Cox, D J; Crescioli, F; Cuenca Almenar, C; Cuevas, J; Culbertson, R; Cully, J C; Dagenhart, D; Datta, M; Davies, T; de Barbaro, P; De Cecco, S; Deisher, A; De Lorenzo, G; Dell'orso, M; Deluca, C; Demortier, L; Deng, J; Deninno, M; Derwent, P F; di Giovanni, G P; Dionisi, C; Di Ruzza, B; Dittmann, J R; D'Onofrio, M; Donati, S; Dong, P; Donini, J; Dorigo, T; Dube, S; Efron, J; Elagin, A; Erbacher, R; Errede, D; Errede, S; Eusebi, R; Fang, H C; Farrington, S; Fedorko, W T; Feild, R G; Feindt, M; Fernandez, J P; Ferrazza, C; Field, R; Flanagan, G; Forrest, R; Franklin, M; Freeman, J C; Furic, I; Gallinaro, M; Galyardt, J; Garberson, F; Garcia, J E; Garfinkel, A F; Genser, K; Gerberich, H; Gerdes, D; Gessler, A; Giagu, S; Giakoumopoulou, V; Giannetti, P; Gibson, K; Gimmell, J L; Ginsburg, C M; Giokaris, N; Giordani, M; Giromini, P; Giunta, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Golossanov, A; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gresele, A; Grinstein, S; Grosso-Pilcher, C; Grundler, U; Guimaraes da Costa, J; Gunay-Unalan, Z; Haber, C; Hahn, K; Hahn, S R; Halkiadakis, E; Han, B-Y; Han, J Y; Handler, R; Happacher, F; Hara, K; Hare, D; Hare, M; Harper, S; Harr, R F; Harris, R M; Hartz, M; Hatakeyama, K; Hauser, J; Hays, C; Heck, M; Heijboer, A; Heinemann, B; Heinrich, J; Henderson, C; Herndon, M; Heuser, J; Hewamanage, S; Hidas, D; Hill, C S; Hirschbuehl, D; Hocker, A; Hou, S; Houlden, M; Hsu, S-C; Huffman, B T; Hughes, R E; Husemann, U; Huston, J; Incandela, J; Introzzi, G; Iori, M; Ivanov, A; James, E; Jayatilaka, B; Jeon, E J; Jha, M K; Jindariani, S; Johnson, W; Jones, M; Joo, K K; Jun, S Y; Jung, J E; Junk, T R; Kamon, T; Kar, D; Karchin, P E; Kato, Y; Kephart, R; Keung, J; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, J E; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kimura, N; Kirsch, L; Klimenko, S; Knuteson, B; Ko, B R; Koay, S A; Kondo, K; Kong, D J; Konigsberg, J; Korytov, A; Kotwal, A V; Kreps, M; Kroll, J; Krop, D; Krumnack, N; Kruse, M; Krutelyov, V; Kubo, T; Kuhr, T; Kulkarni, N P; Kurata, M; Kusakabe, Y; Kwang, S; Laasanen, A T; Lami, S; Lammel, S; Lancaster, M; Lander, R L; Lannon, K; Lath, A; Latino, G; Lazzizzera, I; Lecompte, T; Lee, E; Lee, H S; Lee, S W; Leone, S; Lewis, J D; Lin, C S; Linacre, J; Lindgren, M; Lipeles, E; Lister, A; Litvintsev, D O; Liu, C; Liu, T; Lockyer, N S; Loginov, A; Loreti, M; Lovas, L; Lu, R-S; Lucchesi, D; Lueck, J; Luci, C; Lujan, P; Lukens, P; Lungu, G; Lyons, L; Lys, J; Lysak, R; Lytken, E; Mack, P; Macqueen, D; Madrak, R; Maeshima, K; Makhoul, K; Maki, T; Maksimovic, P; Malde, S; Malik, S; Manca, G; Manousakis-Katsikakis, A; Margaroli, F; Marino, C; Marino, C P; Martin, A; Martin, V; Martínez, M; Martínez-Ballarín, R; Maruyama, T; Mastrandrea, P; Masubuchi, T; Mattson, M E; Mazzanti, P; McFarland, K S; McIntyre, P; McNulty, R; Mehta, A; Mehtala, P; Menzione, A; Merkel, P; Mesropian, C; Miao, T; Miladinovic, N; Miller, R; Mills, C; Milnik, M; Mitra, A; Mitselmakher, G; Miyake, H; Moggi, N; Moon, C S; Moore, R; Morello, M J; Morlok, J; Movilla Fernandez, P; Mülmenstädt, J; Mukherjee, A; Muller, Th; Mumford, R; Murat, P; Mussini, M; Nachtman, J; Nagai, Y; Nagano, A; Naganoma, J; Nakamura, K; Nakano, I; Napier, A; Necula, V; Neu, C; Neubauer, M S; Nielsen, J; Nodulman, L; Norman, M; Norniella, O; Nurse, E; Oakes, L; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Orava, R; Osterberg, K; Pagan Griso, S; Pagliarone, C; Palencia, E; Papadimitriou, V; Papaikonomou, A; Paramonov, A A; Parks, B; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Pellett, D E; Penzo, A; Phillips, T J; Piacentino, G; Pianori, E; Pinera, L; Pitts, K; Plager, C; Pondrom, L; Poukhov, O; Pounder, N; Prakoshyn, F; Pronko, A; Proudfoot, J; Ptohos, F; Pueschel, E; Punzi, G; Pursley, J; Rademacker, J; Rahaman, A; Ramakrishnan, V; Ranjan, N; Redondo, I; Reisert, B; Rekovic, V; Renton, P; Rescigno, M; Richter, S; Rimondi, F; Ristori, L; Robson, A; Rodrigo, T; Rodriguez, T; Rogers, E; Rolli, S; Roser, R; Rossi, M; Rossin, R; Roy, P; Ruiz, A; Russ, J; Rusu, V; Saarikko, H; Safonov, A; Sakumoto, W K; Saltó, O; Santi, L; Sarkar, S; Sartori, L; Sato, K; Savard, P; Savoy-Navarro, A; Scheidle, T; Schlabach, P; Schmidt, A; Schmidt, E E; Schmidt, M A; Schmidt, M P; Schmitt, M; Schwarz, T; Scodellaro, L; Scott, A L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semenov, A; Sexton-Kennedy, L; Sfyrla, A; Shalhout, S Z; Shears, T; Shepard, P F; Sherman, D; Shimojima, M; Shiraishi, S; Shochet, M; Shon, Y; Shreyber, I; Sidoti, A; Sinervo, P; Sisakyan, A; Slaughter, A J; Slaunwhite, J; Sliwa, K; Smith, J R; Snider, F D; Snihur, R; Soha, A; Somalwar, S; Sorin, V; Spalding, J; Spreitzer, T; Squillacioti, P; Stanitzki, M; St Denis, R; Stelzer, B; Stelzer-Chilton, O; Stentz, D; Strologas, J; Stuart, D; Suh, J S; Sukhanov, A; Suslov, I; Suzuki, T; Taffard, A; Takashima, R; Takeuchi, Y; Tanaka, R; Tecchio, M; Teng, P K; Terashi, K; Thom, J; Thompson, A S; Thompson, G A; Thomson, E; Tipton, P; Tiwari, V; Tkaczyk, S; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Totaro, P; Tourneur, S; Tu, Y; Turini, N; Ukegawa, F; Vallecorsa, S; van Remortel, N; Varganov, A; Vataga, E; Vázquez, F; Velev, G; Vellidis, C; Veszpremi, V; Vidal, M; Vidal, R; Vila, I; Vilar, R; Vine, T; Vogel, M; Volobouev, I; Volpi, G; Würthwein, F; Wagner, P; Wagner, R G; Wagner, R L; Wagner-Kuhr, J; Wagner, W; Wakisaka, T; Wallny, R; Wang, S M; Warburton, A; Waters, D; Weinberger, M; Wester, W C; Whitehouse, B; Whiteson, D; Wicklund, A B; Wicklund, E; Williams, G; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, C; Wright, T; Wu, X; Wynne, S M; Xie, S; Yagil, A; Yamamoto, K; Yamaoka, J; Yang, U K; Yang, Y C; Yao, W M; Yeh, G P; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Yu, S S; Yun, J C; Zanello, L; Zanetti, A; Zaw, I; Zhang, X; Zheng, Y; Zucchelli, S

2008-10-31

We present the results of searches for large extra dimensions in samples of events with large missing transverse energy E_{T} and either a photon or a jet produced in pp[over ] collisions at sqrt[s]=1.96 TeV collected with the Collider Detector at Fermilab II. For gamma+E_{T} and jet+E_{T} candidate samples corresponding to 2.0 and 1.1 fb;{-1} of integrated luminosity, respectively, we observe good agreement with standard model expectations and obtain a combined lower limit on the fundamental parameter of the large extra dimensions model M_{D} as a function of the number of extra dimensions in the model.

Coupling of microwave magnetic dynamics in thin ferromagnetic films to stripline transducers in the geometry of the broadband stripline ferromagnetic resonance

Energy Technology Data Exchange (ETDEWEB)

Kostylev, M., E-mail: mikhail.kostylev@uwa.edu.au [School of Physics, The University of Western Australia, Crawley 6009 (Australia)

2016-01-07

We constructed a quasi-analytical self-consistent model of the stripline-based broadband ferromagnetic resonance (FMR) measurements of ferromagnetic films. Exchange-free description of magnetization dynamics in the films allowed us to obtain simple analytical expressions. They enable quick and efficient numerical simulations of the dynamics. With this model, we studied the contribution of radiation losses to the ferromagnetic resonance linewidth, as measured with the stripline FMR. We found that for films with large conductivity of metals the radiation losses are significantly smaller than for magneto-insulating films. Excitation of microwave eddy currents in these materials contributes to the total microwave impedance of the system. This leads to impedance mismatch with the film environment resulting in decoupling of the film from the environment and, ultimately, to smaller radiation losses. We also show that the radiation losses drop with an increase in the stripline width and when the sample is lifted up from the stripline surface. Hence, in order to eliminate this measurement artefact, one needs to use wide striplines and introduce a spacer between the film and the sample surface. The radiation losses contribution is larger for thicker films.

High-frequency behavior of amorphous microwires and its applications

International Nuclear Information System (INIS)

Marin, P.; Cortina, D.; Hernando, A.

2005-01-01

A magnetic microwire is a continuous filament of total diameter less than 100 μm consisting of an inner metallic magnetic nuclei covered by a glassy outer shell, usually obtained by Taylor's technique, with interesting magnetic properties connected with its high axial magnetic anisotropy. Magnetic sensors based on microwires used, as operating principle, the strong connection between the composition and the uniaxial anisotropy through a magnetostriction constant such as the large Barkhausen effect, Mateucci effect and giant magneto-impedance effect. The study of the microwave properties is also very promising technologically. In the microwave region (approaching GHz range), the ferromagnetic resonance (FMR) occurs and it is connected with the spin precession of the magnetisation vector due to the effect of the high-frequency electromagnetic field applied such that the magnetic component is perpendicular to the magnetisation vector. The natural ferromagnetic resonance (NFMR) has been also observed. The frequency depends upon the value of magnetic anisotropy and it is characterised by the single well-distinguished line in the 2-10 GHz range. Tags detector based on the microwires FMR and a new kind of electromagnetic radiation absorbers based on the microwires NFMR have been developed

Local moment formation and magnetic coupling of Mn dopants in Bi2Se3: A low-temperature ferromagnetic resonance study

Science.gov (United States)

Savchenko, D.; Tarasenko, R.; Vališka, M.; Kopeček, J.; Fekete, L.; Carva, K.; Holý, V.; Springholz, G.; Sechovský, V.; Honolka, J.

2018-05-01

We compare the magnetic and electronic configuration of single Mn atoms in molecular beam epitaxy (MBE) grown Bi2Se3 thin films, focusing on electron paramagnetic (ferromagnetic) resonance (EPR and FMR, respectively) and superconducting quantum interference device (SQUID) techniques. X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) reveal the expected increase of disorder with increasing concentration of magnetic guest atoms, however, Kikuchi patterns show that disorder consists majorly of μm-scale 60° twin domains in the hexagonal Bi2Se3 structure, which are promoted by the presence of single unclustered Mn impurities. Ferromagnetism below TC (5.4±0.3) K can be well described by critical scaling laws M (T) (1 - T /TC) β with a critical exponent β = (0.34 ± 0.2) , suggesting 3D Heisenberg class magnetism instead of e.g. 2D-type coupling between Mn-spins in van der Waals gap sites. From EPR hyperfine structure data we determine a Mn2+ (d5, S = 5/2) electronic configuration with a g-factor of 2.002 for -1/2 → +1/2 transitions. In addition, from the strong dependence of the low temperature FMR fields and linewidth on the field strength and orientation with respect to the Bi2Se3 (0001) plane, we derive magnetic anisotropy energies of up to K1 = -3720 erg/cm3 in MBE-grown Mn-doped Bi2Se3, reflecting the first order magneto-crystalline anisotropy of an in-plane magnetic easy plane in a hexagonal (0001) crystal symmetry. We observe an increase of K1 with increasing Mn concentration, which we interpret to be correlated to a Mn-induced in-plane lattice contraction. Across the ferromagnetic-paramagnetic transition the FMR intensity is suppressed and resonance fields converge the paramagnetic limit of Mn2+ (d5, S = 5/2).

Sex- and age-specific percentiles of body composition indices for Chinese adults using dual-energy X-ray absorptiometry.

Science.gov (United States)

Xiao, Zeyu; Guo, Bin; Gong, Jian; Tang, Yongjin; Shang, Jingjie; Cheng, Yong; Xu, Hao

2017-10-01

The aims of the study were to develop sex- and age-specific percentiles for lean mass index (LMI), appendicular LMI (aLMI), fat mass index (FMI), and body fat distribution indices in Chinese adults using dual-energy X-ray absorptiometry (DXA), and to compare those indices with those of other ethnicities using the US NHANES data. Whole-body and regional lean mass and fat mass (FM) were measured using DXA in 5688 healthy males (n = 1693) and females (n = 3995) aged 20-90 years. Body fat distribution indices were expressed as % fat trunk/% fat legs, trunk/appendicular FM ratio (FMR), and android/gynoid FMR. Percentile curves of LMI, aLMI, FMI, and body fat distribution indices were obtained by the Lambda-Mu-Sigma method. The aLMI and LMI were negatively associated with age, decreasing from the fifth decade for males, but were not associated with age in females. Females had more total FM than males, whereas males had greater central adiposity (% fat trunk/% fat legs ratio, trunk/appendicular FMR, and android/gynoid FMR) than females. Moreover, FMI and body fat distribution indices consistently increased with age in both sexes, especially in women. In comparison with white, black, and Mexican populations in the USA, Chinese adults had lower total FM, but had greater central adiposity (% fat trunk/% fat legs ratio and trunk/appendicular FMR). Additionally, older white and Mexican populations showed greater decreases for aLMI and LMI than their Chinese counterparts. We present the sex- and age-specific percentiles for aLMI, LMI, FMI, and body fat distribution indices by DXA in Chinese adults, which may refine the individual assessment of the nutritional status of Chinese adults.

Large-scale structural alteration of brain in epileptic children with SCN1A mutation

Directory of Open Access Journals (Sweden)

Yun-Jeong Lee

2017-01-01

Significance: This study showed large-scale developmental brain changes in patients with epilepsy and SCN1A gene mutation, which may be associated with the core symptoms of the patients. Further longitudinal MRI studies with larger cohorts are required to confirm the effect of SCN1A gene mutation on structural brain development.

Large LOCA-earthquake combination probability assessment - Load combination program. Project 1 summary report

Energy Technology Data Exchange (ETDEWEB)

Lu, S; Streit, R D; Chou, C K

1980-01-01

This report summarizes work performed for the U.S. Nuclear Regulatory Commission (NRC) by the Load Combination Program at the Lawrence Livermore National Laboratory to establish a technical basis for the NRC to use in reassessing its requirement that earthquake and large loss-of-coolant accident (LOCA) loads be combined in the design of nuclear power plants. A systematic probabilistic approach is used to treat the random nature of earthquake and transient loading to estimate the probability of large LOCAs that are directly and indirectly induced by earthquakes. A large LOCA is defined in this report as a double-ended guillotine break of the primary reactor coolant loop piping (the hot leg, cold leg, and crossover) of a pressurized water reactor (PWR). Unit 1 of the Zion Nuclear Power Plant, a four-loop PWR-1, is used for this study. To estimate the probability of a large LOCA directly induced by earthquakes, only fatigue crack growth resulting from the combined effects of thermal, pressure, seismic, and other cyclic loads is considered. Fatigue crack growth is simulated with a deterministic fracture mechanics model that incorporates stochastic inputs of initial crack size distribution, material properties, stress histories, and leak detection probability. Results of the simulation indicate that the probability of a double-ended guillotine break, either with or without an earthquake, is very small (on the order of 10{sup -12}). The probability of a leak was found to be several orders of magnitude greater than that of a complete pipe rupture. A limited investigation involving engineering judgment of a double-ended guillotine break indirectly induced by an earthquake is also reported. (author)

Large LOCA-earthquake combination probability assessment - Load combination program. Project 1 summary report

International Nuclear Information System (INIS)

Lu, S.; Streit, R.D.; Chou, C.K.

1980-01-01

This report summarizes work performed for the U.S. Nuclear Regulatory Commission (NRC) by the Load Combination Program at the Lawrence Livermore National Laboratory to establish a technical basis for the NRC to use in reassessing its requirement that earthquake and large loss-of-coolant accident (LOCA) loads be combined in the design of nuclear power plants. A systematic probabilistic approach is used to treat the random nature of earthquake and transient loading to estimate the probability of large LOCAs that are directly and indirectly induced by earthquakes. A large LOCA is defined in this report as a double-ended guillotine break of the primary reactor coolant loop piping (the hot leg, cold leg, and crossover) of a pressurized water reactor (PWR). Unit 1 of the Zion Nuclear Power Plant, a four-loop PWR-1, is used for this study. To estimate the probability of a large LOCA directly induced by earthquakes, only fatigue crack growth resulting from the combined effects of thermal, pressure, seismic, and other cyclic loads is considered. Fatigue crack growth is simulated with a deterministic fracture mechanics model that incorporates stochastic inputs of initial crack size distribution, material properties, stress histories, and leak detection probability. Results of the simulation indicate that the probability of a double-ended guillotine break, either with or without an earthquake, is very small (on the order of 10 -12 ). The probability of a leak was found to be several orders of magnitude greater than that of a complete pipe rupture. A limited investigation involving engineering judgment of a double-ended guillotine break indirectly induced by an earthquake is also reported. (author)

Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model

NARCIS (Netherlands)

Heulens, Inge; D'Hulst, Charlotte; Van Dam, Debby; De Deyn, Peter P.; Kooy, R. Frank

2012-01-01

Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABA(A) receptors are the main inhibitory receptors in the brain and the GABA(A) receptor was proposed as a novel target for treatment of the fragile X

Effect of spacer layer on the magnetization dynamics of permalloy/rare-earth/permalloy trilayers

International Nuclear Information System (INIS)

Luo, Chen; Yin, Yuli; Zhang, Dong; Jiang, Sheng; Yue, Jinjin; Zhai, Ya; Du, Jun; Zhai, Hongru

2015-01-01

The permalloy/rare-earth/permalloy trilayers with different types (Gd and Nd) and thicknesses of spacer layer are investigated using frequency dependence of ferromagnetic resonance (FMR) measurements at room temperature, which shows different behaviors with different rare earth spacer layers. By fitting the frequency dependence of the FMR resonance field and linewidth, we find that the in-plane uniaxial anisotropy retains its value for all samples, the perpendicular anisotropy remains almost unchanged for different thickness of Gd layer but the values are tailored by different thicknesses of Nd layer. The Gilbert damping is almost unchanged with different thicknesses of Gd; however, the Gilbert damping is significantly enhanced from 8.4×10 −3 to 20.1×10 −3 with 6 nm of Nd and then flatten out when the Nd thickness rises above 6 nm

Identifiability of large-scale non-linear dynamic network models applied to the ADM1-case study.

Science.gov (United States)

Nimmegeers, Philippe; Lauwers, Joost; Telen, Dries; Logist, Filip; Impe, Jan Van

2017-06-01

In this work, both the structural and practical identifiability of the Anaerobic Digestion Model no. 1 (ADM1) is investigated, which serves as a relevant case study of large non-linear dynamic network models. The structural identifiability is investigated using the probabilistic algorithm, adapted to deal with the specifics of the case study (i.e., a large-scale non-linear dynamic system of differential and algebraic equations). The practical identifiability is analyzed using a Monte Carlo parameter estimation procedure for a 'non-informative' and 'informative' experiment, which are heuristically designed. The model structure of ADM1 has been modified by replacing parameters by parameter combinations, to provide a generally locally structurally identifiable version of ADM1. This means that in an idealized theoretical situation, the parameters can be estimated accurately. Furthermore, the generally positive structural identifiability results can be explained from the large number of interconnections between the states in the network structure. This interconnectivity, however, is also observed in the parameter estimates, making uncorrelated parameter estimations in practice difficult. Copyright © 2017. Published by Elsevier Inc.

Co{sub 2}FeAl Heusler thin films grown on Si and MgO substrates: Annealing temperature effect

Energy Technology Data Exchange (ETDEWEB)

Belmeguenai, M., E-mail: belmeguenai.mohamed@univ-paris13.fr; Tuzcuoglu, H.; Zighem, F.; Chérif, S. M.; Moch, P. [LSPM (CNRS-UPR 3407), 99 avenue Jean-Baptiste Clément, Université Paris 13, 93430 Villetaneuse (France); Gabor, M. S., E-mail: mihai.gabor@phys.utcluj.ro; Petrisor, T. [Center for Superconductivity, Spintronics and Surface Science, Technical University of Cluj-Napoca, Str. Memorandumului No. 28 RO-400114 Cluj-Napoca (Romania); Tiusan, C. [Center for Superconductivity, Spintronics and Surface Science, Technical University of Cluj-Napoca, Str. Memorandumului No. 28 RO-400114 Cluj-Napoca (Romania); Institut Jean Lamour, CNRS, Université de Nancy, BP 70239, F–54506 Vandoeuvre (France)

2014-01-28

10 nm and 50 nm Co{sub 2}FeAl (CFA) thin films have been deposited on MgO(001) and Si(001) substrates by magnetron sputtering and annealed at different temperatures. X-rays diffraction revealed polycrystalline or epitaxial growth (according to CFA(001)[110]//MgO(001)[100] epitaxial relation) for CFA films grown on a Si and on a MgO substrate, respectively. For these later, the chemical order varies from the A2 phase to the B2 phase when increasing the annealing temperature (T{sub a}), while only the A2 disorder type has been observed for CFA grown on Si. Microstrip ferromagnetic resonance (MS-FMR) measurements revealed that the in-plane anisotropy results from the superposition of a uniaxial and a fourfold symmetry term for CFA grown on MgO substrates. This fourfold anisotropy, which disappears completely for samples grown on Si, is in accord with the crystal structure of the samples. The fourfold anisotropy field decreases when increasing T{sub a}, while the uniaxial anisotropy field is nearly unaffected by T{sub a} within the investigated range. The MS-FMR data also allow for concluding that the gyromagnetic factor remains constant and that the exchange stiffness constant increases with T{sub a}. Finally, the FMR linewidth decreases when increasing T{sub a}, due to the enhancement of the chemical order. We derive a very low intrinsic damping parameter (1.1×10{sup −3} and 1.3×10{sup −3} for films of 50 nm thickness annealed at 615 °C grown on MgO and on Si, respectively)

Co2FeAl Heusler thin films grown on Si and MgO substrates: Annealing temperature effect

International Nuclear Information System (INIS)

Belmeguenai, M.; Tuzcuoglu, H.; Zighem, F.; Chérif, S. M.; Moch, P.; Gabor, M. S.; Petrisor, T.; Tiusan, C.

2014-01-01

10 nm and 50 nm Co 2 FeAl (CFA) thin films have been deposited on MgO(001) and Si(001) substrates by magnetron sputtering and annealed at different temperatures. X-rays diffraction revealed polycrystalline or epitaxial growth (according to CFA(001)[110]//MgO(001)[100] epitaxial relation) for CFA films grown on a Si and on a MgO substrate, respectively. For these later, the chemical order varies from the A2 phase to the B2 phase when increasing the annealing temperature (T a ), while only the A2 disorder type has been observed for CFA grown on Si. Microstrip ferromagnetic resonance (MS-FMR) measurements revealed that the in-plane anisotropy results from the superposition of a uniaxial and a fourfold symmetry term for CFA grown on MgO substrates. This fourfold anisotropy, which disappears completely for samples grown on Si, is in accord with the crystal structure of the samples. The fourfold anisotropy field decreases when increasing T a , while the uniaxial anisotropy field is nearly unaffected by T a within the investigated range. The MS-FMR data also allow for concluding that the gyromagnetic factor remains constant and that the exchange stiffness constant increases with T a . Finally, the FMR linewidth decreases when increasing T a , due to the enhancement of the chemical order. We derive a very low intrinsic damping parameter (1.1×10 −3 and 1.3×10 −3 for films of 50 nm thickness annealed at 615 °C grown on MgO and on Si, respectively)

Magnetic study of nanocrystalline 0.95MnO/0.05ZnO

International Nuclear Information System (INIS)

Guskos, N.; Dudek, M.; Zolnierkiewicz, G.; Typek, J.; Berczynski, P.; Lendzion-Bielun, Z.; Sibera, D.; Narkiewicz, U.

2013-01-01

Nanocrystalline 0.95MnO/0.05ZnO sample has been prepared by coprecipitation and calcination processes. X-ray diffraction showed the presence of Mn 3 O 4 nanocrystallites with an average size of 43 nm. Magnetic properties of the 0.95MnO/0.05ZnO sample have been investigated by dc magnetization and magnetic resonances (electron paramagnetic resonance (EPR), ferromagnetic resonance (FMR)) methods. The magnetization study has shown the presence of dominating Mn 3 O 4 paramagnetic and ferrimagnetic (below 46 K) phases. The blocking temperature determined from magnetization measurements was 41 K. An FMR study has shown the evidence of the spread of nanoparticles sizes. An EPR signal from paramagnetic phase of Mn 3 O 4 was observed at temperatures above 45 K and from defects/spurious phases in the low temperature range (T<16 K). Magnetic anisotropies of the sample in the FMR spectra were taken into account by fitting the observed spectra by two lines corresponding to parallel and perpendicular orientations of nanoparticles in an applied magnetic field. - Highlights: ► Magnetic properties of 0.95MnO/0.05ZnO have been studied by dc magnetization and magnetic resonance. ► FMR and EPR spectra were identified and attributed to various spin systems. ► From the spread of blocking temperatures obtained from magnetic resonance the spread of nanoparticles sizes was estimated.

Energetic fitness: Field metabolic rates assessed via 3D accelerometry complement conventional fitness metrics

Science.gov (United States)

Grémillet, David; Lescroël, Amelie; Ballard, Grant; Dugger, Katie M.; Massaro, Melanie; Porzig, Elizabeth L.; Ainley, David G.

2018-01-01

Evaluating the fitness of organisms is an essential step towards understanding their responses to environmental change. Connections between energy expenditure and fitness have been postulated for nearly a century. However, testing this premise among wild animals is constrained by difficulties in measuring energy expenditure while simultaneously monitoring conventional fitness metrics such as survival and reproductive output.We addressed this issue by exploring the functional links between field metabolic rate (FMR), body condition, sex, age and reproductive performance in a wild population.We deployed 3D accelerometers on 115 Adélie penguins Pygoscelis adeliae during four breeding seasons at one of the largest colonies of this species, Cape Crozier, on Ross Island, Antarctica. The demography of this population has been studied for the past 18 years. From accelerometry recordings, collected for birds of known age and breeding history, we determined the vector of the dynamic body acceleration (VeDBA) and used it as a proxy for FMR.This allowed us to demonstrate relationships among FMR, a breeding quality index (BQI) and body condition. Notably, we found a significant quadratic relationship between mean VeDBA during foraging and BQI for experienced breeders, and individuals in better body condition showed lower rates of energy expenditure.We conclude that using FMR as a fitness component complementary to more conventional fitness metrics will yield greater understanding of evolutionary and conservation physiology.

Induction of lacI- mutations in Escherichia coli cells after single and split-dose irradiation

International Nuclear Information System (INIS)

Kozubek, S.; Ryznar, L.

1992-01-01

In the lacI system of Escherichia coli, X-ray mutagenesis follows a linear-quadratic curve with suppression; the survival curve is exponential. Dose fractionation leads to nearly complete repair of premutational lesions during an incubation interval of 3.5 h. Repair starts with a delay of 1.5-2 h, suggesting the involvement of an inducible repair/mutation fixation system. The dose-dependence of mutagenesis is described by a simple model assuming two hits being required. A probable explanation might be that the premutagenic lesions consist of two closely spaced lesions on the opposite strands of the DNA molecule. (author)

75 FR 28253 - Federal Management Regulation (FMR); Notice of GSA Bulletin FMR B-26

Science.gov (United States)

2010-05-20

... responsibility to provide guidance to agencies on property management accountability systems. This bulletin is... agencies maintain adequate inventory controls and accountability systems for property under their control... General and other executive agencies to develop accounting systems for Federal property. The term ``system...

Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D).

Science.gov (United States)

Gurney, Mark E; Cogram, Patricia; Deacon, Robert M; Rex, Christopher; Tranfaglia, Michael

2017-11-07

Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.

Magnetic excitations in ferromagnetic semiconductors

International Nuclear Information System (INIS)

Furdyna, J.K.; Liu, X.; Zhou, Y.Y.

2009-01-01

Magnetic excitations in a series of GaMnAs ferromagnetic semiconductor films were studied by ferromagnetic resonance (FMR). Using the FMR approach, multi-mode spin wave resonance spectra have been observed, whose analysis provides information on magnetic anisotropy (including surface anisotropy), distribution of magnetization precession within the GaMnAs film, dynamic surface spin pinning (derived from surface anisotropy), and the value of exchange stiffness constant D. These studies illustrate a combination of magnetism and semiconductor physics that is unique to magnetic semiconductors

Uncovering a facile large-scale synthesis of LiNi1/3Co1/3Mn1/3O2 nanoflowers for high power lithium-ion batteries

Science.gov (United States)

Hua, Wei-Bo; Guo, Xiao-Dong; Zheng, Zhuo; Wang, Yan-Jie; Zhong, Ben-He; Fang, Baizeng; Wang, Jia-Zhao; Chou, Shu-Lei; Liu, Heng

2015-02-01

Developing advanced electrode materials that deliver high energy at ultra-fast charge and discharge rates are very crucial to meet an increasing large-scale market demand for high power lithium ion batteries (LIBs). A three-dimensional (3D) nanoflower structure is successfully developed in the large-scale synthesis of LiNi1/3Co1/3Mn1/3O2 material for the first time. The fast co-precipitation is the key technique to prepare the nanoflower structure in our method. After heat treatment, the obtained LiNi1/3Co1/3Mn1/3O2 nanoflowers (NL333) pronouncedly present a pristine flower-like nano-architecture and provide fast pathways for the transport of Li-ions and electrons. As a cathode material in a LIB, the prepared NL333 electrode demonstrates an outstanding high-rate capability. Particularly, in a narrow voltage range of 2.7-4.3 V, the discharge capacity at an ultra-fast charge-discharge rate (20C) is up to 126 mAh g-1, which reaches 78% of that at 0.2C, and is much higher than that (i.e., 44.17%) of the traditional bulk LiNi1/3Co1/3Mn1/3O2.

Instantons and Large N

Science.gov (United States)

Mariño, Marcos

2015-09-01

Preface; Part I. Instantons: 1. Instantons in quantum mechanics; 2. Unstable vacua in quantum field theory; 3. Large order behavior and Borel summability; 4. Non-perturbative aspects of Yang-Mills theories; 5. Instantons and fermions; Part II. Large N: 6. Sigma models at large N; 7. The 1=N expansion in QCD; 8. Matrix models and matrix quantum mechanics at large N; 9. Large N QCD in two dimensions; 10. Instantons at large N; Appendix A. Harmonic analysis on S3; Appendix B. Heat kernel and zeta functions; Appendix C. Effective action for large N sigma models; References; Author index; Subject index.

Large quantum rings in the ν > 1 quantum Hall regime

International Nuclear Information System (INIS)

Raesaenen, E; Aichinger, M

2009-01-01

We study computationally the ground-state properties of large quantum rings in the filling-factor ν>1 quantum Hall regime. We show that the arrangement of electrons into different Landau levels leads to clear signatures in the total energies as a function of the magnetic field. In this context, we discuss possible approximations for the filling factor ν in the system. We are able to characterize integer-ν states in quantum rings in an analogy with conventional quantum Hall droplets. We also find a partially spin-polarized state between ν = 2 and 3. Despite the specific topology of a quantum ring, this state is strikingly reminiscent of the recently found ν = 5/2 state in a quantum dot.

Large quantum rings in the ν > 1 quantum Hall regime.

Science.gov (United States)

Räsänen, E; Aichinger, M

2009-01-14

We study computationally the ground-state properties of large quantum rings in the filling-factor ν>1 quantum Hall regime. We show that the arrangement of electrons into different Landau levels leads to clear signatures in the total energies as a function of the magnetic field. In this context, we discuss possible approximations for the filling factor ν in the system. We are able to characterize integer-ν states in quantum rings in an analogy with conventional quantum Hall droplets. We also find a partially spin-polarized state between ν = 2 and 3. Despite the specific topology of a quantum ring, this state is strikingly reminiscent of the recently found ν = 5/2 state in a quantum dot.

Magnetic properties and microstructure investigation of electrodeposited FeNi/ITO films with different thickness

International Nuclear Information System (INIS)

Cao, Derang; Wang, Zhenkun; Feng, Erxi; Wei, Jinwu; Wang, Jianbo; Liu, Qingfang

2013-01-01

Highlights: •FeNi alloy thin films with different thickness deposited on Indium Tin Oxides (ITOs) conductive glass substrates by electrodeposition method. •A columnar crystalline microstructure and domain structure were obtained in FeNi thin films. •Particular FMR spectra of FeNi alloy with different thickness were studied. -- Abstract: FeNi alloy thin films with different thickness deposited on Indium Tin Oxides (ITOs) conductive glass substrates from the electrolytes by electrodeposition method have been studied by magnetic force microscopy (MFM), scanning electron microscopy (SEM) and ferromagnetic resonance (FMR) technique. For these films possessing an in-plane isotropy, the remanence decreases with the increasing of film thickness and the critical thickness that a stripe domain structure emerges is about 116 nm. Characteristic differences of the FMR spectra of different thickness are also observed. The results show that the resonance field at high measured angle increases firstly then decreases with increasing thickness, which may be related to the striped domain structure

Systematic errors in the determination of the spectroscopic g-factor in broadband ferromagnetic resonance spectroscopy: A proposed solution

Science.gov (United States)

Gonzalez-Fuentes, C.; Dumas, R. K.; García, C.

2018-01-01

A theoretical and experimental study of the influence of small offsets of the magnetic field (δH) on the measurement accuracy of the spectroscopic g-factor (g) and saturation magnetization (Ms) obtained by broadband ferromagnetic resonance (FMR) measurements is presented. The random nature of δH generates systematic and opposite sign deviations of the values of g and Ms with respect to their true values. A δH on the order of a few Oe leads to a ˜10% error of g and Ms for a typical range of frequencies employed in broadband FMR experiments. We propose a simple experimental methodology to significantly minimize the effect of δH on the fitted values of g and Ms, eliminating their apparent dependence in the range of frequencies employed. Our method was successfully tested using broadband FMR measurements on a 5 nm thick Ni80Fe20 film for frequencies ranging between 3 and 17 GHz.

Targeted Upregulation of FMRP Expression as an Approach to the Treatment of Fragile X Syndrome

Science.gov (United States)

2016-10-01

connectivity . To further assess the potential impacts of altered Ca2+ dynamics observed with premutation neurons , we investigated whether the levels and...synaptic signals that maintain influence long-term neuronal connectivity and neuronal survival, that when disturbed, may promote progressive neuronal ...that found in wild-type neurons (Figure 4). A potentially significant finding linking chronic Ca2+ dysregulation, abnormal synaptic connectivity

Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report

Science.gov (United States)

Saldarriaga, Wilmar; Ruiz, Fabian Andres; Tassone, Flora; Hagerman, Randi

2017-01-01

Background: Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. Methods: Cytogenetic testing detected the presence of…

Experimental determination of magnetocrystalline anisotropy constants and saturation magnetostriction constants of NiZn and NiZnCo ferrites intended to be used for antennas miniaturization

Energy Technology Data Exchange (ETDEWEB)

Mattei, Jean-Luc, E-mail: mattei@univ-brest.fr [Lab-STICC, Université de Bretagne Occidentale, CS 93837, 6 Avenue Le Gorgeu, 29238 Brest Cedex 3 (France); Le Guen, Emmanuel, E-mail: emmanuel.leguen@hotmail.fr [Lab-STICC, Université de Bretagne Occidentale, CS 93837, 6 Avenue Le Gorgeu, 29238 Brest Cedex 3 (France); IETR, Université de Rennes 1, 263 Avenue General Leclerc, 35042 Rennes Cedex (France); Chevalier, Alexis, E-mail: alexis.chevalier@univ-brest.fr [Lab-STICC, Université de Bretagne Occidentale, CS 93837, 6 Avenue Le Gorgeu, 29238 Brest Cedex 3 (France); Tarot, Anne-Claude, E-mail: anne-claude.tarot@univ-rennes1.fr [IETR, Université de Rennes 1, 263 Avenue General Leclerc, 35042 Rennes Cedex (France)

2015-01-15

This study investigates the magnetocrystalline anisotropy constants (K{sub 1}) and the saturation magnetostriction constants (λ{sub S}) of Ni{sub 1−x}Zn{sub x}Fe{sub 2}O{sub 4} (NiZn) and Ni{sub 0.8−x}Zn{sub x}Co{sub 0.2}Fe{sub 1.98}O{sub 4−δ} (NiZnCo) ferrites intended to be used for antenna downsizing. Composite materials constituted of soft ferrite nanosized particles (NiZn or NiZnCo ferrites) embedded in an epoxy matrix are realized. Measurements of their magnetic permeability in the frequency range of 200 MHz–6 GHz are performed. The influence of compressive stress (in the range of 32–96 MPa) on their Ferrimagnetic Resonance (FMR) is demonstrated. An analytical modeling of stress-induced FMR changes is proposed that allows simultaneous determinations of the Natural Ferrimagnetic Resonance (NFMR, F{sub 0}), K{sub 1} and λ{sub S} of Ni{sub 1−x}Zn{sub x}Fe{sub 2}O{sub 4} and Ni{sub 0.8−x}Zn{sub x}Co{sub 0.2}Fe{sub 1.98}O{sub 4−δ} ferrites. The obtained results for NiZn ferrites are in agreement with literature data, validating both the experimental process and the proposed modeling of the stress-induced FMR changes. Regarding NiZnCo ferrites, extended data on K{sub 1} and λ{sub S} are presented for the first time. Increasing zinc content (x) induces a spin disorder that reduces in a same time K{sub 1} and the magnetization at saturation M{sub S}. The rapid variation of K{sub 1}(x) is related to that of the magnetization M{sub S}(x) through a power law. The single-ion anisotropy model allows a satisfactory interpretation of K{sub 1} dependence on zinc content. The unexpected low values of λ{sub S} got for NiZnCo ferrites, compared to those got for NiZn ferrites, are also discussed. Application of compressive stress lowers noticeably magnetic losses of Ni{sub 0.6}Zn{sub 0.2}Co{sub 0.2}Fe{sub 1.98}O{sub 4−δ} at given frequency, thereby enhancing the ability of this spinel ferrite to be used as a substrate in the aim of antenna

76 FR 12985 - Request for Comments on Trend Factor Methodology Used in the Calculation of Fair Market Rents

Science.gov (United States)

2011-03-09

... Trend Factor Methodology Used in the Calculation of Fair Market Rents AGENCY: Office of the Assistant... used to calculate the trend factor component of the Fair Market Rent estimates. SUMMARY: Section 8(c)(1... comment regarding the manner in which HUD calculates the trend factor used in the Fair Market Rent (FMR...

Fragile X Syndrome: An Aging Perspective

Science.gov (United States)

Schneider, Andrea; Ligsay, Andrew; Hagerman, Randi J.

2013-01-01

Cognitive and behavioral correlates of molecular variations related to the FMR1 gene have been studied rather extensively, but research about the long-term outcome in individuals with fragile X spectrum disorders remains sparse. In this review, we present an overview of aging research and recent findings in regard to cellular and clinical…

FMR measurements in fire ants: evidence of magnetic material

Energy Technology Data Exchange (ETDEWEB)

Esquivel, Darci M.S.; Acosta-Avalos, Daniel; El-Jaick, Lea J.; Cunha, Alexandra D.M.; Malheiros, Maria G.; Wajnberg, Eliane [Centro Brasileiro de Pesquisas Fisicas (CBPF), Rio de Janeiro, RJ (Brazil); Linhares, Marilia P. [Centro de Ciencias do Estado, do Rio de Janeiro, Rio de Janeiro, RJ (Brazil)

1998-01-01

Based on the behavioral and the localization of iron-containing tissue fire ants were examined by EPR for magnetic material. Results suggest the presence of magnetite particles. (author) 12 refs., 1 fig.

Static and dynamic magnetic properties of B2 ordered Co2MnAl film epitaxially grown on GaAs

International Nuclear Information System (INIS)

Liu, Jihong; Qiao, Shuang

2015-01-01

Co 2 MnAl, considering its potential 100% spin polarization and high Curie temperature, is expected to be one of the most promising materials for realizing half metallicity. However, on the premise of high polarization, the optimization of the magnetic damping constant is directly determined the critical current density for spin torque transfer switching and also the stability of spin polarization for spin injection transfer, thus research on damping constant is also very important. In this paper, we have systematically investigated the magnetic damping constant in Co 2 MnAl film epitaxially grown on GaAs(100) substrate by FMR and TR-MOKE measurements, and found that the damping constant of 0.023 extracted by FMR is comparable with that of TR-MOKE at low field. While, considering field-dependent spin orientation, we think that the field-dependent damping constant deduced by TR-MOKE may provide important information for Co 2 MnAl/GaAs heterostructure and its potential application in spintronics. - Graphical abstract: Co 2 MnAl, considering its potential 100% spin polarization and high Curie temperature, is expected to be one of the most promising materials for realizing half metallicity. In this paper, we have successfully grown the B2-ordered Co 2 MnAl film on GaAs (100) substrate and systematically investigated the magnetic damping constant in Co 2 MnAl film epitaxially grown on GaAs(100) substrate by employing both FMR and TR-MOKE measurements. Our results show that the damping constant of 0.023 extracted by FMR is comparable with that of TR-MOKE at low field. However, considering field-dependent spin orientation, we think that the field-dependent damping constant deduced by TR-MOKE may be more useful for Co 2 MnAl/GaAs heterostructure and its possible application in spintronics. - Highlights: • B2 ordered Co 2 MnAl was successfully prepared and studied by LMOKE and ROT-MOKE. • Static magnetic measurements show clear cubic anisotropy with K C of 5.0 × 10 4

Product study of 1-adamantyl and 1-bicyclo[2.2.2]octyl radicals in hydrocarbon solvents. An unusually large hydrogen isotope effect

International Nuclear Information System (INIS)

Engel, P.S.; Chae, W.K.; Baughman, S.A.; Marschke, G.E.; Lewis, E.S.; Timberlake, J.W.; Luedtke, A.E.

1983-01-01

1-Adamantyl (ada.) and 1-bicyclo[2.2.2]octyl (bo.) radicals have been generated by photolysis of the corresponding azoalkanes in various hydrocarbon solvents. Both radicals abstract hydrogen readily from saturated hydrocarbons and they add to aromatic rings much faster than tert-butyl. does. Despite its reactivity, ada. is remarkably selective in hydrogen atom abstraction, preferring a benzylic hydrogen 25:1 over a cyclohexane hydrogen. The effect of solvent viscosity indicates that formation of the radical dimers biada and bibo occurs in the solvent cage. The most striking result of this work is a deuterium isotope effect of 25 for hydrogen transfer from cyclohexane to ada. at 65 0 C. Steric compression in the transition state is postulated to cause an unusually large tunnel correction and hence a large k/sub H//k/sub D/. 6 tables

Microwave monolithic filter and phase shifter using magnetic nanostructures

Science.gov (United States)

Aslam, Shehreen; Khanna, Manoj; Veenugopal, Veerakumar; Kuanr, Bijoy K.

2018-05-01

Monolithic Microwave Integrated Circuit (MMIC) have major impact on the development of microwave communication technology. Transition metal based ferromagnetic nano-wired (FMNWs) substrate are of special interest in order to fabricate these MMIC devices. Their saturation magnetization is comparatively higher than ferrites which makes them suitable for high frequency (>10 ˜ 40 GHz) operation at zero or a small applied magnetic field. The CoFeB nanowires in anodic alumina templates were synthesized using three-electrode electro-deposition system. After electro-deposition, 1μm thick Cu layer was sputtered on the top surface of FMNW substrate and lithography was done to design microstrip lines. These microstrip transmission lines were tested for band-stop filters and phase shifters based on ferromagnetic resonance (FMR) over a wide applied magnetic field (H) range. It was observed that attenuation and frequency increase with the increase of magnetic field (upto 5.3 kOe). For phase shifter, the influence of magnetic material was studied for two frequency regions: (i) below FMR and (ii) above FMR. These two frequency regions were suitable for many practical device applications as the insertion loss was very less in these regions in comparison to resonance frequency regions. In the high frequency region (at 35 GHz), the optimal differential phase shift increased significantly to ˜ 250 deg/cm and around low frequency region (at 24 GHz), the optimal differential phase shift is ˜175 deg/cm at the highest field (H) value.

Microwave monolithic filter and phase shifter using magnetic nanostructures

Directory of Open Access Journals (Sweden)

Shehreen Aslam

2018-05-01

Full Text Available Monolithic Microwave Integrated Circuit (MMIC have major impact on the development of microwave communication technology. Transition metal based ferromagnetic nano-wired (FMNWs substrate are of special interest in order to fabricate these MMIC devices. Their saturation magnetization is comparatively higher than ferrites which makes them suitable for high frequency (>10 ∼ 40 GHz operation at zero or a small applied magnetic field. The CoFeB nanowires in anodic alumina templates were synthesized using three-electrode electro-deposition system. After electro-deposition, 1μm thick Cu layer was sputtered on the top surface of FMNW substrate and lithography was done to design microstrip lines. These microstrip transmission lines were tested for band-stop filters and phase shifters based on ferromagnetic resonance (FMR over a wide applied magnetic field (H range. It was observed that attenuation and frequency increase with the increase of magnetic field (upto 5.3 kOe. For phase shifter, the influence of magnetic material was studied for two frequency regions: (i below FMR and (ii above FMR. These two frequency regions were suitable for many practical device applications as the insertion loss was very less in these regions in comparison to resonance frequency regions. In the high frequency region (at 35 GHz, the optimal differential phase shift increased significantly to ∼ 250 deg/cm and around low frequency region (at 24 GHz, the optimal differential phase shift is ∼175 deg/cm at the highest field (H value.

Metal-Poor, Strongly Star-Forming Galaxies in the DEEP2 Survey: The Relationship Between Stellar Mass, Temperature-Based Metallicity, and Star Formation Rate

Science.gov (United States)

Ly, Chun; Rigby, Jane R.; Cooper, Michael; Yan, Renbin

2015-01-01

We report on the discovery of 28 redshift (z) approximately equal to 0.8 metal-poor galaxies in DEEP2. These galaxies were selected for their detection of the weak [O (sub III)] lambda 4363 emission line, which provides a "direct" measure of the gas-phase metallicity. A primary goal for identifying these rare galaxies is to examine whether the fundamental metallicity relation (FMR) between stellar mass, gas metallicity, and star formation rate (SFR) holds for low stellar mass and high SFR galaxies. The FMR suggests that higher SFR galaxies have lower metallicity (at fixed stellar mass). To test this trend, we combine spectroscopic measurements of metallicity and dust-corrected SFR with stellar mass estimates from modeling the optical photometry. We find that these galaxies are 1.05 plus or minus 0.61 dex above the redshift (z) approximately 1 stellar mass-SFR relation and 0.23 plus or minus 0.23 dex below the local mass-metallicity relation. Relative to the FMR, the latter offset is reduced to 0.01 dex, but significant dispersion remains dex with 0.16 dex due to measurement uncertainties). This dispersion suggests that gas accretion, star formation, and chemical enrichment have not reached equilibrium in these galaxies. This is evident by their short stellar mass doubling timescale of approximately equal to 100 (sup plus 310) (sub minus 75) million years which suggests stochastic star formation. Combining our sample with other redshift (z) of approximately 1 metal-poor galaxies, we find a weak positive SFR-metallicity dependence (at fixed stellar mass) that is significant at 94.4 percent confidence. We interpret this positive correlation as recent star formation that has enriched the gas but has not had time to drive the metal-enriched gas out with feedback mechanisms.

Long term results of childhood dysphonia treatment.

Science.gov (United States)

Mackiewicz-Nartowicz, Hanna; Sinkiewicz, Anna; Bielecka, Arleta; Owczarzak, Hanna; Mackiewicz-Milewska, Magdalena; Winiarski, Piotr

2014-05-01

The aim of this study was to assess the long term results of treatment and rehabilitation of childhood dysphonia. This study included a group of adolescents (n=29) aged from 15 to 20 who were treated due to pediatric hyperfunctional dysphonia and soft vocal fold nodules during their pre-mutational period (i.e. between 5 and 12 years of age). The pre-mutational therapy was comprised of proper breathing pattern training, voice exercises and psychological counseling. Laryngostroboscopic examination and perceptual analysis of voice were performed in each patient before treatment and one to four years after mutation was complete. The laryngostroboscopic findings, i.e. symmetry, amplitude, mucosal wave and vocal fold closure, were graded with NAPZ scale, and the GRBAS scale was used for the perceptual voice analysis. Complete regression of the childhood dysphonia was observed in all male patients (n=14). Voice disorders regressed completely also in 8 out of 15 girls, but symptoms of dysphonia documented on perceptual scale persisted in the remaining seven patients. Complex voice therapy implemented in adolescence should be considered as either the treatment or preventive measure of persistent voice strain, especially in girls. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Field testing of bioenergetic models

International Nuclear Information System (INIS)

Nagy, K.A.

1985-01-01

Doubly labeled water provides a direct measure of the rate of carbon dioxide production by free-living animals. With appropriate conversion factors, based on chemical composition of the diet and assimilation efficiency, field metabolic rate (FMR), in units of energy expenditure, and field feeding rate can be estimated. Validation studies indicate that doubly labeled water measurements of energy metabolism are accurate to within 7% in reptiles, birds, and mammals. This paper discusses the use of doubly labeled water to generate empirical models for FMR and food requirements for a variety of animals

Fragile X syndrome: Current insight | Dean | Egyptian Journal of ...

African Journals Online (AJOL)

Fragile X syndrome (FXS) is a multigenerational disorder having massive adverse effect not only on the individuals but also on their families. It is the most common type of intellectual disability after Down's syndrome. Over two decades have passed since the discovery of FMR1, the causal gene for FXS, but still little is known ...