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Sample records for fragile site expression

  1. MUS81 promotes common fragile site expression

    Ying, Songmin; Minocherhomji, Sheroy; Chan, Kok Lung

    2013-01-01

    Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the fait......Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair...... the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early...

  2. Effects of hyperoxia and caffeine on the expression of fragile site at Xq27.3

    Rafi, S.K.; Surana, R.B.; Christopher, K.L. [Armed Forces Institute of Pathology, Washington, DC (United States)] [and others

    1996-02-02

    To enhance the cytogenetic expression of the fragile X chromosome, we studied the effects of hyperoxia and caffeine on the induction of fragile Xq27.3. A lymphoblastoid cell line (GM 06912) derived from a fragile X male proband was cultured in RPMI 1640 containing 16% dialyzed fetal calf serum. The cells were synchronously subjected to one of 3 different atmospheric oxygen tensions (21%, 21.3 kPa, hyperoxic) during the last 24 hours of the 72 hour culture, immediately after the addition of 2{prime}-deoxy-5-fluorouridine (FUdR) at 25 ng/ml. To study the enhancing effect of caffeine, with or without hyperoxia, a second set of cultures was additionally subjected to caffeine (2.5 mM) during the last 6 hours of the culture. When the fragility of hyperoxic cells (38.1 kPa dissolved oxygen) was compared to that of normoxic control cells (13.3 kPa dissolved oxygen), the difference was significant (P < 0.05). These data suggest that there is a mean increase in the fragile Xq27.3 expressivity as the dissolved oxygen tension increases. Additionally, we observed that caffeine, with or without hyperoxia, significantly (P <0.05) suppressed the expression of the fragile X site in this lymphoblastoid cell line. 34 refs., 2 tabs.

  3. Increased expression of aphidicolin-induced common fragile sites in Tourette syndrome: The key to understand the genetics of comorbid phenotypes?

    Gericke, G.S.; Simonic, I.; Cloete, E.; Becker, P.J. [Univ. of Pretoria (South Africa)

    1996-02-16

    In a comparison of 80 common aphidicolin-induced fragile sites (FS) between 26 DSM-IV Tourette syndrome (TS) and 24 control individuals, the mean of the summed break frequencies following mild aphidicolin pretreatment was significantly higher in TS individuals than in controls (P < 0.001). Other breakpoints encountered during this study, i.e., random breaks, breaks corresponding to rare FS, and breakpoints recorded by others but not listed as common FS according to the Chromosome Coordinating Meeting were listed as category II breakpoints. By using the most significantly different mean FS breakage figures between TS and control individuals, further stepwise discriminant analysis allowed identification of TS individuals from only a few sites in both the common FS and category II breakpoint groups. Future research needs to focus on confirmation of altered common fragile site expression in association with behavioral variation, whether expression of certain discriminatory sites concurs with specific comorbid disorder expression; the nature of the molecular alterations at these FS and the implications of a genomic instability phenotype for the mapping of a primary TS gene or genes. 45 refs., 1 fig., 2 tabs.

  4. The Detection and Analysis of Chromosome Fragile Sites

    Bjerregaard, Victoria A; Özer, Özgün; Hickson, Ian D

    2018-01-01

    A fragile site is a chromosomal locus that is prone to form a gap or constriction visible within a condensed metaphase chromosome, particularly following exposure of cells to DNA replication stress. Based on their frequency, fragile sites are classified as either common (CFSs; present in all...... for detection and analysis of chromosome fragile sites....

  5. A novel approach to simultaneously scan genes at fragile sites

    Willem, Pascale; Brown, Jacqueline; Schouten, Jan

    2006-01-01

    Fragile sites are regions of the genome sensitive to replication stress and to exposure to environmental carcinogens. The two most commonly expressed fragile sites FRA3B and FRA16D host the histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX) genes respectively. There is growing evidence that both genes contribute to cancer development and they are frequently altered by allelic and homozygous deletions in a variety of tumors. Their status is linked to prognosis in several malignancies and they are thought to be involved in early tumorigenesis. The loci for FHIT and WWOX both span over a megabase but the genes encode for small transcripts. Thus the screening of intragenic deletion can be difficult and has relied on loss of heterozygosity LOH assays, or genomic arrays. Multiplex ligation dependent probe amplification MLPA, allows for the detection of deletions/duplications and relative quantification of up to 40 specific probes in a single assay. A FHIT/WWOX MLPA assay was designed, applied and validated in five esophageal squamous cell carcinoma ESCC, cell lines established in South Africa where this cancer is of high prevalence. Sixteen probes covered all FHIT exons and 7 probes covered WWOX. Both homozygous and hemizygous deletions were detected in FHIT, in four of the cell lines with a preferential deletion of exons 5 and 4. Chromosome 3 short arm was present in normal copy number indicating that deletions were site specific. In contrast WWOX was not altered in any cell lines. RT-PCR expression pattern paralleled the pattern of deletions. Ten primary ESCC tumor specimens were subsequently screened with this assay. FHIT exon deletions were found in four of them. This method offers an alternative to loss of heterozygosity studies. Simultaneous scanning of FHIT and WWOX exons in the context of early tumorigenesis and tumor progression, may help clarify the mechanistic events related to cancer development which are not revealed by imuno

  6. Fragile sites, dysfunctional telomere and chromosome fusions: What is 5S rDNA role?

    Barros, Alain Victor; Wolski, Michele Andressa Vier; Nogaroto, Viviane; Almeida, Mara Cristina; Moreira-Filho, Orlando; Vicari, Marcelo Ricardo

    2017-04-15

    Repetitive DNA regions are known as fragile chromosomal sites which present a high flexibility and low stability. Our focus was characterize fragile sites in 5S rDNA regions. The Ancistrus sp. species shows a diploid number of 50 and an indicative Robertsonian fusion at chromosomal pair 1. Two sequences of 5S rDNA were identified: 5S.1 rDNA and 5S.2 rDNA. The first sequence gathers the necessary structures to gene expression and shows a functional secondary structure prediction. Otherwise, the 5S.2 rDNA sequence does not contain the upstream sequences that are required to expression, furthermore its structure prediction reveals a nonfunctional ribosomal RNA. The chromosomal mapping revealed several 5S.1 and 5S.2 rDNA clusters. In addition, the 5S.2 rDNA clusters were found in acrocentric and metacentric chromosomes proximal regions. The pair 1 5S.2 rDNA cluster is co-located with interstitial telomeric sites (ITS). Our results indicate that its clusters are hotspots to chromosomal breaks. During the meiotic prophase bouquet arrangement, double strand breaks (DSBs) at proximal 5S.2 rDNA of acrocentric chromosomes could lead to homologous and non-homologous repair mechanisms as Robertsonian fusions. Still, ITS sites provides chromosomal instability, resulting in telomeric recombination via TRF2 shelterin protein and a series of breakage-fusion-bridge cycles. Our proposal is that 5S rDNA derived sequences, act as chromosomal fragile sites in association with some chromosomal rearrangements of Loricariidae. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. FANCD2 binding identifies conserved fragile sites at large transcribed genes in avian cells

    Pentzold, Constanze; Shah, Shiraz Ali; Hansen, Niels Richard

    2018-01-01

    Common Chromosomal Fragile Sites (CFSs) are specific genomic regions prone to form breaks on metaphase chromosomes in response to replication stress. Moreover, CFSs are mutational hotspots in cancer genomes, showing that the mutational mechanisms that operate at CFSs are highly active in cancer c...

  8. Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response.

    Idit Hazan

    2016-12-01

    Full Text Available The role of common fragile sites (CFSs in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.

  9. Profiles of Receptive and Expressive Language Abilities in Boys with Comorbid Fragile X Syndrome and Autism

    McDuffie, Andrea; Kover, Sara; Abbeduto, Leonard; Lewis, Pamela; Brown, Ted

    2012-01-01

    The authors examined receptive and expressive language profiles for a group of verbal male children and adolescents who had fragile X syndrome along with varying degrees of autism symptoms. A categorical approach for assigning autism diagnostic classification, based on the combined use of the Autism Diagnostic Interview--Revised and the Autism…

  10. Effects of Sampling Context on Spontaneous Expressive Language in Males with Fragile X Syndrome or Down Syndrome

    Kover, Sara T.; McDuffie, Andrea; Abbeduto, Leonard; Brown, W. Ted

    2012-01-01

    Purpose: In this study, the authors examined the impact of sampling context on multiple aspects of expressive language in male participants with fragile X syndrome in comparison to male participants with Down syndrome or typical development. Method: Participants with fragile X syndrome (n = 27), ages 10-17 years, were matched groupwise on…

  11. Fragile X mental retardation protein controls ion channel expression and activity.

    Ferron, Laurent

    2016-10-15

    Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome, the most common cause of inherited intellectual disability and autism. FMRP is an RNA-binding protein involved in the control of local translation, which has pleiotropic effects, in particular on synaptic function. Analysis of the brain FMRP transcriptome has revealed hundreds of potential mRNA targets encoding postsynaptic and presynaptic proteins, including a number of ion channels. FMRP has been confirmed to bind voltage-gated potassium channels (K v 3.1 and K v 4.2) mRNAs and regulates their expression in somatodendritic compartments of neurons. Recent studies have uncovered a number of additional roles for FMRP besides RNA regulation. FMRP was shown to directly interact with, and modulate, a number of ion channel complexes. The sodium-activated potassium (Slack) channel was the first ion channel shown to directly interact with FMRP; this interaction alters the single-channel properties of the Slack channel. FMRP was also shown to interact with the auxiliary β4 subunit of the calcium-activated potassium (BK) channel; this interaction increases calcium-dependent activation of the BK channel. More recently, FMRP was shown to directly interact with the voltage-gated calcium channel, Ca v 2.2, and reduce its trafficking to the plasma membrane. Studies performed on animal models of fragile X syndrome have revealed links between modifications of ion channel activity and changes in neuronal excitability, suggesting that these modifications could contribute to the phenotypes observed in patients with fragile X-associated disorders. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

  12. Genome instability in the context of chromatin structure and fragile sites

    Bártová, Eva; Galiová-Šustáčková, Gabriela; Legartová, Soňa; Stixová, Lenka; Jugová, Alžbeta; Kozubek, Stanislav

    2010-01-01

    Roč. 20, č. 3 (2010), s. 181-194 ISSN 1045-4403 R&D Projects: GA MŠk ME 919; GA ČR(CZ) GAP302/10/1022 Grant - others:GA MŠk(CZ) LC06027; GA MŠk(CZ) LC535 Program:LC; LC Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : gene amplification * fragile sites * chromatin structure Subject RIV: BO - Biophysics Impact factor: 4.111, year: 2010

  13. Fragile X mental retardation protein expression in Alzheimer’s disease

    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.

  14. Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites

    Pierce Levi CT

    2009-01-01

    Full Text Available Abstract Background Gene rearrangements such as chromosomal translocations have been shown to contribute to cancer development. Human chromosomal fragile sites are regions of the genome especially prone to breakage, and have been implicated in various chromosome abnormalities found in cancer. However, there has been no comprehensive and quantitative examination of the location of fragile sites in relation to all chromosomal aberrations. Results Using up-to-date databases containing all cancer-specific recurrent translocations, we have examined 444 unique pairs of genes involved in these translocations to determine the correlation of translocation breakpoints and fragile sites in the gene pairs. We found that over half (52% of translocation breakpoints in at least one gene of these gene pairs are mapped to fragile sites. Among these, we examined the DNA sequences within and flanking three randomly selected pairs of translocation-prone genes, and found that they exhibit characteristic features of fragile DNA, with frequent AT-rich flexibility islands and the potential of forming highly stable secondary structures. Conclusion Our study is the first to examine gene pairs involved in all recurrent chromosomal translocations observed in tumor cells, and to correlate the location of more than half of breakpoints to positions of known fragile sites. These results provide strong evidence to support a causative role for fragile sites in the generation of cancer-specific chromosomal rearrangements.

  15. RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis

    Di Marco, Stefano; Hasanova, Zdenka; Kanagaraj, Radhakrishnan

    2017-01-01

    The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent...... on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain...

  16. Prevalence of Sarcopenia and Its Relationship with Sites of Fragility Fractures in Elderly Chinese Men and Women.

    Wei Hong

    Full Text Available Sarcopenia might be associated with bone fragility in elderly individuals. This study aimed to investigate the prevalence of sarcopenia and its association with fragility fracture sites in elderly Chinese patients.Patients (322 men and 435 women aged 65-94 years and with a history of fragility fractures in the ankle, wrist, vertebrae or hip, and healthy men (n = 1263 and women (n = 1057 aged 65-92 years without a history of fractures were enrolled. Whole-body dual energy X-ray absorptiometry was used to analyze skeletal muscle mass index (SMI, fat mass and bone mineral density. Sarcopenia was defined as SMI less than two standard deviations below the mean of a young reference group.Sarcopenia occurrence varied with fracture location. Sarcopenia was more common in females with vertebral and hip fractures and in men with hip and ankle fractures than in the non-fracture group. Sarcopenia was significantly more prevalent in men with wrist, hip and ankle fractures than in women. SMI was correlated with BMD in different fracture groups. Logistic regression analyses revealed that lower SMI was associated with an increased risk of hip fracture both in men and women and ankle fracture in men.Sarcopenia may be an independent risk factor for hip and ankle fractures in men, and for hip fractures in women.

  17. Prevalence of Sarcopenia and Its Relationship with Sites of Fragility Fractures in Elderly Chinese Men and Women.

    Hong, Wei; Cheng, Qun; Zhu, Xiaoying; Zhu, Hanmin; Li, Huilin; Zhang, Xuemei; Zheng, Songbai; Du, Yanping; Tang, Wenjing; Xue, Sihong; Ye, Zhibin

    2015-01-01

    Sarcopenia might be associated with bone fragility in elderly individuals. This study aimed to investigate the prevalence of sarcopenia and its association with fragility fracture sites in elderly Chinese patients. Patients (322 men and 435 women) aged 65-94 years and with a history of fragility fractures in the ankle, wrist, vertebrae or hip, and healthy men (n = 1263) and women (n = 1057) aged 65-92 years without a history of fractures were enrolled. Whole-body dual energy X-ray absorptiometry was used to analyze skeletal muscle mass index (SMI), fat mass and bone mineral density. Sarcopenia was defined as SMI less than two standard deviations below the mean of a young reference group. Sarcopenia occurrence varied with fracture location. Sarcopenia was more common in females with vertebral and hip fractures and in men with hip and ankle fractures than in the non-fracture group). Sarcopenia was significantly more prevalent in men with wrist, hip and ankle fractures than in women. SMI was correlated with BMD in different fracture groups. Logistic regression analyses revealed that lower SMI was associated with an increased risk of hip fracture both in men and women and ankle fracture in men. Sarcopenia may be an independent risk factor for hip and ankle fractures in men, and for hip fractures in women.

  18. Expressed information needs of patients with osteoporosis and/or fragility fractures: a systematic review.

    Raybould, Grace; Babatunde, Opeyemi; Evans, Amy L; Jordan, Joanne L; Paskins, Zoe

    2018-05-08

    This systematic review identified patients have unmet information needs about the nature of osteoporosis, medication, self-management and follow-up. Clinician knowledge and attitudes appear to be of key importance in determining whether these needs are met. Unmet information needs appear to have psychosocial consequences and result in poor treatment adherence. Patient education is an integral component of the management of osteoporosis, yet patients are dissatisfied with the information they receive and see this as an area of research priority. This study aimed to describe and summarise the specific expressed information needs of patients in previously published qualitative research. Using terms relating to osteoporosis, fragility fracture and information needs, seven databases were searched. Articles were screened using predefined inclusion and exclusion criteria. Full-text articles selected for inclusion underwent data extraction and quality appraisal. Findings were drawn together using narrative synthesis. The search identified 11,024 articles. Sixteen empirical studies were included in the review. Thematic analysis revealed three overarching themes relating to specific information needs, factors influencing whether information needs are met and the impact of unmet information needs. Specific information needs identified included the following: the nature of osteoporosis/fracture risk; medication; self-management and understanding the role of dual energy x-ray absorptiometry and follow-up. Perceived physician knowledge and attitudes, and the attitudes, beliefs and behaviours of patients were important factors in influencing whether information needs were met, in addition to contextual factors and the format of educational resources. Failure to elicit and address information needs appears to be associated with poor treatment adherence, deterioration of the doctor-patient relationship and important psychosocial consequences. This is the first study to describe the

  19. Generalized Fragility Relationships with Local Site Conditions for Probabilistic Performance-based Seismic Risk Assessment of Bridge Inventories

    Sivathayalan S.

    2012-01-01

    Full Text Available The current practice of detailed seismic risk assessment cannot be easily applied to all the bridges in a large transportation networks due to limited resources. This paper presents a new approach for seismic risk assessment of large bridge inventories in a city or national bridge network based on the framework of probabilistic performance based seismic risk assessment. To account for the influences of local site effects, a procedure to generate site-specific hazard curves that includes seismic hazard microzonation information has been developed for seismic risk assessment of bridge inventories. Simulated ground motions compatible with the site specific seismic hazard are used as input excitations in nonlinear time history analysis of representative bridges for calibration. A normalizing procedure to obtain generalized fragility relationships in terms of structural characteristic parameters of bridge span and size and longitudinal and transverse reinforcement ratios is presented. The seismic risk of bridges in a large inventory can then be easily evaluated using the normalized fragility relationships without the requirement of carrying out detailed nonlinear time history analysis.

  20. 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.

    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.

  1. A functional genetic variant in fragile-site gene FATS modulates the risk of breast cancer in triparous women

    Song, Fangfang; Zhang, Jun; Qiu, Li; Zhao, Yawen; Xing, Pan; Lu, Jiachun; Chen, Kexin; Li, Zheng

    2015-01-01

    The fragile-site associated tumor suppressor (FATS, formerly known as C10orf90), a regulator of p53-p21 pathway has been involved in the onset of breast cancer. Recent data support the idea that the crosstalk between FATS and p53 may be of physiological importance for reproduction during evolution. The aim of the current study was to test the hypothesis that FATS genetic polymorphism can influence the risk of breast cancer. We conducted population-based studies in two independent cohorts comprising 1 532 cases and 1 573 controls in Tianjin of North China, and 804 cases and 835 controls in Guangzhou of South China, coupled with functional validation methods, to investigate the role of FATS genetic variant in breast cancer risk. We identified a functional variant rs11245007 (905C > T, 262D/N) in fragile-site gene FATS that modulates p53 activation. FATS-262 N exhibited stronger E3 activity to polyubiquitinate p53 than did FATS-262D, leading to the stronger transcriptional activity of p53 and more pronounced stabilization of p53 protein and its activation in response to DNA damage. Case–control studies found that CT or TT genotype was significantly associated with a protective effect on breast cancer risk in women with parity ≥ 3, which was not affected by family history. Our findings suggest the role of FATS-p53 signaling cascade in suppressing pregnancy-related carcinogenesis and potential application of FATS genotyping in breast cancer prevention. The online version of this article (doi:10.1186/s12885-015-1570-9) contains supplementary material, which is available to authorized users

  2. Common chromosomal fragile sites (CFS) may be involved in normal and traumatic cognitive stress memory consolidation and altered nervous system immunity.

    Gericke, G S

    2010-05-01

    Previous reports of specific patterns of increased fragility at common chromosomal fragile sites (CFS) found in association with certain neurobehavioural disorders did not attract attention at the time due to a shift towards molecular approaches to delineate neuropsychiatric disorder candidate genes. Links with miRNA, altered methylation and the origin of copy number variation indicate that CFS region characteristics may be part of chromatinomic mechanisms that are increasingly linked with neuroplasticity and memory. Current reports of large-scale double-stranded DNA breaks in differentiating neurons and evidence of ongoing DNA demethylation of specific gene promoters in adult hippocampus may shed new light on the dynamic epigenetic changes that are increasingly appreciated as contributing to long-term memory consolidation. The expression of immune recombination activating genes in key stress-induced memory regions suggests the adoption by the brain of this ancient pattern recognition and memory system to establish a structural basis for long-term memory through controlled chromosomal breakage at highly specific genomic regions. It is furthermore considered that these mechanisms for management of epigenetic information related to stress memory could be linked, in some instances, with the transfer of the somatically acquired information to the germline. Here, rearranged sequences can be subjected to further selection and possible eventual retrotranscription to become part of the more stable coding machinery if proven to be crucial for survival and reproduction. While linkage of cognitive memory with stress and fear circuitry and memory establishment through structural DNA modification is proposed as a normal process, inappropriate activation of immune-like genomic rearrangement processes through traumatic stress memory may have the potential to lead to undesirable activation of neuro-inflammatory processes. These theories could have a significant impact on the

  3. Systematic identification of fragile sites via genome-wide location analysis of γ-H2AX

    Szilard, Rachel K.; Jacques, Pierre-Étienne; Laramée, Louise; Cheng, Benjamin; Galicia, Sarah; Bataille, Alain R.; Yeung, ManTek; Mendez, Megan; Bergeron, Maxime; Robert, François; Durocher, Daniel

    2011-01-01

    Phosphorylation of histone H2AX is an early response to DNA damage in eukaryotes. In Saccharomyces cerevisiae, DNA damage or replication fork stalling results in histone H2A phosphorylation to yield γ-H2A (yeast γ-H2AX) in a Mec1 (ATR)- and Tel1 (ATM)- dependent manner. Here, we describe the genome-wide location analysis of γ-H2A as a strategy to identify loci prone to engage the Mec1 and Tel1 pathways. Remarkably, γ-H2A enrichment overlaps with loci prone to replication fork stalling and is caused by the action of Mec1 and Tel1, indicating that these loci are prone to breakage. Moreover, about half the sites enriched for γ-H2A map to repressed protein-coding genes, and histone deacetylases are necessary for formation of γ-H2A at these loci. Finally, our work indicates that high resolution mapping of γ-H2AX is a fruitful route to map fragile sites in eukaryotic genomes. PMID:20139982

  4. Protein expression profiling of the drosophila fragile X mutant brain reveals up-regulation of monoamine synthesis.

    Zhang, Yong Q; Friedman, David B; Wang, Zhe; Woodruff, Elvin; Pan, Luyuan; O'donnell, Janis; Broadie, Kendal

    2005-03-01

    Fragile X syndrome is the most common form of inherited mental retardation, associated with both cognitive and behavioral anomalies. The disease is caused by silencing of the fragile X mental retardation 1 (fmr1) gene, which encodes the mRNA-binding, translational regulator FMRP. Previously we established a disease model through mutation of Drosophila fmr1 (dfmr1) and showed that loss of dFMRP causes defects in neuronal structure, function, and behavioral output similar to the human disease state. To uncover molecular targets of dFMRP in the brain, we use here a proteomic approach involving two-dimensional difference gel electrophoresis analyses followed by mass spectrometry identification of proteins with significantly altered expression in dfmr1 null mutants. We then focus on two misregulated enzymes, phenylalanine hydroxylase (Henna) and GTP cyclohydrolase (Punch), both of which mediate in concert the synthetic pathways of two key monoamine neuromodulators, dopamine and serotonin. Brain enzymatic assays show a nearly 2-fold elevation of Punch activity in dfmr1 null mutants. Consistently brain neurochemical assays show that both dopamine and serotonin are significantly increased in dfmr1 null mutants. At a cellular level, dfmr1 null mutant neurons display a highly significant elevation of the dense core vesicles that package these monoamine neuromodulators for secretion. Taken together, these data indicate that dFMRP normally down-regulates the monoamine pathway, which is consequently up-regulated in the mutant condition. Elevated brain levels of dopamine and serotonin provide a plausible mechanistic explanation for aspects of cognitive and behavioral deficits in human patients.

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

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

    1995-01-01

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

  6. 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.

    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

  7. Comparative genomic mapping of the bovine Fragile Histidine Triad (FHIT tumour suppressor gene: characterization of a 2 Mb BAC contig covering the locus, complete annotation of the gene, analysis of cDNA and of physiological expression profiles

    Boussaha Mekki

    2006-05-01

    Full Text Available Abstract Background The Fragile Histidine Triad gene (FHIT is an oncosuppressor implicated in many human cancers, including vesical tumors. FHIT is frequently hit by deletions caused by fragility at FRA3B, the most active of human common fragile sites, where FHIT lays. Vesical tumors affect also cattle, including animals grazing in the wild on bracken fern; compounds released by the fern are known to induce chromosome fragility and may trigger cancer with the interplay of latent Papilloma virus. Results The bovine FHIT was characterized by assembling a contig of 78 BACs. Sequence tags were designed on human exons and introns and used directly to select bovine BACs, or compared with sequence data in the bovine genome database or in the trace archive of the bovine genome sequencing project, and adapted before use. FHIT is split in ten exons like in man, with exons 5 to 9 coding for a 149 amino acids protein. VISTA global alignments between bovine genomic contigs retrieved from the bovine genome database and the human FHIT region were performed. Conservation was extremely high over a 2 Mb region spanning the whole FHIT locus, including the size of introns. Thus, the bovine FHIT covers about 1.6 Mb compared to 1.5 Mb in man. Expression was analyzed by RT-PCR and Northern blot, and was found to be ubiquitous. Four cDNA isoforms were isolated and sequenced, that originate from an alternative usage of three variants of exon 4, revealing a size very close to the major human FHIT cDNAs. Conclusion A comparative genomic approach allowed to assemble a contig of 78 BACs and to completely annotate a 1.6 Mb region spanning the bovine FHIT gene. The findings confirmed the very high level of conservation between human and bovine genomes and the importance of comparative mapping to speed the annotation process of the recently sequenced bovine genome. The detailed knowledge of the genomic FHIT region will allow to study the role of FHIT in bovine cancerogenesis

  8. Comparative genomic mapping of the bovine Fragile Histidine Triad (FHIT) tumour suppressor gene: characterization of a 2 Mb BAC contig covering the locus, complete annotation of the gene, analysis of cDNA and of physiological expression profiles.

    Uboldi, Cristina; Guidi, Elena; Roperto, Sante; Russo, Valeria; Roperto, Franco; Di Meo, Giulia Pia; Iannuzzi, Leopoldo; Floriot, Sandrine; Boussaha, Mekki; Eggen, André; Ferretti, Luca

    2006-05-23

    The Fragile Histidine Triad gene (FHIT) is an oncosuppressor implicated in many human cancers, including vesical tumors. FHIT is frequently hit by deletions caused by fragility at FRA3B, the most active of human common fragile sites, where FHIT lays. Vesical tumors affect also cattle, including animals grazing in the wild on bracken fern; compounds released by the fern are known to induce chromosome fragility and may trigger cancer with the interplay of latent Papilloma virus. The bovine FHIT was characterized by assembling a contig of 78 BACs. Sequence tags were designed on human exons and introns and used directly to select bovine BACs, or compared with sequence data in the bovine genome database or in the trace archive of the bovine genome sequencing project, and adapted before use. FHIT is split in ten exons like in man, with exons 5 to 9 coding for a 149 amino acids protein. VISTA global alignments between bovine genomic contigs retrieved from the bovine genome database and the human FHIT region were performed. Conservation was extremely high over a 2 Mb region spanning the whole FHIT locus, including the size of introns. Thus, the bovine FHIT covers about 1.6 Mb compared to 1.5 Mb in man. Expression was analyzed by RT-PCR and Northern blot, and was found to be ubiquitous. Four cDNA isoforms were isolated and sequenced, that originate from an alternative usage of three variants of exon 4, revealing a size very close to the major human FHIT cDNAs. A comparative genomic approach allowed to assemble a contig of 78 BACs and to completely annotate a 1.6 Mb region spanning the bovine FHIT gene. The findings confirmed the very high level of conservation between human and bovine genomes and the importance of comparative mapping to speed the annotation process of the recently sequenced bovine genome. The detailed knowledge of the genomic FHIT region will allow to study the role of FHIT in bovine cancerogenesis, especially of vesical papillomavirus-associated cancers of

  9. Role of DNA Repair Factor Xeroderma Pigmentosum Protein Group C in Response to Replication Stress As Revealed by DNA Fragile Site Affinity Chromatography and Quantitative Proteomics.

    Beresova, Lucie; Vesela, Eva; Chamrad, Ivo; Voller, Jiri; Yamada, Masayuki; Furst, Tomas; Lenobel, Rene; Chroma, Katarina; Gursky, Jan; Krizova, Katerina; Mistrik, Martin; Bartek, Jiri

    2016-12-02

    Replication stress (RS) fuels genomic instability and cancer development and may contribute to aging, raising the need to identify factors involved in cellular responses to such stress. Here, we present a strategy for identification of factors affecting the maintenance of common fragile sites (CFSs), which are genomic loci that are particularly sensitive to RS and suffer from increased breakage and rearrangements in tumors. A DNA probe designed to match the high flexibility island sequence typical for the commonly expressed CFS (FRA16D) was used as specific DNA affinity bait. Proteins significantly enriched at the FRA16D fragment under normal and replication stress conditions were identified using stable isotope labeling of amino acids in cell culture-based quantitative mass spectrometry. The identified proteins interacting with the FRA16D fragment included some known CFS stabilizers, thereby validating this screening approach. Among the hits from our screen so far not implicated in CFS maintenance, we chose Xeroderma pigmentosum protein group C (XPC) for further characterization. XPC is a key factor in the DNA repair pathway known as global genomic nucleotide excision repair (GG-NER), a mechanism whose several components were enriched at the FRA16D fragment in our screen. Functional experiments revealed defective checkpoint signaling and escape of DNA replication intermediates into mitosis and the next generation of XPC-depleted cells exposed to RS. Overall, our results provide insights into an unexpected biological role of XPC in response to replication stress and document the power of proteomics-based screening strategies to elucidate mechanisms of pathophysiological significance.

  10. Fragile Butterfly

    2011-01-01

    Valg af materiale/medie/form: Med indlevelse og en unik balance af sårbarhed i stemmen synger og fortolker Heidie sine egne sange, hvis lyriske tekster grundlæggende har to temaer: En dyb kærlighed til livet og det at turde kærligheden. Toneuniverset i Fragile Butterfly tager sit afsæt i jazzen...

  11. Autism genetic database (AGD: a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites

    Talebizadeh Zohreh

    2009-09-01

    Full Text Available Abstract Background Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood. In the present work, the Autism Genetic Database (AGD was developed as a literature-driven, web-based, and easy to access database designed with the aim of creating a comprehensive repository for all the currently reported genes and genomic copy number variations (CNVs associated with autism in order to further facilitate the assessment of these autism susceptibility genetic factors. Description AGD is a relational database that organizes data resulting from exhaustive literature searches for reported susceptibility genes and CNVs associated with autism. Furthermore, genomic information about human fragile sites and noncoding RNAs was also downloaded and parsed from miRBase, snoRNA-LBME-db, piRNABank, and the MIT/ICBP siRNA database. A web client genome browser enables viewing of the features while a web client query tool provides access to more specific information for the features. When applicable, links to external databases including GenBank, PubMed, miRBase, snoRNA-LBME-db, piRNABank, and the MIT siRNA database are provided. Conclusion AGD comprises a comprehensive list of susceptibility genes and copy number variations reported to-date in association with autism, as well as all known human noncoding RNA genes and fragile sites. Such a unique and inclusive autism genetic database will facilitate the evaluation of autism susceptibility factors in relation to known human noncoding RNAs and fragile sites, impacting on human diseases. As a result, this new autism database offers a valuable tool for the research

  12. Three Faces of Fragile X.

    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.

  13. Fragile Elite

    Bregnbæk, Susanne

    China's One Child Policy and its rigorous national focus on educational testing are well known. But what happens to those "lucky" few at the very top of the pyramid? Fragile Elite explores the contradictions of being an elite student through ethnographic research conducted at two top universities...... in China. It uncovers the intimate psychological strains students suffer under the pressure imposed on them by parents and state, where the state acts as a parent, and the parents sometimes reinforce the state. The book offers insights into the intergenerational tensions as work in relation to the ongoing...... shifts in educational policy and definition of what a "quality" student, child, and citizen is in contemporary China....

  14. Seismic fragility of nuclear power plant components (Phase 2): A fragility handbook on eighteen components

    Bandyopadhyay, K.K.; Hofmayer, C.H.; Kassir, M.K.; Shteyngart, S.

    1991-06-01

    Fragility estimates of seven equipment classes were published in earlier reports. This report presents fragility analysis results from eleven additional equipment categories. The fragility levels are expressed in probabilistic terms. For users' convenience, this concluding report includes a summary of fragility results of all eighteen equipment classes. A set of conversion factors based on judgment is recommended for use of the information for early vintage equipment. The knowledge gained in conducting the Component Fragility Program and similar other programs is expected to provide a new direction for seismic verification and qualification of equipment. 15 refs., 12 tabs

  15. Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms

    Weixiang Guo

    2015-06-01

    Full Text Available Fragile X mental retardation protein (FMRP and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2 is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.

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

    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

  17. Deficient plakophilin-1 expression due to a mutation in PKP1 causes ectodermal dysplasia-skin fragility syndrome in Chesapeake Bay retriever dogs.

    Thierry Olivry

    Full Text Available In humans, congenital and hereditary skin diseases associated with epidermal cell-cell separation (acantholysis are very rare, and spontaneous animal models of these diseases are exceptional. Our objectives are to report a novel congenital acantholytic dermatosis that developed in Chesapeake Bay retriever dogs. Nine affected puppies in four different litters were born to eight closely related clinically normal dogs. The disease transmission was consistent with an autosomal recessive mode of inheritance. Clinical signs occurred immediately after birth with superficial epidermal layers sloughing upon pressure. At three month of age, dogs exhibited recurrent superficial skin sloughing and erosions at areas of friction and mucocutaneous junctions; their coat was also finer than normal and there were patches of partial hair loss. At birth, histopathology revealed severe suprabasal acantholysis, which became less severe with ageing. Electron microscopy demonstrated a reduced number of partially formed desmosomes with detached and aggregated keratin intermediate filaments. Immunostaining for desmosomal adhesion molecules revealed a complete lack of staining for plakophilin-1 and anomalies in the distribution of desmoplakin and keratins 10 and 14. Sequencing revealed a homozygous splice donor site mutation within the first intron of PKP1 resulting in a premature stop codon, thereby explaining the inability to detect plakophilin-1 in the skin. Altogether, the clinical and pathological findings, along with the PKP1 mutation, were consistent with the diagnosis of ectodermal dysplasia-skin fragility syndrome with plakophilin-1 deficiency. This is the first occurrence of ectodermal dysplasia-skin fragility syndrome in an animal species. Controlled mating of carrier dogs would yield puppies that could, in theory, be tested for gene therapy of this rare but severe skin disease of children.

  18. Lithium ameliorates open-field and elevated plus maze behaviors, and brain phospho-glycogen synthase kinase 3-beta expression in fragile X syndrome model mice.

    Chen, Xi; Sun, Weiwen; Pan, Ying; Yang, Quan; Cao, Kaiyi; Zhang, Jin; Zhang, Yizhi; Chen, Mincong; Chen, Feidi; Huang, Yueling; Dai, Lijun; Chen, Shengqiang

    2013-10-01

    To investigate whether lithium modifies open-field and elevated plus maze behavior, and brain phospho-glycogen synthase kinase 3 (P-GSK3beta) expression in Fmr1 knockout mice. One hundred and eighty FVB mice, including knockout and wild type, with an age of 30 days were used. An open-field and elevated plus maze was utilized to test behavior, while western blot was used to measure the P-GSK3beta expression. Six groups were formed: control (saline), lithium chloride 30, 60, 90, 120, and 200 mg/kg. The experiments were carried out in the Institute of Neuroscience, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China between January and June 2012. Lithium significantly decreased total distance, crossing, central area time, and center entry in the open-field test (popen-arm tracking, open-arm entry, and open-arm time in the elevated plus maze (popen-field and elevated plus maze behaviors of Fmr1 knockout mice. This effect may be related to its enhancement of P-GSK3beta expression. Our findings suggest that lithium might have a therapeutic effect in fragile X syndrome.

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

    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

  20. Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair

    Gelincik, Ozkan; Blecua, Pedro; Edelmann, Winfried; Kucherlapati, Raju; Zhou, Kathy; Jasin, Maria; Gümüş, Zeynep H.; Lipkin, Steven M.

    2017-01-01

    Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1, Pms2, and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters. Additionally, when DSBs are induced by gamma-radiation, Mlh1, Pms2 and Mlh3 mutant MEFs have higher DR copy number alterations (CNAs), including DR CNA hotspots previously identified in mouse MMR-deficient colorectal cancer (dMMR CRC). Analysis of The Cancer Genome Atlas CRC data revealed that dMMR CRCs have higher genome-wide DR HeR rates than MMR proficient CRCs, and that dMMR CRCs have deletion hotspots in tumor suppressors FHIT/WWOX at chromosomal fragile sites FRA3B and FRA16D (which have elevated DSB rates) flanked by paired homologous DRs and inverted repeats (IR). Overall, these data provide novel insights into the MMR-dependent HeR inhibition mechanism and its role in tumor suppression. PMID:29069730

  1. A note on families of fragility curves

    Kaplan, S.; Bier, V.M.; Bley, D.C.

    1989-01-01

    In the quantitative assessment of seismic risk, uncertainty in the fragility of a structural component is usually expressed by putting forth a family of fragility curves, with probability serving as the parameter of the family. Commonly, a lognormal shape is used both for the individual curves and for the expression of uncertainty over the family. A so-called composite single curve can also be drawn and used for purposes of approximation. This composite curve is often regarded as equivalent to the mean curve of the family. The equality seems intuitively reasonable, but according to the authors has never been proven. The paper presented proves this equivalence hypothesis mathematically. Moreover, the authors show that this equivalence hypothesis between fragility curves is itself equivalent to an identity property of the standard normal probability curve. Thus, in the course of proving the fragility curve hypothesis, the authors have also proved a rather obscure, but interesting and perhaps previously unrecognized, property of the standard normal curve

  2. Fragile X syndrome

    ... problems, or intellectual disability may not be present. Symptoms Behavior problems associated with fragile X syndrome include: Autism spectrum disorder Delay in crawling, walking, or twisting Hand flapping ...

  3. Equipment fragility testing

    Holman, G.S.; Chou, C.K.; Cummings, G.E.

    1985-01-01

    Current probabilistic risk assessment (PRA) methods for nuclear power plants utilize component fragilities which are for the most part based on a limited data base and engineering judgement. The seismic design of components is based on code limits and NRC requirements that do not reflect the actual capacity of a component to resist failure. In order to improve the present component fragility data base and establish component seismic design margins, the NRC has commissioned a projected three-year program to compile existing fragilities data and at the same time independently perform fragilities tests on selected mechanical and electrical components. This paper presents the planning and technical approach being taken by LLNL in the NRC Component Fragility Program

  4. Ectodermal Dysplasia Skin Fragility Syndrome

    Ayça Alan Atalay

    2014-06-01

    Full Text Available Ectodermal dysplasia-skin fragility syndrome (EDSFS is a rare autosomal recessive genodermatosis first described in 1997 by Mc Grath. EDSFS results from loss of function mutations in plakophilin-1 (PKP1. PKP1 is a structural component of desmosomes, cellcell adhesion complexes. It is also found as a nuclear protein in several cell types that are lack of desmosomes. In skin, however, PKP1 expression is confined mainly to suprabasal keratinocytes and the outer root sheath of hair follicules. Loss of function mutation in PKP1 leads to extensive skin fragility, bullae and erosions following minor trauma, focal keratoderma with painful fissures, alopecia, and nail dystrophy. In some patients hypohidrosis may also be seen. EDSFS is now considered as a specific suprabasal form of epidermolysis bullosa simplex. In this report we describe a 20 year old EDSFS case.

  5. Trio Fragile / Olga Kaljundi

    Kaljundi, Olga, 1941-2001

    1998-01-01

    Tallinna Vene Draamateatri galeriis esinenud trupi "Trio Fragile" vernissaazhist. Trio loomingust ja osalejatest : kahe muusiku seltskonnas esineb ka 1984.a. Kunstiülikooli lõpetanud kunstnik Tõnu Talve.

  6. Cities could hold the key to understanding fragility | IDRC ...

    Cities are engines of economic growth and the primary sites of basic service delivery. Yet weak governance, along with inequalities related to income, social class, religion, and gender, may lead to a breakdown of systems and structures, and eventually to "fragile cities." Although the fragile cities concept is relatively new, ...

  7. Cities could hold the key to understanding fragility | CRDI - Centre ...

    Cities are engines of economic growth and the primary sites of basic service delivery. Yet weak governance, along with inequalities related to income, social class, religion, and gender, may lead to a breakdown of systems and structures, and eventually to "fragile cities." Although the fragile cities concept is relatively new, ...

  8. Frequency of fragile-x in x‑linked mental retardation

    ... with isolated mental retardation or autism of unknown etiology with considerable fragile X dysmorphic features or established family history of fragile X syndrome, chromosomal study that identifies the fragile site at Xq27.3 in addition to other cytogenetic abnormalities could be useful or early diagnosis and intervention by ...

  9. Meta-Analysis of DNA Tumor-Viral Integration Site Selection Indicates a Role for Repeats, Gene Expression and Epigenetics

    Janet M. Doolittle-Hall

    2015-11-01

    Full Text Available Oncoviruses cause tremendous global cancer burden. For several DNA tumor viruses, human genome integration is consistently associated with cancer development. However, genomic features associated with tumor viral integration are poorly understood. We sought to define genomic determinants for 1897 loci prone to hosting human papillomavirus (HPV, hepatitis B virus (HBV or Merkel cell polyomavirus (MCPyV. These were compared to HIV, whose enzyme-mediated integration is well understood. A comprehensive catalog of integration sites was constructed from the literature and experimentally-determined HPV integration sites. Features were scored in eight categories (genes, expression, open chromatin, histone modifications, methylation, protein binding, chromatin segmentation and repeats and compared to random loci. Random forest models determined loci classification and feature selection. HPV and HBV integrants were not fragile site associated. MCPyV preferred integration near sensory perception genes. Unique signatures of integration-associated predictive genomic features were detected. Importantly, repeats, actively-transcribed regions and histone modifications were common tumor viral integration signatures.

  10. Clinical aspects of the fragile X syndrome.

    Brown, W Ted

    2012-01-01

    Fragile X syndrome patients express a wide array of cognitive and other gender-specific phenotypic features. These manifestations result not only from molecular mechanisms that are altered as a result of the expansion of a CGG-repeat region in the FMR1 promoter, but also genetic factors such as founder effects and mosaicism. In this chapter, I will summarize the many and varied features of fragile X syndrome as they present themselves in a clinical setting and describe the procedures that are used to diagnose patients. Finally, I will briefly touch on recent developments that will affect patient screening in the future.

  11. Upregulation of inflammatory genes and downregulation of sclerostin gene expression are key elements in the early phase of fragility fracture healing.

    Joana Caetano-Lopes

    Full Text Available BACKGROUND: Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients. METHODOLOGY/PRINCIPAL FINDINGS: Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13; between the 4(th and 7(th day (n = 33; and after one week from the fracture (n = 10. Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4(th-7(th days after fracture. Sclerostin expression diminished during the first days after fracture. CONCLUSIONS: The expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.

  12. Telomeric expression sites are highly conserved in Trypanosoma brucei.

    Christiane Hertz-Fowler

    Full Text Available Subtelomeric regions are often under-represented in genome sequences of eukaryotes. One of the best known examples of the use of telomere proximity for adaptive purposes are the bloodstream expression sites (BESs of the African trypanosome Trypanosoma brucei. To enhance our understanding of BES structure and function in host adaptation and immune evasion, the BES repertoire from the Lister 427 strain of T. brucei were independently tagged and sequenced. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of expression site associated genes (ESAGs. The consequences of duplicated or missing ESAGs, including ESAG9, a newly named ESAG12, and additional variant surface glycoprotein genes (VSGs were evaluated by functional assays after BESs were tagged with a drug-resistance gene. Phylogenetic analysis of constituent ESAG families suggests that BESs are sequence mosaics and that extensive recombination has shaped the evolution of the BES repertoire. This work opens important perspectives in understanding the molecular mechanisms of antigenic variation, a widely used strategy for immune evasion in pathogens, and telomere biology.

  13. Genome Organization Drives Chromosome Fragility.

    Canela, Andres; Maman, Yaakov; Jung, Seolkyoung; Wong, Nancy; Callen, Elsa; Day, Amanda; Kieffer-Kwon, Kyong-Rim; Pekowska, Aleksandra; Zhang, Hongliang; Rao, Suhas S P; Huang, Su-Chen; Mckinnon, Peter J; Aplan, Peter D; Pommier, Yves; Aiden, Erez Lieberman; Casellas, Rafael; Nussenzweig, André

    2017-07-27

    In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT. Published by Elsevier Inc.

  14. Component fragility research program

    Tsai, N.C.; Mochizuki, G.L.; Holman, G.S.

    1989-11-01

    To demonstrate how ''high-level'' qualification test data can be used to estimate the ultimate seismic capacity of nuclear power plant equipment, we assessed in detail various electrical components tested by the Pacific Gas ampersand Electric Company for its Diablo Canyon plant. As part of our Phase I Component Fragility Research Program, we evaluated seismic fragility for five Diablo Canyon components: medium-voltage (4kV) switchgear; safeguard relay board; emergency light battery pack; potential transformer; and station battery and racks. This report discusses our Phase II fragility evaluation of a single Westinghouse Type W motor control center column, a fan cooler motor controller, and three local starters at the Diablo Canyon nuclear power plant. These components were seismically qualified by means of biaxial random motion tests on a shaker table, and the test response spectra formed the basis for the estimate of the seismic capacity of the components. The seismic capacity of each component is referenced to the zero period acceleration (ZPA) and, in our Phase II study only, to the average spectral acceleration (ASA) of the motion at its base. For the motor control center, the seismic capacity was compared to the capacity of a Westinghouse Five-Star MCC subjected to actual fragility tests by LLNL during the Phase I Component Fragility Research Program, and to generic capacities developed by the Brookhaven National Laboratory for motor control center. Except for the medium-voltage switchgear, all of the components considered in both our Phase I and Phase II evaluations were qualified in their standard commercial configurations or with only relatively minor modifications such as top bracing of cabinets. 8 refs., 67 figs., 7 tabs

  15. Expression and site-directed mutagenesis of human dihydrofolate reductase

    Prendergast, N.J.; Delcamp, T.J.; Smith, P.L.; Freisheim, J.H.

    1988-05-17

    A procaryotic high-level expression vector for human dihydrofolate reductase has been constructed and the protein characterized as a first step toward structure-function studies of this enzyme. A vector bearing the tac promoter, four synthetic oligodeoxynucleotides, and a restriction fragment from the dihydrofolate reductase cDNA were ligated in a manner which optimized the transcriptional and translational frequency of the enzyme mRNA. The reductase, comprising ca. 17% of the total soluble protein in the host bacteria, was purified to apparent homogeneity as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and characterized by amino acid composition, partial amino acid sequence, and steady-sate kinetic analysis. This expression vector has been used as a template for double-stranded plasmid DNA site-specific mutagenesis. Functional studies on a Cys-6 ..-->.. Ser-6 mutant enzyme support the contention that Cys-6 is obligatory for organomercurial activation of human dihydrofolate reductase. The Ser-6 mutant enzyme was not activated to any extent following a 24-h incubation with p-(hydroxymercuri)benzoate and nicotinamide adenine dinucleotide phosphate (reduced) (NADPH), whereas the k/sub cat/ for Cys-6 reductase increased 2-fold under identical conditions. The specific activities of the Cys-6 and Ser-6 enzymes were virtually identical as determined by methotrexate titration as were the K/sub m/ values for both dihydrofolate and NADPH. The Ser-6 mutant showed a decreased temperature stability and was more sensitive to inactivation by ..cap alpha..-chymotrypsin when compared to the wild-type enzyme. These results suggest that the Ser-6 mutant reductase is conformationally altered relative to the Cys-6 native enzyme.

  16. Expression and site-directed mutagenesis of human dihydrofolate reductase

    Prendergast, N.J.; Delcamp, T.J.; Smith, P.L.; Freisheim, J.H.

    1988-01-01

    A procaryotic high-level expression vector for human dihydrofolate reductase has been constructed and the protein characterized as a first step toward structure-function studies of this enzyme. A vector bearing the tac promoter, four synthetic oligodeoxynucleotides, and a restriction fragment from the dihydrofolate reductase cDNA were ligated in a manner which optimized the transcriptional and translational frequency of the enzyme mRNA. The reductase, comprising ca. 17% of the total soluble protein in the host bacteria, was purified to apparent homogeneity as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and characterized by amino acid composition, partial amino acid sequence, and steady-sate kinetic analysis. This expression vector has been used as a template for double-stranded plasmid DNA site-specific mutagenesis. Functional studies on a Cys-6 → Ser-6 mutant enzyme support the contention that Cys-6 is obligatory for organomercurial activation of human dihydrofolate reductase. The Ser-6 mutant enzyme was not activated to any extent following a 24-h incubation with p-(hydroxymercuri)benzoate and nicotinamide adenine dinucleotide phosphate (reduced) (NADPH), whereas the k/sub cat/ for Cys-6 reductase increased 2-fold under identical conditions. The specific activities of the Cys-6 and Ser-6 enzymes were virtually identical as determined by methotrexate titration as were the K/sub m/ values for both dihydrofolate and NADPH. The Ser-6 mutant showed a decreased temperature stability and was more sensitive to inactivation by α-chymotrypsin when compared to the wild-type enzyme. These results suggest that the Ser-6 mutant reductase is conformationally altered relative to the Cys-6 native enzyme

  17. Seismic fragility analyses

    Kostov, Marin

    2000-01-01

    In the last two decades there is increasing number of probabilistic seismic risk assessments performed. The basic ideas of the procedure for performing a Probabilistic Safety Analysis (PSA) of critical structures (NUREG/CR-2300, 1983) could be used also for normal industrial and residential buildings, dams or other structures. The general formulation of the risk assessment procedure applied in this investigation is presented in Franzini, et al., 1984. The probability of failure of a structure for an expected lifetime (for example 50 years) can be obtained from the annual frequency of failure, β E determined by the relation: β E ∫[d[β(x)]/dx]P(flx)dx. β(x) is the annual frequency of exceedance of load level x (for example, the variable x may be peak ground acceleration), P(fI x) is the conditional probability of structure failure at a given seismic load level x. The problem leads to the assessment of the seismic hazard β(x) and the fragility P(fl x). The seismic hazard curves are obtained by the probabilistic seismic hazard analysis. The fragility curves are obtained after the response of the structure is defined as probabilistic and its capacity and the associated uncertainties are assessed. Finally the fragility curves are combined with the seismic loading to estimate the frequency of failure for each critical scenario. The frequency of failure due to seismic event is presented by the scenario with the highest frequency. The tools usually applied for probabilistic safety analyses of critical structures could relatively easily be adopted to ordinary structures. The key problems are the seismic hazard definitions and the fragility analyses. The fragility could be derived either based on scaling procedures or on the base of generation. Both approaches have been presented in the paper. After the seismic risk (in terms of failure probability) is assessed there are several approaches for risk reduction. Generally the methods could be classified in two groups. The

  18. Seismic fragility of nuclear power plant components (Phase II)

    Bandyopadhyay, K.K.; Hofmayer, C.H.; Kassir, M.K.; Pepper, S.E.

    1990-02-01

    As part of the Component Fragility Program which was initiated in FY 1985, three additional equipment classes have been evaluated. This report contains the fragility results and discussions on these equipment classes which are switchgear, I and C panels and relays. Both low and medium voltage switchgear assemblies have been considered and a separate fragility estimate for each type is provided. Test data on cabinets from the nuclear instrumentation/neutron monitoring system, plant/process protection system, solid state protective system and engineered safeguards test system comprise the BNL data base for I and C panels (NSSS). Fragility levels have been determined for various failure modes of switchgear and I ampersand C panels, and the deterministic results are presented in terms of test response spectra. In addition, the test data have been evaluated for estimating the respective probabilistic fragility levels which are expressed in terms of a median value, an uncertainty coefficient, a randomness coefficient and an HCLPF value. Due to a wide variation of relay design and the fragility level, a generic fragility level cannot be established for relays. 7 refs., 13 figs., 12 tabs

  19. Fluorescent in-situ hybridization of cattle and sheep chromosomes with cloned human fragile-X DNA

    Ali, Ahmd; Thomsen, Preben Dybdahl; Babar, M.E.

    2009-01-01

    An extensive study on spontaneous and 5-Fluorodeoxyuridine induced fragile sites identified Xq31 in cattle (Bos taurus) and (Xq24, Xq26) in sheep (Ovis aries) in addition to several autosomal fragile sites (under publication). A ZOO-FISH study using three cloned human fragile-X probes with CCG....../CGG(n) trinucleotide repeat sequence was carried out to determine homology between human and bovine fragile-X. The hybridisation results showed only a weak signal on a human chromosome that was not an X with all three fragile site probes. No signals were detected in sheep chromosomes. The signal of all three human...... fragile-X probes on cattle chromosomes was however, medium-prominent sub-centromeric signal on two homologues. BrdU administration in 12 h before harvesting identified these homologues to be chromosome number 5. In addition retrospective slides of cattle and sheep chromosomes used for fragile site studies...

  20. Genetics Home Reference: fragile X syndrome

    ... Facebook Twitter Home Health Conditions Fragile X syndrome Fragile X syndrome Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Fragile X syndrome is a genetic condition that causes a ...

  1. Breastfeeding of a medically fragile foster child.

    Gribble, Karleen D

    2005-02-01

    A case is presented in which a medically fragile baby was breastfed by her foster mother. As a result, the child's physical and emotional health were improved. The mechanisms whereby human milk improves health are well known. The act of breastfeeding may also have an analgesic and relaxant effect as a result of hormonal influences and skin-to-skin contact. Many foster babies may benefit from human milk or breastfeeding. However, the risk of disease transmission must be minimized. Provision of human milk to all medically fragile foster babies is desirable. Breastfeeding by the foster mother may be applicable in cases in which the child is likely to be in long-term care, the child has been previously breastfed, or the child's mother expresses a desire that the infant be breastfed. However, social barriers must be overcome before breastfeeding of foster babies can become more common.

  2. Fragile Thermodynamic Order

    Bernhoeft, N.; Lander, G.H.; Colineau, E.

    2003-01-01

    An asymmetric shift in the position of the magnetic Bragg peak with respect to the fiducial lattice has been observed by resonant X-ray scattering in a diverse series of antiferromagnetic compounds. This apparent violation of Bragg's law is interpreted in terms of a dynamically phased order parameter. We demonstrate the use of this effect as a novel probe of fragile or dynamic thermodynamic order in strongly correlated electronic systems. In particular, fresh light is shed on the paradoxical situation encountered in URu 2 Si 2 where the measured entropy gain on passing through T Neel is incompatible with the ground state moment estimated by neutron diffraction. The intrinsic space-time averaging of the probe used to characterise the thermodynamic macroscopic state may play a crucial and previously neglected role. In turn, this suggests the further use of resonant X-ray scattering in investigations of systems dominated by quantum fluctuations. (author)

  3. The promoter for a variant surface glycoprotein gene expression site in Trypanosoma brucei

    Zomerdijk, J. C.; Ouellette, M.; ten Asbroek, A. L.; Kieft, R.; Bommer, A. M.; Clayton, C. E.; Borst, P.

    1990-01-01

    The variant-specific surface glycoprotein (VSG) gene 221 of Trypanosoma brucei is transcribed as part of a 60 kb expression site (ES). We have identified the promoter controlling this multigene transcription unit by the use of 221 chromosome-enriched DNA libraries and VSG gene 221 expression site

  4. Flooding Fragility Experiments and Prediction

    Smith, Curtis L. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Tahhan, Antonio [Idaho National Lab. (INL), Idaho Falls, ID (United States); Muchmore, Cody [Idaho National Lab. (INL), Idaho Falls, ID (United States); Nichols, Larinda [Idaho National Lab. (INL), Idaho Falls, ID (United States); Bhandari, Bishwo [Idaho National Lab. (INL), Idaho Falls, ID (United States); Pope, Chad [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-09-01

    This report describes the work that has been performed on flooding fragility, both the experimental tests being carried out and the probabilistic fragility predictive models being produced in order to use the text results. Flooding experiments involving full-scale doors have commenced in the Portal Evaluation Tank. The goal of these experiments is to develop a full-scale component flooding experiment protocol and to acquire data that can be used to create Bayesian regression models representing the fragility of these components. This work is in support of the Risk-Informed Safety Margin Characterization (RISMC) Pathway external hazards evaluation research and development.

  5. Chromosome fragility at FRAXA in human cleavage stage embryos at risk for fragile X syndrome.

    Verdyck, Pieter; Berckmoes, Veerle; De Vos, Anick; Verpoest, Willem; Liebaers, Inge; Bonduelle, Maryse; De Rycke, Martine

    2015-10-01

    Fragile X syndrome (FXS), the most common inherited intellectual disability syndrome, is caused by expansion and hypermethylation of the CGG repeat in the 5' UTR of the FMR1 gene. This expanded repeat, also known as the rare fragile site FRAXA, causes X chromosome fragility in cultured cells from patients but only when induced by perturbing pyrimidine synthesis. We performed preimplantation genetic diagnosis (PGD) on 595 blastomeres biopsied from 442 cleavage stage embryos at risk for FXS using short tandem repeat (STR) markers. In six blastomeres, from five embryos an incomplete haplotype was observed with loss of all alleles telomeric to the CGG repeat. In all five embryos, the incomplete haplotype corresponded to the haplotype carrying the CGG repeat expansion. Subsequent analysis of additional blastomeres from three embryos by array comparative genomic hybridization (aCGH) confirmed the presence of a terminal deletion with a breakpoint close to the CGG repeat in two blastomeres from one embryo. A blastomere from another embryo showed the complementary duplication. We conclude that a CGG repeat expansion at FRAXA causes X chromosome fragility in early human IVF embryos at risk for FXS. © 2015 Wiley Periodicals, Inc.

  6. Modeling Fragile X Syndrome in Drosophila

    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

  7. Incarceration in fragile families.

    Wildeman, Christopher; Western, Bruce

    2010-01-01

    Since the mid-1970s the U.S. imprisonment rate has increased roughly fivefold. As Christopher Wildeman and Bruce Western explain, the effects of this sea change in the imprisonment rate--commonly called mass imprisonment or the prison boom--have been concentrated among those most likely to form fragile families: poor and minority men with little schooling. Imprisonment diminishes the earnings of adult men, compromises their health, reduces familial resources, and contributes to family breakup. It also adds to the deficits of poor children, thus ensuring that the effects of imprisonment on inequality are transferred intergenerationally. Perversely, incarceration has its most corrosive effects on families whose fathers were involved in neither domestic violence nor violent crime before being imprisoned. Because having a parent go to prison is now so common for poor, minority children and so negatively affects them, the authors argue that mass imprisonment may increase future racial and class inequality--and may even lead to more crime in the long-term, thereby undoing any benefits of the prison boom. U.S. crime policy has thus, in the name of public safety, produced more vulnerable families and reduced the life chances of their children. Wildeman and Western advocate several policy reforms, such as limiting prison time for drug offenders and for parolees who violate the technical conditions of their parole, reconsidering sentence enhancements for repeat offenders, and expanding supports for prisoners and ex-prisoners. But Wildeman and Western argue that criminal justice reform alone will not solve the problems of school failure, joblessness, untreated addiction, and mental illness that pave the way to prison. In fact, focusing solely on criminal justice reforms would repeat the mistakes the nation made during the prison boom: trying to solve deep social problems with criminal justice policies. Addressing those broad problems, they say, requires a greater social

  8. International Companies in Fragile States

    Patey, Luke; Kragelund, Peter

    Denmark must not fail to promote corporate social responsibility in fragile states. International companies remain active in these environments, and often worsen rather than alleviate poor governance. Financial transparency and human rights initiatives offer the first step in ensuring...

  9. Shocks in fragile matter

    Vitelli, Vincenzo

    2012-02-01

    Non-linear sound is an extreme phenomenon typically observed in solids after violent explosions. But granular media are different. Right when they unjam, these fragile and disordered solids exhibit vanishing elastic moduli and sound speed, so that even tiny mechanical perturbations form supersonic shocks. Here, we perform simulations in which two-dimensional jammed granular packings are continuously compressed, and demonstrate that the resulting excitations are strongly nonlinear shocks, rather than linear waves. We capture the full dependence of the shock speed on pressure and compression speed by a surprisingly simple analytical model. We also treat shear shocks within a simplified viscoelastic model of nearly-isostatic random networks comprised of harmonic springs. In this case, anharmonicity does not originate locally from nonlinear interactions between particles, as in granular media; instead, it emerges from the global architecture of the network. As a result, the diverging width of the shear shocks bears a nonlinear signature of the diverging isostatic length associated with the loss of rigidity in these floppy networks.

  10. Reduction in the copy number and expression level of the recurrent human papillomavirus integration gene fragile histidine triad (FHIT predicts the transition of cervical lesions.

    Liming Wang

    Full Text Available Cervical cancer is the second most common cancer and the third leading cause of cancer death in females worldwide, especially in developing countries. High risk human papillomavirus (HR-HPV infection causes cervical cancer and precancerous cervical intraepithelial neoplasia (CIN. Integration of the HR-HPV genome into the host chromatin is an important step in cervical carcinogenesis. The detection of integrated papillomavirus sequences-PCR (DIPS-PCR allowed us to explore HPV integration in the human genome and to determine the pattern of this integration. We performed DIPS-PCR for 4 cell lines including 3 cervical cancer cell lines and 40 tissue samples. Overall, 32 HR-HPV integration loci were detected in the clinical samples and the HeLa and SiHa cell lines. Among all the integration loci, we identified three recurrent integration loci: 3p14.2 (3 samples, 13q22.1 (2 samples and a SiHa cell line and 8q24 (1 sample and a HeLa cell line. To further explore the effect of HR-HPV integration in the 3p14.2 locus, we used fluorescence in situ hybridization (FISH to determine the copy number of the 3p14.2 locus and immunohistochemistry (IHC to determine the protein expression levels of the related FHIT gene in the clinical samples. Both the 3p14.2 locus copy number and FHIT protein expression levels showed significant decreases when CIN transitioned to cervical cancer. HPV copy number was also evaluated in these clinical samples, and the copy number of HPV increased significantly between CIN and cervical cancer samples. Finally, we employed receiver operating characteristic curve (ROC curve analysis to evaluate the potential of all these indexes in distinguishing CIN and cervical cancer, and the HPV copy number, FHIT copy number and FHIT protein expression levels have good diagnostic efficiencies.

  11. The Seismic Fragility Evaluation of an Offsite Transformer according to Aging Effects

    Kim, Min Kyu; Choi, In Kil

    2008-01-01

    A seismic fragility analysis was performed, especially for an aged electric power transmission system, in this study. A real electric transformer system for Korean Nuclear Power Plants was selected for the seismic fragility evaluation. In the case of a seismic fragility analysis we should use design material properties and conditions. However material properties and environmental conditions of most structures and equipment are changed according to a lapse of time. Aging conditions greatly affect the integrity of the structures and equipment at NPP sites, but it is very difficult to estimate them qualitatively. Integrity of an anchor bolt system was considered with the aging conditions for an electric transformer system. At first, a seismic fragility analysis was performed for a fine condition for an electric transformer system. After that, a seismic fragility analysis according to the fastener of an anchor bolt system was conducted. This study showed that a looser anchor bolt creates seismic responses and seismic fragility changes of more 10%

  12. 75 FR 49526 - Halliburton Company, Duncan Mfg., Including On-Site Leased Workers from Express Personnel...

    2010-08-13

    ... Company, Duncan Mfg., Including On-Site Leased Workers from Express Personnel, Clayton Personnel Service, and Manpower Planning, Duncan, OK; Halliburton Company, Technology and Engineering Division, Finance... Halliburton Company, Technology and Engineering Division, and Finance and Administration Division, Duncan...

  13. Expression of antibacterial resistance at the site of a delayed hypersensitivity reaction.

    Patel, P J

    1980-01-01

    The site of a delayed hypersensitivity reaction to tuberculin or bovine serum ablumin was shown to contain mechanisms that expressed increased antibacterial activity, as evidenced by restricted growth of a local inoculum of Listeria monocytogenes. As was the case with a delayed hypersensitivity reaction, the local generation of antibacterial activity was antigen specific and T-cell dependent. Antibacterial resistance was always expressed at the site of injection of specific antigen in sensiti...

  14. Handbook of nuclear power plant seismic fragilities, Seismic Safety Margins Research Program

    Cover, L.E.; Bohn, M.P.; Campbell, R.D.; Wesley, D.A.

    1983-12-01

    The Seismic Safety Margins Research Program (SSMRP) has a gola to develop a complete fully coupled analysis procedure (including methods and computer codes) for estimating the risk of an earthquake-induced radioactive release from a commercial nuclear power plant. As part of this program, calculations of the seismic risk from a typical commercial nuclear reactor were made. These calculations required a knowledge of the probability of failure (fragility) of safety-related components in the reactor system which actively participate in the hypothesized accident scenarios. This report describes the development of the required fragility relations and the data sources and data reduction techniques upon which they are based. Both building and component fragilities are covered. The building fragilities are for the Zion Unit 1 reactor which was the specific plant used for development of methodology in the program. Some of the component fragilities are site-specific also, but most would be usable for other sites as well

  15. Normal RNAi response in human fragile x fibroblasts

    Madsen, Charlotte; Grønskov, Karen; Brøndum-Nielsen, Karen

    2009-01-01

    BACKGROUND: Fragile x syndrome is caused by loss of expression of the FMRP protein involved in the control of a large number of mRNA targets. The Drosophila ortholog dFXR interacts with a protein complex that includes Argonaute2, an essential component of the RNA-induced silencing complex (RISC...

  16. Seismic fragility capacity of equipment

    Iijima, Toru; Abe, Hiroshi; Suzuki, Kenichi

    2006-01-01

    Seismic probabilistic safety assessment (PSA) is an available method to evaluate residual risks of nuclear plants that are designed on definitive seismic conditions. From our preliminary seismic PSA analysis, horizontal shaft pumps are important components that have significant influences on the core damage frequency (CDF). An actual horizontal shaft pump and some kinds of elements were tested to evaluate realistic fragility capacities. Our test results showed that the realistic fragility capacity of horizontal shaft pump would be at least four times as high as a current value, 1.6 x 9.8 m/s 2 , used for our seismic PSA. We are going to incorporate the fragility capacity data that were obtained from those tests into our seismic PSA analysis, and we expect that the reliability of seismic PSA should increase. (author)

  17. Resilience and the Fragile City

    John de Boer

    2015-04-01

    Full Text Available Humanitarian, security, and development actors are witnessing two distinct but intertwined trends that will have a dramatic impact on their operations. The first relates to the fact that the locus of global poverty and vulnerability to disaster are increasingly concentrated in fragile and conflict affected states. The second trend is associated with the notion that the world has entered a period of unprecedented urbanization. For the first time in history, more people live inside urban centres than outside of them. As the world continues to urbanize, global emergencies will increasingly be concentrated in cities, particularly in lower income and fragile countries where the pace of urbanization is fastest. Yet, despite the growing risks facing urban populations living in fragile and conflict affected countries, there is very little understanding of what can be done to reduce the risks posed to these cities and their populations.

  18. Developing empirical collapse fragility functions for global building types

    Jaiswal, K.; Wald, D.; D'Ayala, D.

    2011-01-01

    Building collapse is the dominant cause of casualties during earthquakes. In order to better predict human fatalities, the U.S. Geological Survey’s Prompt Assessment of Global Earthquakes for Response (PAGER) program requires collapse fragility functions for global building types. The collapse fragility is expressed as the probability of collapse at discrete levels of the input hazard defined in terms of macroseismic intensity. This article provides a simple procedure for quantifying collapse fragility using vulnerability criteria based on the European Macroseismic Scale (1998) for selected European building types. In addition, the collapse fragility functions are developed for global building types by fitting the beta distribution to the multiple experts’ estimates for the same building type (obtained from EERI’s World Housing Encyclopedia (WHE)-PAGER survey). Finally, using the collapse probability distributions at each shaking intensity level as a prior and field-based collapse-rate observations as likelihood, it is possible to update the collapse fragility functions for global building types using the Bayesian procedure.

  19. Autism Spectrum Disorder and Fragile X Syndrome

    ... only after another family member has been diagnosed. Autism Spectrum Disorder and Fragile X Syndrome Fragile X syndrome is ... gene cause of ASD What Is Autism Spectrum Disorder? Autism spectrum disorder (ASD) is a behavioral diagnosis. The range ...

  20. Effective updating process of seismic fragilities using Bayesian method and information entropy

    Kato, Masaaki; Takata, Takashi; Yamaguchi, Akira

    2008-01-01

    Seismic probabilistic safety assessment (SPSA) is an effective method for evaluating overall performance of seismic safety of a plant. Seismic fragilities are estimated to quantify the seismically induced accident sequences. It is a great concern that the SPSA results involve uncertainties, a part of which comes from the uncertainty in the seismic fragility of equipment and systems. A straightforward approach to reduce the uncertainty is to perform a seismic qualification test and to reflect the results on the seismic fragility estimate. In this paper, we propose a figure-of-merit to find the most cost-effective condition of the seismic qualification tests about the acceleration level and number of components tested. Then a mathematical method to reflect the test results on the fragility update is developed. A Bayesian method is used for the fragility update procedure. Since a lognormal distribution that is used for the fragility model does not have a Bayes conjugate function, a parameterization method is proposed so that the posterior distribution expresses the characteristics of the fragility. The information entropy is used as the figure-of-merit to express importance of obtained evidence. It is found that the information entropy is strongly associated with the uncertainty of the fragility. (author)

  1. Systems fragility: The sociology of chaos.

    Hodges, Lori R

    2016-01-01

    This article examines the concept of community fragility in emergency management from a systems perspective. Using literature that addresses fragility in four areas of complex systems, including ecosystems, social systems, sociotechnical systems, and complex adaptive systems, a theoretical framework focused on the emergency management field is created. These findings illustrate how community fragility factors can be used in the emergency management field to not only improve overall outcomes after disaster but also build less fragile systems and communities in preparation for future disasters.

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

    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.

  3. Msx1 is expressed in retina endothelial cells at artery branching sites

    Miguel Lopes

    2012-02-01

    Msx1 and Msx2 encode homeodomain transcription factors that play a role in several embryonic developmental processes. Previously, we have shown that in the adult mouse, Msx1lacZ is expressed in vascular smooth muscle cells (VSMCs and pericytes, and that Msx2lacZ is also expressed in VSMCs as well as in a few endothelial cells (ECs. The mouse retina and choroid are two highly vascularized tissues. Vessel alterations in the retina are associated with several human diseases and the retina has been intensely used for angiogenesis studies, whereas the choroid has been much less investigated. Using the Msx1lacZ and Msx2lacZ reporter alleles, we observed that Msx2 is not expressed in the eye vascular tree in contrast to Msx1, for which we establish the spatial and temporal expression pattern in these tissues. In the retina, expression of Msx1 takes place from P3, and by P10, it becomes confined to a subpopulation of ECs at branching points of superficial arterioles. These branching sites are characterized by a subpopulation of mural cells that also show specific expression programs. Specific Msx gene inactivation in the endothelium, using Msx1 and Msx2 conditional mutant alleles together with a Tie2-Cre transgene, did not lead to conspicuous structural defects in the retinal vascular network. Expression of Msx1 at branching sites might therefore be linked to vessel physiology. The retinal blood flow is autonomously regulated and perfusion of capillaries has been proposed to depend on arteriolar precapillary structures that might be the sites for Msx1 expression. On the other hand, branching sites are subject to shear stress that might induce Msx1 expression. In the choroid vascular layer Msx1lacZ is expressed more broadly and dynamically. At birth Msx1lacZ expression takes place in the endothelium but at P21 its expression has shifted towards the mural layer. We discuss the possible functions of Msx1 in the eye vasculature.

  4. Msx1 is expressed in retina endothelial cells at artery branching sites.

    Lopes, Miguel; Goupille, Olivier; Saint Cloment, Cécile; Robert, Benoît

    2012-04-15

    Msx1 and Msx2 encode homeodomain transcription factors that play a role in several embryonic developmental processes. Previously, we have shown that in the adult mouse, Msx1(lacZ) is expressed in vascular smooth muscle cells (VSMCs) and pericytes, and that Msx2(lacZ) is also expressed in VSMCs as well as in a few endothelial cells (ECs). The mouse retina and choroid are two highly vascularized tissues. Vessel alterations in the retina are associated with several human diseases and the retina has been intensely used for angiogenesis studies, whereas the choroid has been much less investigated. Using the Msx1(lacZ) and Msx2(lacZ) reporter alleles, we observed that Msx2 is not expressed in the eye vascular tree in contrast to Msx1, for which we establish the spatial and temporal expression pattern in these tissues. In the retina, expression of Msx1 takes place from P3, and by P10, it becomes confined to a subpopulation of ECs at branching points of superficial arterioles. These branching sites are characterized by a subpopulation of mural cells that also show specific expression programs. Specific Msx gene inactivation in the endothelium, using Msx1 and Msx2 conditional mutant alleles together with a Tie2-Cre transgene, did not lead to conspicuous structural defects in the retinal vascular network. Expression of Msx1 at branching sites might therefore be linked to vessel physiology. The retinal blood flow is autonomously regulated and perfusion of capillaries has been proposed to depend on arteriolar precapillary structures that might be the sites for Msx1 expression. On the other hand, branching sites are subject to shear stress that might induce Msx1 expression. In the choroid vascular layer Msx1(lacZ) is expressed more broadly and dynamically. At birth Msx1(lacZ) expression takes place in the endothelium but at P21 its expression has shifted towards the mural layer. We discuss the possible functions of Msx1 in the eye vasculature.

  5. Positron Emission Tomography (PET Quantification of GABAA Receptors in the Brain of Fragile X Patients.

    Charlotte D'Hulst

    Full Text Available Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS, a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

  6. Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma.

    Ahmed, Ikhlak; Karedath, Thasni; Andrews, Simeon S; Al-Azwani, Iman K; Mohamoud, Yasmin Ali; Querleu, Denis; Rafii, Arash; Malek, Joel A

    2016-06-14

    Recently, a class of endogenous species of RNA called circular RNA (circRNA) has been shown to regulate gene expression in mammals and their role in cellular function is just beginning to be understood. To investigate the role of circRNAs in ovarian cancer, we performed paired-end RNA sequencing of primary sites, peritoneal and lymph node metastases from three patients with stage IIIC ovarian cancer. We developed an in-house computational pipeline to identify and characterize the circRNA expression from paired-end RNA-Seq libraries. This pipeline revealed thousands of circular isoforms in Epithelial Ovarian Carcinoma (EOC). These circRNAs are enriched for potentially effective miRNA seed matches. A significantly larger number of circRNAs are differentially expressed between tumor sites than mRNAs. Circular and linear expression exhibits an inverse trend for many cancer related pathways and signaling pathways like NFkB, PI3k/AKT and TGF-β typically activated for mRNA in metastases are inhibited for circRNA expression. Further, circRNAs show a more robust expression pattern across patients than mRNA forms indicating their suitability as biomarkers in highly heterogeneous cancer transcriptomes. The consistency of circular RNA expression may offer new candidates for cancer treatment and prognosis.

  7. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS

    Babcock, Alicia A; Kuziel, William A; Rivest, Serge

    2003-01-01

    Innate responses in the CNS are critical to first line defense against infection and injury. Leukocytes migrate to inflammatory sites in response to chemokines. We studied leukocyte migration and glial chemokine expression within the denervated hippocampus in response to axonal injury caused by e...

  8. Preserved entropy and fragile magnetism.

    Canfield, Paul C; Bud'ko, Sergey L

    2016-08-01

    A large swath of quantum critical and strongly correlated electron systems can be associated with the phenomena of preserved entropy and fragile magnetism. In this overview we present our thoughts and plans for the discovery and development of lanthanide and transition metal based, strongly correlated systems that are revealed by suppressed, fragile magnetism, quantum criticality, or grow out of preserved entropy. We will present and discuss current examples such as YbBiPt, YbAgGe, YbFe2Zn20, PrAg2In, BaFe2As2, CaFe2As2, LaCrSb3 and LaCrGe3 as part of our motivation and to provide illustrative examples.

  9. Financial Liberalization and Financial Fragility

    Enrica Detragiache; Asli Demirgüç-Kunt

    1998-01-01

    The authors study the empirical relationship between banking crises and financial liberalization using a panel of data for 53 countries for 1980-95. They find that banking crises are more likely to occur in liberalized financial systems. But financial liberalization's impact on a fragile banking sector is weaker where the institutional environment is strong--especially where there is respect for the rule of law, a low level of corruption, and good contract enforcement. They examine evidence o...

  10. Different modulation by dietary restriction of adipokine expression in white adipose tissue sites in the rat

    Esteve Montserrat

    2009-07-01

    Full Text Available Abstract Background White adipose tissue (WAT is a disperse organ acting as energy storage depot and endocrine/paracrine controlling factor in the management of energy availability and inflammation. WAT sites response under energy-related stress is not uniform. In the present study we have analyzed how different WAT sites respond to limited food restriction as a way to better understand the role of WAT in the pathogenesis of the metabolic syndrome. Methods Overweight male rats had their food intake reduced a 40% compared with free-feeding controls. On day ten, the rats were killed; circulating glucose, insulin, leptin, adiponectin, triacylglycerols and other parameters were measured. The main WAT sites were dissected: mesenteric, retroperitoneal, epididymal and subcutaneous inguinal, which were weighed and frozen. Later all subcutaneous WAT was also dissected and weighed. Samples were used for DNA (cellularity analysis and mRNA extraction and semiquantitarive RT-PCR analysis of specific cytokine gene expressions. Results There was a good correlation between serum leptin and cumulative WAT leptin gene mRNA, but not for adiponectin. Food restriction reduced WAT size, but not its DNA content (except for epididymal WAT. Most cytokines were correlated to WAT site weight, but not to DNA. There was WAT site specialization in the differential expression (and probably secretion of adipokines: subcutaneous WAT showed the highest concentration for leptin, CD68 and MCP-1, mesenteric WAT for TNFα (and both tissues for the interleukins 1β and 6; resistin was highly expressed in subcutaneous and retroperitoneal WAT. Conclusion Food restriction induced different patterns for mesenteric and the other WAT sites, which may be directly related to both the response to intestine-derived energy availability, and an inflammatory-related response. However, retroperitoneal WAT, and to a lower extent, subcutaneous and epididymal, reacted decreasing the expression of

  11. Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand*

    Teasley, Daniel C.; Parajuli, Shankar; Nguyen, Mai; Moore, Hayley R.; Alspach, Elise; Lock, Ying Jie; Honaker, Yuchi; Saharia, Abhishek; Piwnica-Worms, Helen; Stewart, Sheila A.

    2015-01-01

    The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer. PMID:25922071

  12. Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand.

    Teasley, Daniel C; Parajuli, Shankar; Nguyen, Mai; Moore, Hayley R; Alspach, Elise; Lock, Ying Jie; Honaker, Yuchi; Saharia, Abhishek; Piwnica-Worms, Helen; Stewart, Sheila A

    2015-06-12

    The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Post-surgical rehabilitative approach to fragility fractures.

    Gimigliano, F; Iolascon, G; Riccio, I; Frizzi, L; Gimigliano, R

    2013-10-01

    Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. The most frequent sites of fragility fractures are the hip, the distal radius, the spine, the proximal humerus, and the ankle. In most cases, a surgical approach with subsequent rehabilitative treatment is required. The general aims of rehabilitation are to increase functioning and improve patients' activities, participation level, and quality of life.

  14. Seismic component fragility data base for IPEEE

    Bandyopadhyay, K.; Hofmayer, C.

    1990-01-01

    Seismic probabilistic risk assessment or a seismic margin study will require a reliable data base of seismic fragility of various equipment classes. Brookhaven National Laboratory (BNL) has selected a group of equipment and generically evaluated the seismic fragility of each equipment class by use of existing test data. This paper briefly discusses the evaluation methodology and the fragility results. The fragility analysis results when used in the Individual Plant Examination for External Events (IPEEE) Program for nuclear power plants are expected to provide insights into seismic vulnerabilities of equipment for earthquakes beyond the design basis. 3 refs., 1 fig., 1 tab

  15. [The fragility of the self].

    Rubia Vila, Francisco José

    2002-01-01

    This presentation raises the hypothesis that the "self" is a construction of the brain and extremely fragile. In order to support this statement, Prof. Rubia provides three different reasonings: firstly, we are not borne with the "self", but rather it is the result of development during childhood; secondly, the self is subject to cultural influences, so that the perception of this "self" or of the own personality varies according to different cultures. And thirdly, the self is not indivisible, as shown by epileptic patients with a "split-brain" operation, or the psychiatric cases of double personality or the multiple personality disorder.

  16. Divergent effects of obesity on fragility fractures

    Caffarelli C

    2014-09-01

    Full Text Available Carla Caffarelli, Chiara Alessi, Ranuccio Nuti, Stefano Gonnelli Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy Abstract: Obesity was commonly thought to be advantageous for maintaining healthy bones due to the higher bone mineral density observed in overweight individuals. However, several recent studies have challenged the widespread belief that obesity is protective against fracture and have suggested that obesity is a risk factor for certain fractures. The effect of obesity on fracture risk is site-dependent, the risk being increased for some fractures (humerus, ankle, upper arm and decreased for others (hip, pelvis, wrist. Moreover, the relationship between obesity and fracture may also vary by sex, age, and ethnicity. Risk factors for fracture in obese individuals appear to be similar to those in nonobese populations, although patterns of falling are particularly important in the obese. Research is needed to determine if and how visceral fat and metabolic complications of obesity (type 2 diabetes mellitus, insulin resistance, chronic inflammation, etc are causally associated with bone status and fragility fracture risk. Vitamin D deficiency and hypogonadism may also influence fracture risk in obese individuals. Fracture algorithms such as FRAX® might be expected to underestimate fracture probability. Studies specifically designed to evaluate the antifracture efficacy of different drugs in obese patients are not available; however, literature data may suggest that in obese patients higher doses of the bisphosphonates might be required in order to maintain efficacy against nonvertebral fractures. Therefore, the search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with obesity might be considered a clinical priority which could improve the prevention of fracture in obese individuals. Keywords: bone mineral density, BMI

  17. Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.

    Sun, Miao-Kun; Hongpaisan, Jarin; Alkon, Daniel L

    2016-05-01

    Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  18. Financial fragility in the Great Moderation

    Bezemer, Dirk; Grydaki, Maria

    2014-01-01

    A nascent literature explores the measurement of financial fragility. This paper considers evidence for rising financial fragility during the 1984-2007 Great Moderation in the U.S. The literature suggests that macroeconomic stability combined with strong growth of credit to asset markets, in asset

  19. Seismic margins review of nuclear power plants: Fragility aspects

    Ravindra, M.K.; Hardy, G.S.; Hashimoto, P.S.

    1987-01-01

    The fragility analysis is utilised in the seismic margin review in initial screening of certain components in the plant based on their generically high seismic capacities. A detailed walkdown of the plant is conducted to confirm that the initial screening is valid i.e., the generically high seismic capacity components do not possess any potential weaknesses (e.g., inadequate bracing, inadequate anchorage and potential systems interaction). For the components that are screened in, their seismic capacities are evaluated using either a probabilistic analysis of a deterministic evaluation. Based on a system analysis, the Boolean expressions for critical accident sequences are derived. These Boolean expressions are quantified using the component fragilities and nonseismic unavailabilities of components. The final product is the High Confidence Low Probability of Failure (HCLPF) capacity of the plant and the identification of potential seismic vulnerabilities in the plant. The objective of the paper is to describe the application of fragility analysis procedures in the seismic margin review of Maine Yankee and to document the insights obtained in this trial plant review. (orig./HP)

  20. Expression of fra(10)(q25) in peripheral blood and bone marrow in familial neutropenia.

    Holmes, J A; Thompson, P W

    1988-01-01

    We report on the expression of fra(10)(q25) in a mother and daughter with familial chronic neutropenia. Differences in expression of the fragile site in bone marrow cells compared with peripheral blood lymphocytes were observed. Short term bone marrow cultures in complete medium showed high levels of spontaneous expression, whereas in 72 hour stimulated blood cultures it was virtually absent. There were also differences in the types of lesions found; chromosome type lesions predominated in th...

  1. Seismic fragility analyses of nuclear power plant structures based on the recorded earthquake data in Korea

    Cho, Sung Gook; Joe, Yang Hee

    2005-01-01

    By nature, the seismic fragility analysis results will be considerably affected by the statistical data of design information and site-dependent ground motions. The engineering characteristics of small magnitude earthquake spectra recorded in the Korean peninsula during the last several years are analyzed in this paper. An improved method of seismic fragility analysis is evaluated by comparative analyses to verify its efficiency for practical application to nuclear power plant structures. The effects of the recorded earthquake on the seismic fragilities of Korean nuclear power plant structures are also evaluated from the comparative studies. Observing the obtained results, the proposed method is more efficient for the multi-modes structures. The case study results show that seismic fragility analysis based on the Newmark's spectra in Korea might over-estimate the seismic capacities of Korean facilities

  2. Seismic fragility analyses of nuclear power plant structures based on the recorded earthquake data in Korea

    Cho, Sung Gook [Department of Civil and Environmental System Engineering, University of Incheon, 177 Dohwa-dong, Nam-gu, Incheon 402-749 (Korea, Republic of)]. E-mail: sgcho@incheon.ac.kr; Joe, Yang Hee [Department of Civil and Environmental System Engineering, University of Incheon, 177 Dohwa-dong, Nam-gu, Incheon 402-749 (Korea, Republic of)

    2005-08-01

    By nature, the seismic fragility analysis results will be considerably affected by the statistical data of design information and site-dependent ground motions. The engineering characteristics of small magnitude earthquake spectra recorded in the Korean peninsula during the last several years are analyzed in this paper. An improved method of seismic fragility analysis is evaluated by comparative analyses to verify its efficiency for practical application to nuclear power plant structures. The effects of the recorded earthquake on the seismic fragilities of Korean nuclear power plant structures are also evaluated from the comparative studies. Observing the obtained results, the proposed method is more efficient for the multi-modes structures. The case study results show that seismic fragility analysis based on the Newmark's spectra in Korea might over-estimate the seismic capacities of Korean facilities.

  3. Chromosome fragility in Freemartin cattle

    V. Barbieri

    2010-04-01

    Full Text Available The aim of the present study was to verify chromosome fragility in freemartin cattle using chromosome aberration (CA and sister chromatid exchange (SCE tests. A total of eighteen co-twins were investigated. Fourteen animals were identified as cytogenetically chimeric (2n=60, XX/XY while 4 were classified as normal. Freemartin cattle showed a higher percentage of aneuploid cells (18.64% and highly significant statistical differences (P < 0.001 in mean values of gaps (4.53 ± 2.05, chromatid breaks (0.26 ± 0.51, and significant statistical differences (P < 0.005 in mean values of chromosome breaks (0.12 ± 0.43 when compared to 10 control animals from single births (aneuploid cells, 11.20%; gaps, 2.01 ± 1.42; chromatid breaks, 0.05 ± 0.22; chromosome breaks, 0.02 ± 0.14.

  4. Fragile X syndrome: Current insight

    Deepika Delsa Dean

    2016-10-01

    Full Text Available 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 about the pathophysiology of this disease. This lack of knowledge presents the major barrier encountered by the scientific community for early diagnosis and effective treatment. Since early diagnosis has important implication in determining the disease status among members of the family tree so the genetic counseling and supportive therapy get hampered in larger perspective. The present review emphasizes on the recent findings in FXS pathophysiology, therapeutics and technical challenges in molecular diagnosis.

  5. Site-specific proteolytic degradation of IgG monoclonal antibodies expressed in tobacco plants.

    Hehle, Verena K; Lombardi, Raffaele; van Dolleweerd, Craig J; Paul, Mathew J; Di Micco, Patrizio; Morea, Veronica; Benvenuto, Eugenio; Donini, Marcello; Ma, Julian K-C

    2015-02-01

    Plants are promising hosts for the production of monoclonal antibodies (mAbs). However, proteolytic degradation of antibodies produced both in stable transgenic plants and using transient expression systems is still a major issue for efficient high-yield recombinant protein accumulation. In this work, we have performed a detailed study of the degradation profiles of two human IgG1 mAbs produced in plants: an anti-HIV mAb 2G12 and a tumour-targeting mAb H10. Even though they use different light chains (κ and λ, respectively), the fragmentation pattern of both antibodies was similar. The majority of Ig fragments result from proteolytic degradation, but there are only a limited number of plant proteolytic cleavage events in the immunoglobulin light and heavy chains. All of the cleavage sites identified were in the proximity of interdomain regions and occurred at each interdomain site, with the exception of the VL /CL interface in mAb H10 λ light chain. Cleavage site sequences were analysed, and residue patterns characteristic of proteolytic enzymes substrates were identified. The results of this work help to define common degradation events in plant-produced mAbs and raise the possibility of predicting antibody degradation patterns 'a priori' and designing novel stabilization strategies by site-specific mutagenesis. © 2014 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  6. Trypanosoma brucei gambiense adaptation to different mammalian sera is associated with VSG expression site plasticity.

    Cordon-Obras, Carlos; Cano, Jorge; González-Pacanowska, Dolores; Benito, Agustin; Navarro, Miguel; Bart, Jean-Mathieu

    2013-01-01

    Trypanosoma brucei gambiense infection is widely considered an anthroponosis, although it has also been found in wild and domestic animals. Thus, fauna could act as reservoir, constraining the elimination of the parasite in hypo-endemic foci. To better understand the possible maintenance of T. b. gambiense in local fauna and investigate the molecular mechanisms underlying adaptation, we generated adapted cells lines (ACLs) by in vitro culture of the parasites in different mammalian sera. Using specific antibodies against the Variant Surface Glycoproteins (VSGs) we found that serum ACLs exhibited different VSG variants when maintained in pig, goat or human sera. Although newly detected VSGs were independent of the sera used, the consistent appearance of different VSGs suggested remodelling of the co-transcribed genes at the telomeric Expression Site (VSG-ES). Thus, Expression Site Associated Genes (ESAGs) sequences were analysed to investigate possible polymorphism selection. ESAGs 6 and 7 genotypes, encoding the transferrin receptor (TfR), expressed in different ACLs were characterised. In addition, we quantified the ESAG6/7 mRNA levels and analysed transferrin (Tf) uptake. Interestingly, the best growth occurred in pig and human serum ACLs, which consistently exhibited a predominant ESAG7 genotype and higher Tf uptake than those obtained in calf and goat sera. We also detected an apparent selection of specific ESAG3 genotypes in the pig and human serum ACLs, suggesting that other ESAGs could be involved in the host adaptation processes. Altogether, these results suggest a model whereby VSG-ES remodelling allows the parasite to express a specific set of ESAGs to provide selective advantages in different hosts. Finally, pig serum ACLs display phenotypic adaptation parameters closely related to human serum ACLs but distinct to parasites grown in calf and goat sera. These results suggest a better suitability of swine to maintain T. b. gambiense infection supporting

  7. Component fragilities - data collection, analysis and interpretation

    Bandyopadhyay, K.K.; Hofmayer, C.H.

    1986-01-01

    As part of the component fragility research program sponsored by the US Nuclear Regulatory Commission, BNL is involved in establishing seismic fragility levels for various nuclear power plant equipment with emphasis on electrical equipment, by identifying, collecting and analyzing existing test data from various sources. BNL has reviewed approximately seventy test reports to collect fragility or high level test data for switchgears, motor control centers and similar electrical cabinets, valve actuators and numerous electrical and control devices of various manufacturers and models. Through a cooperative agreement, BNL has also obtained test data from EPRI/ANCO. An analysis of the collected data reveals that fragility levels can best be described by a group of curves corresponding to various failure modes. The lower bound curve indicates the initiation of malfunctioning or structural damage, whereas the upper bound curve corresponds to overall failure of the equipment based on known failure modes occurring separately or interactively. For some components, the upper and lower bound fragility levels are observed to vary appreciably depending upon the manufacturers and models. An extensive amount of additional fragility or high level test data exists. If completely collected and properly analyzed, the entire data bank is expected to greatly reduce the need for additional testing to establish fragility levels for most equipment

  8. Discriminating Down Syndrome and Fragile X Syndrome Based on Language Ability

    Finestack, Lizbeth H.; Sterling, Audra M.; Abbeduto, Leonard

    2013-01-01

    This study compared the receptive and expressive language profiles of verbally expressive children and adolescents with Down Syndrome (DS) and those with Fragile X syndrome (FXS) and examined the extent to which these profiles reliably differentiate the diagnostic groups. A total of twenty-four verbal participants with DS (mean age: 12 years),…

  9. RTEL1 Inhibits Trinucleotide Repeat Expansions and Fragility

    Aisling Frizzell

    2014-03-01

    Full Text Available Human RTEL1 is an essential, multifunctional helicase that maintains telomeres, regulates homologous recombination, and helps prevent bone marrow failure. Here, we show that RTEL1 also blocks trinucleotide repeat expansions, the causal mutation for 17 neurological diseases. Increased expansion frequencies of (CTG⋅CAG repeats occurred in human cells following knockdown of RTEL1, but not the alternative helicase Fbh1, and purified RTEL1 efficiently unwound triplet repeat hairpins in vitro. The expansion-blocking activity of RTEL1 also required Rad18 and HLTF, homologs of yeast Rad18 and Rad5. These findings are reminiscent of budding yeast Srs2, which inhibits expansions, unwinds hairpins, and prevents triplet-repeat-induced chromosome fragility. Accordingly, we found expansions and fragility were suppressed in yeast srs2 mutants expressing RTEL1, but not Fbh1. We propose that RTEL1 serves as a human analog of Srs2 to inhibit (CTG⋅CAG repeat expansions and fragility, likely by unwinding problematic hairpins.

  10. RTEL1 inhibits trinucleotide repeat expansions and fragility.

    Frizzell, Aisling; Nguyen, Jennifer H G; Petalcorin, Mark I R; Turner, Katherine D; Boulton, Simon J; Freudenreich, Catherine H; Lahue, Robert S

    2014-03-13

    Human RTEL1 is an essential, multifunctional helicase that maintains telomeres, regulates homologous recombination, and helps prevent bone marrow failure. Here, we show that RTEL1 also blocks trinucleotide repeat expansions, the causal mutation for 17 neurological diseases. Increased expansion frequencies of (CTG⋅CAG) repeats occurred in human cells following knockdown of RTEL1, but not the alternative helicase Fbh1, and purified RTEL1 efficiently unwound triplet repeat hairpins in vitro. The expansion-blocking activity of RTEL1 also required Rad18 and HLTF, homologs of yeast Rad18 and Rad5. These findings are reminiscent of budding yeast Srs2, which inhibits expansions, unwinds hairpins, and prevents triplet-repeat-induced chromosome fragility. Accordingly, we found expansions and fragility were suppressed in yeast srs2 mutants expressing RTEL1, but not Fbh1. We propose that RTEL1 serves as a human analog of Srs2 to inhibit (CTG⋅CAG) repeat expansions and fragility, likely by unwinding problematic hairpins. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

    Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

    2012-01-01

    The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome;…

  12. A dominant control region from the human β-globin locus conferring integration site-independent gene expression.

    Talbot, D.; Collis, P.; Antoniou, Michael; Vidal, M.; Grosveld, Frank; Greaves, David

    1989-01-01

    textabstractThe regulatory elements that determine the expression pattern of a number of eukaryotic genes expressed specifically in certain tissues have been defined and studied in detail. In general, however, the expression conferred by these elements on genes reintroduced into the genomes of cell lines and transgenic animals has turned out to be at a low level relative to that of endogenous genes, and influenced by the chromosomal site of insertion of the exogenous construct. We have previo...

  13. Regulation of CCL2 expression by an upstream TALE homeodomain protein-binding site that synergizes with the site created by the A-2578G SNP.

    Page, Stephen H; Wright, Edward K; Gama, Lucio; Clements, Janice E

    2011-01-01

    CC Chemokine Ligand 2 (CCL2) is a potent chemoattractant produced by macrophages and activated astrocytes during periods of inflammation within the central nervous system. Increased CCL2 expression is correlated with disease progression and severity, as observed in pulmonary tuberculosis, HCV-related liver disease, and HIV-associated dementia. The CCL2 distal promoter contains an A/G polymorphism at position -2578 and the homozygous -2578 G/G genotype is associated with increased CCL2 production and inflammation. However, the mechanisms that contribute to the phenotypic differences in CCL2 expression are poorly understood. We previously demonstrated that the -2578 G polymorphism creates a TALE homeodomain protein binding site (TALE binding site) for PREP1/PBX2 transcription factors. In this study, we identified the presence of an additional TALE binding site 22 bp upstream of the site created by the -2578 G polymorphism and demonstrated the synergistic effects of the two sites on the activation of the CCL2 promoter. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated increased binding of the TALE proteins PREP1 and PBX2 to the -2578 G allele, and binding of IRF1 to both the A and G alleles. The presence of TALE binding sites that form inverted repeats within the -2578 G allele results in increased transcriptional activation of the CCL2 distal promoter while the presence of only the upstream TALE binding site within the -2578 A allele exerts repression of promoter activity.

  14. Using Improved Entropy-Cloud Model to Select High-Speed Railway Express Freight Train Service Sites

    Wencheng Huang

    2017-01-01

    Full Text Available High-speed railway (HSR express freight train service sites selection is critical to the development of China’s Third Party Logistics market. In this paper, we formulate an improved entropy-cloud model based approach to solve the HSR express sites selection problem for the first time. The basic data of the indicators, for example, existing railway network conditions, traffic environment, express freight market demand, and policy, will be used as the inputs. We apply improved entropy method to obtain each subindicator’s weight. The cloud model will be used to select and classify each station under evaluation.

  15. Learning and Behavioral Deficits Associated with the Absence of the Fragile X Mental Retardation Protein: What a Fly and Mouse Model Can Teach Us

    Santos, Ana Rita; Kanellopoulos, Alexandros K.; Bagni, Claudia

    2014-01-01

    The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the "FMR1" gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain…

  16. Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

    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...

  17. Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

    Lalani, Aly-Khan A; Gray, Kathryn P; Albiges, Laurence; Callea, Marcella; Pignon, Jean-Christophe; Pal, Soumitro; Gupta, Mamta; Bhatt, Rupal S; McDermott, David F; Atkins, Michael B; Woude, G F Vande; Harshman, Lauren C; Choueiri, Toni K; Signoretti, Sabina

    2017-11-28

    In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

  18. Trans-acting GC-rich non-coding RNA at var expression site modulates gene counting in malaria parasite.

    Guizetti, Julien; Barcons-Simon, Anna; Scherf, Artur

    2016-11-16

    Monoallelic expression of the var multigene family enables immune evasion of the malaria parasite Plasmodium falciparum in its human host. At a given time only a single member of the 60-member var gene family is expressed at a discrete perinuclear region called the 'var expression site'. However, the mechanism of var gene counting remains ill-defined. We hypothesize that activation factors associating specifically with the expression site play a key role in this process. Here, we investigate the role of a GC-rich non-coding RNA (ncRNA) gene family composed of 15 highly homologous members. GC-rich genes are positioned adjacent to var genes in chromosome-central gene clusters but are absent near subtelomeric var genes. Fluorescence in situ hybridization demonstrates that GC-rich ncRNA localizes to the perinuclear expression site of central and subtelomeric var genes in trans. Importantly, overexpression of distinct GC-rich ncRNA members disrupts the gene counting process at the single cell level and results in activation of a specific subset of var genes in distinct clones. We identify the first trans-acting factor targeted to the elusive perinuclear var expression site and open up new avenues to investigate ncRNA function in antigenic variation of malaria and other protozoan pathogens. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

    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.

  20. Synaptic vesicle dynamic changes in a model of fragile X.

    Broek, Jantine A C; Lin, Zhanmin; de Gruiter, H Martijn; van 't Spijker, Heleen; Haasdijk, Elize D; Cox, David; Ozcan, Sureyya; van Cappellen, Gert W A; Houtsmuller, Adriaan B; Willemsen, Rob; de Zeeuw, Chris I; Bahn, Sabine

    2016-01-01

    Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS.

  1. Relay testing parametric investigation of seismic fragility

    Bandyopadhyay, K.; Hofmayer, C.; Kassir, M.; Pepper, S.

    1989-01-01

    The seismic capacity of most electrical equipment is governed by malfunction of relays. An evaluation of the existing relay test data base at Brookhaven National Laboratory (BNL) has indicated that the seismic fragility of a relay may depend on various parameters related to the design or the input motion. In particular, the electrical mode, contact state, adjustment, chatter duration acceptance limit, and the frequency and the direction of the vibration input have been considered to influence the relay fragility level. For a particular relay type, the dynamics of its moving parts depends on the exact model number and vintage and hence, these parameters may also influence the fragility level. In order to investigate the effect of most of these parameters on the seismic fragility level, BNL has conducted a relay test program. The testing has been performed at Wyle Laboratories. Establishing the correlation between the single frequency fragility test input and the corresponding multifrequency response spectrum (TRS) is also an objective of this test program. This paper discusses the methodology used for testing and presents a brief summary of important test results. 1 ref., 10 figs

  2. Component fragilities. Data collection, analysis and interpretation

    Bandyopadhyay, K.K.; Hofmayer, C.H.

    1985-01-01

    As part of the component fragility research program sponsored by the US NRC, BNL is involved in establishing seismic fragility levels for various nuclear power plant equipment with emphasis on electrical equipment. To date, BNL has reviewed approximately seventy test reports to collect fragility or high level test data for switchgears, motor control centers and similar electrical cabinets, valve actuators and numerous electrical and control devices, e.g., switches, transmitters, potentiometers, indicators, relays, etc., of various manufacturers and models. BNL has also obtained test data from EPRI/ANCO. Analysis of the collected data reveals that fragility levels can best be described by a group of curves corresponding to various failure modes. The lower bound curve indicates the initiation of malfunctioning or structural damage, whereas the upper bound curve corresponds to overall failure of the equipment based on known failure modes occurring separately or interactively. For some components, the upper and lower bound fragility levels are observed to vary appreciably depending upon the manufacturers and models. For some devices, testing even at the shake table vibration limit does not exhibit any failure. Failure of a relay is observed to be a frequent cause of failure of an electrical panel or a system. An extensive amount of additional fregility or high level test data exists

  3. Vulnerability and fragility risk indices for non-renewable resources.

    Miller, Anne E; Steele, Nicholas; Tobin, Benjamin W

    2018-06-02

    Protected areas are tasked with mitigating impacts to a wide range of invaluable resources. These resources are often subject to a variety of potential natural and anthropogenic impacts that require monitoring efforts and management actions to minimize the degradation of these resources. However, due to insufficient funding and staff, managers often have to prioritize efforts, leaving some resources at higher risk to impact. Attempts to address this issue have resulted in numerous qualitative and semi-quantitative frameworks for prioritization based on resource vulnerability. Here, we add to those methods by modifying an internationally standardized vulnerability framework, quantify both resource vulnerability, susceptibility to human disturbance, and fragility, susceptibility to natural disturbance. This modified framework quantifies impacts through a six-step process: identifying the resource and management objectives, identifying exposure and sensitivity indicators, define scoring criteria for each indicator, collect and compile data, calculate indices, and prioritize sites for mitigations. We applied this methodology to two resource types in Grand Canyon National Park (GRCA): caves and fossil sites. Three hundred sixty-five cave sites and 127 fossil sites in GRCA were used for this analysis. The majority of cave and fossil sites scored moderate to low vulnerability (0-6 out of 10 points) and moderate to low fragility for fossils. The percentage of sites that fell in the high-priority range was 5.5% for fossils and 21.9% for caves. These results are consistent with the known state of these resources and the results present a tool for managers to utilize to prioritize monitoring and management needs.

  4. Transcription-replication conflicts at chromosomal fragile sites—consequences in M phase and beyond

    Østergaard, Vibe Hallundbæk; Lisby, Michael

    2017-01-01

    transcription and replication patterns. At the same time, these chromosomal fragile sites engage in aberrant DNA structures in mitosis. Here, we discuss the mechanistic details of transcription–replication conflicts including putative scenarios for R-loop-induced replication inhibition to understand how...... transcription–replication conflicts transition from S phase into various aberrant DNA structures in mitosis....

  5. Language Development in School-Age Girls with Fragile X Syndrome

    Sterling, A.; Abbeduto, L.

    2012-01-01

    Background: Girls with fragile X syndrome (FXS) have a wide range of cognitive and language abilities. The range of language outcomes experienced by girls with FXS, however, has been relatively unexplored. The purpose of this exploratory study was to examine receptive and expressive language, with a focus on vocabulary and syntax, in a group of…

  6. Kerr black holes are not fragile

    McInnes, Brett, E-mail: matmcinn@nus.edu.sg [Centro de Estudios Cientificos (CECs), Valdivia (Chile); National University of Singapore (Singapore)

    2012-04-21

    Certain AdS black holes are 'fragile', in the sense that, if they are deformed excessively, they become unstable to a fundamental non-perturbative stringy effect analogous to Schwinger pair-production [of branes]. Near-extremal topologically spherical AdS-Kerr black holes, which are natural candidates for string-theoretic models of the very rapidly rotating black holes that have actually been observed to exist, do represent a very drastic deformation of the AdS-Schwarzschild geometry. One therefore has strong reason to fear that these objects might be 'fragile', which in turn could mean that asymptotically flat rapidly rotating black holes might be fragile in string theory. Here we show that this does not happen: despite the severe deformation implied by near-extremal angular momenta, brane pair-production around topologically spherical AdS-Kerr-Newman black holes is always suppressed.

  7. Melanoma transition is frequently accompanied by a loss of cytoglobin expression in melanocytes: a novel expression site of cytoglobin.

    Yoshihiko Fujita

    Full Text Available The tissue distribution and function of hemoglobin or myoglobin are well known; however, a newly found cytoglobin (CYGB, which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2'-, 7'-dichlorofluorescein diacetate (DCFH-DA, an indicator of reactive oxygen species (ROS, revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition.

  8. Initiation of genome instability and preneoplastic processes through loss of Fhit expression.

    Joshua C Saldivar

    Full Text Available Genomic instability drives tumorigenesis, but how it is initiated in sporadic neoplasias is unknown. In early preneoplasias, alterations at chromosome fragile sites arise due to DNA replication stress. A frequent, perhaps earliest, genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus, leading to loss of Fhit protein expression. Because common chromosome fragile sites are exquisitely sensitive to replication stress, it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products. Here, we show in normal, transformed, and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks. Using DNA combing, we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse. The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels; notably, restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells. Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest, allowing continued cell proliferation and ongoing chromosomal instability. This finding was in accord with in vivo studies, as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci. Furthermore, cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications, including amplification of the Mdm2 gene, suggesting that Fhit loss-induced genome instability facilitates transformation. We propose that loss of Fhit expression in precancerous lesions is the first step in the

  9. Fragile X mental retardation protein participates in non-coding RNA pathways.

    Li, En-Hui; Zhao, Xin; Zhang, Ce; Liu, Wei

    2018-02-20

    Fragile X syndrome is one of the most common forms of inherited intellectual disability. It is caused by mutations of the Fragile X mental retardation 1(FMR1) gene, resulting in either the loss or abnormal expression of the Fragile X mental retardation protein (FMRP). Recent research showed that FMRP participates in non-coding RNA pathways and plays various important roles in physiology, thereby extending our knowledge of the pathogenesis of the Fragile X syndrome. Initial studies showed that the Drosophila FMRP participates in siRNA and miRNA pathways by interacting with Dicer, Ago1 and Ago2, involved in neural activity and the fate determination of the germline stem cells. Subsequent studies showed that the Drosophila FMRP participates in piRNA pathway by interacting with Aub, Ago1 and Piwi in the maintenance of normal chromatin structures and genomic stability. More recent studies showed that FMRP is associated with lncRNA pathway, suggesting a potential role for the involvement in the clinical manifestations. In this review, we summarize the novel findings and explore the relationship between FMRP and non-coding RNA pathways, particularly the piRNA pathway, thereby providing critical insights on the molecular pathogenesis of Fragile X syndrome, and potential translational applications in clinical management of the disease.

  10. Race and the fragility of the legal distinction between juveniles and adults.

    Aneeta Rattan

    Full Text Available Legal precedent establishes juvenile offenders as inherently less culpable than adult offenders and thus protects juveniles from the most severe of punishments. But how fragile might these protections be? In the present study, simply bringing to mind a Black (vs. White juvenile offender led participants to view juveniles in general as significantly more similar to adults in their inherent culpability and to express more support for severe sentencing. Indeed, these differences in participants' perceptions of this foundational legal precedent distinguishing between juveniles and adults accounted for their greater support for severe punishment. These results highlight the fragility of protections for juveniles when race is in play. Furthermore, we suggest that this fragility may have broad implications for how juveniles are seen and treated in the criminal justice system.

  11. Stabilization of bacterially expressed erythropoietin by single site-specific introduction of short branched PEG chains at naturally occurring glycosylation sites.

    Hoffmann, E; Streichert, K; Nischan, N; Seitz, C; Brunner, T; Schwagerus, S; Hackenberger, C P R; Rubini, M

    2016-05-24

    The covalent attachment of polyethylene glycol (PEG) to therapeutic proteins can improve their physicochemical properties. In this work we utilized the non-natural amino acid p-azidophenylalanine (pAzF) in combination with the chemoselective Staudinger-phosphite reaction to install branched PEG chains to recombinant unglycosylated erythropoietin (EPO) at each single naturally occurring glycosylation site. PEGylation with two short 750 or 2000 Da PEG units at positions 24, 38, or 83 significantly decreased unspecific aggregation and proteolytic degradation while biological activity in vitro was preserved or even increased in comparison to full-glycosylated EPO. This site-specific bioconjugation approach permits to analyse the impact of PEGylation at single positions. These results represent an important step towards the engineering of site-specifically modified EPO variants from bacterial expression with increased therapeutic efficacy.

  12. Molecular characterization of X chromosome fragility in idiopathic ...

    Heba Alla Hosny Omar

    2015-11-23

    Nov 23, 2015 ... Frequency of fragile X syndrome among male siblings and relatives of mentally retarded patients ... hence the wide clinical spectrum of disorders caused by this ... fragile X syndrome, autism and other less well-characterized.

  13. Genetics Home Reference: fragile X-associated primary ovarian insufficiency

    ... Share: Email Facebook Twitter Home Health Conditions FXPOI Fragile X-associated primary ovarian insufficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Fragile X-associated primary ovarian insufficiency ( FXPOI ) is a condition ...

  14. A Trial of Metformin in Individuals With Fragile X Syndrome

    2018-04-10

    Fragile X Syndrome; Fragile X Mental Retardation Syndrome; Mental Retardation, X Linked; Genetic Diseases, X-Linked; Trinucleotide Repeat Expansion; Fra(X) Syndrome; Intellectual Disability; FXS; Neurobehavioral Manifestations; Sex Chromosome Disorders

  15. Abnormal neural precursor cell regulation in the early postnatal Fragile X mouse hippocampus.

    Sourial, Mary; Doering, Laurie C

    2017-07-01

    The regulation of neural precursor cells (NPCs) is indispensable for a properly functioning brain. Abnormalities in NPC proliferation, differentiation, survival, or integration have been linked to various neurological diseases including Fragile X syndrome. Yet, no studies have examined NPCs from the early postnatal Fragile X mouse hippocampus despite the importance of this developmental time point, which marks the highest expression level of FMRP, the protein missing in Fragile X, in the rodent hippocampus and is when hippocampal NPCs have migrated to the dentate gyrus (DG) to give rise to lifelong neurogenesis. In this study, we examined NPCs from the early postnatal hippocampus and DG of Fragile X mice (Fmr1-KO). Immunocytochemistry on neurospheres showed increased Nestin expression and decreased Ki67 expression, which collectively indicated aberrant NPC biology. Intriguingly, flow cytometric analysis of the expression of the antigens CD15, CD24, CD133, GLAST, and PSA-NCAM showed a decreased proportion of neural stem cells (GLAST + CD15 + CD133 + ) and an increased proportion of neuroblasts (PSA-NCAM + CD15 + ) in the DG of P7 Fmr1-KO mice. This was mirrored by lower expression levels of Nestin and the mitotic marker phospho-histone H3 in vivo in the P9 hippocampus, as well as a decreased proportion of cells in the G 2 /M phases of the P7 DG. Thus, the absence of FMRP leads to fewer actively cycling NPCs, coinciding with a decrease in neural stem cells and an increase in neuroblasts. Together, these results show the importance of FMRP in the developing hippocampal formation and suggest abnormalities in cell cycle regulation in Fragile X. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  16. Impact of MicroRNA Levels, Target-Site Complementarity, and Cooperativity on Competing Endogenous RNA-Regulated Gene Expression.

    Denzler, Rémy; McGeary, Sean E; Title, Alexandra C; Agarwal, Vikram; Bartel, David P; Stoffel, Markus

    2016-11-03

    Expression changes of competing endogenous RNAs (ceRNAs) have been proposed to influence microRNA (miRNA) activity and thereby regulate other transcripts containing miRNA-binding sites. Here, we find that although miRNA levels define the extent of repression, they have little effect on the magnitude of the ceRNA expression change required to observe derepression. Canonical 6-nt sites, which typically mediate modest repression, can nonetheless compete for miRNA binding, with potency ∼20% of that observed for canonical 8-nt sites. In aggregate, low-affinity/background sites also contribute to competition. Sites with extensive additional complementarity can appear as more potent, but only because they induce miRNA degradation. Cooperative binding of proximal sites for the same or different miRNAs does increase potency. These results provide quantitative insights into the stoichiometric relationship between miRNAs and target abundance, target-site spacing, and affinity requirements for ceRNA-mediated gene regulation, and the unusual circumstances in which ceRNA-mediated gene regulation might be observed. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Multiple ETS family proteins regulate PF4 gene expression by binding to the same ETS binding site.

    Yoshiaki Okada

    Full Text Available In previous studies on the mechanism underlying megakaryocyte-specific gene expression, several ETS motifs were found in each megakaryocyte-specific gene promoter. Although these studies suggested that several ETS family proteins regulate megakaryocyte-specific gene expression, only a few ETS family proteins have been identified. Platelet factor 4 (PF4 is a megakaryocyte-specific gene and its promoter includes multiple ETS motifs. We had previously shown that ETS-1 binds to an ETS motif in the PF4 promoter. However, the functions of the other ETS motifs are still unclear. The goal of this study was to investigate a novel functional ETS motif in the PF4 promoter and identify proteins binding to the motif. In electrophoretic mobility shift assays and a chromatin immunoprecipitation assay, FLI-1, ELF-1, and GABP bound to the -51 ETS site. Expression of FLI-1, ELF-1, and GABP activated the PF4 promoter in HepG2 cells. Mutation of a -51 ETS site attenuated FLI-1-, ELF-1-, and GABP-mediated transactivation of the promoter. siRNA analysis demonstrated that FLI-1, ELF-1, and GABP regulate PF4 gene expression in HEL cells. Among these three proteins, only FLI-1 synergistically activated the promoter with GATA-1. In addition, only FLI-1 expression was increased during megakaryocytic differentiation. Finally, the importance of the -51 ETS site for the activation of the PF4 promoter during physiological megakaryocytic differentiation was confirmed by a novel reporter gene assay using in vitro ES cell differentiation system. Together, these data suggest that FLI-1, ELF-1, and GABP regulate PF4 gene expression through the -51 ETS site in megakaryocytes and implicate the differentiation stage-specific regulation of PF4 gene expression by multiple ETS factors.

  18. Seismic Fragility of the LANL Fire Water Distribution System

    Greg Mertz

    2007-03-30

    The purpose of this report is to present the results of a site-wide system fragility assessment. This assessment focuses solely on the performance of the water distribution systems that supply Chemical and Metallurgy Research (CMR), Weapons Engineering and Tritium Facility (WETF), Radioactive Liquid Waste Treatment Facility (RLWTF), Waste Characterization, Reduction, Repackaging Facility (WCRRF), and Transuranic Waste Inspectable Storage Project (TWISP). The analysis methodology is based on the American Lifelines Alliance seismic fragility formulations for water systems. System fragilities are convolved with the 1995 LANL seismic hazards to develop failure frequencies. Acceptance is determined by comparing the failure frequencies to the DOE-1020 Performance Goals. This study concludes that: (1) If a significant number of existing isolation valves in the water distribution system are closed to dedicate the entire water system to fighting fires in specific nuclear facilities; (2) Then, the water distribution systems for WETF, RLWTF, WCRRF, and TWISP meet the PC-2 performance goal and the water distribution system for CMR is capable of surviving a 0.06g earthquake. A parametric study of the WETF water distribution system demonstrates that: (1) If a significant number of valves in the water distribution system are NOT closed to dedicate the entire water system to fighting fires in WETF; (2) Then, the water distribution system for WETF has an annual probability of failure on the order of 4 x 10{sup -3} that does not meet the PC-2 performance goal. Similar conclusions are expected for CMR, RLWTF, WCRRF, and TWISP. It is important to note that some of the assumptions made in deriving the results should be verified by personnel in the safety-basis office and may need to be incorporated in technical surveillance requirements in the existing authorization basis documentation if credit for availability of fire protection water is taken at the PC-2 level earthquake levels

  19. Seismic Fragility of the LANL Fire Water Distribution System

    Greg Mertz Jason Cardon Mike Salmon

    2007-01-01

    The purpose of this report is to present the results of a site-wide system fragility assessment. This assessment focuses solely on the performance of the water distribution systems that supply Chemical and Metallurgy Research (CMR), Weapons Engineering and Tritium Facility (WETF), Radioactive Liquid Waste Treatment Facility (RLWTF), Waste Characterization, Reduction, Repackaging Facility (WCRRF), and Transuranic Waste Inspectable Storage Project (TWISP). The analysis methodology is based on the American Lifelines Alliance seismic fragility formulations for water systems. System fragilities are convolved with the 1995 LANL seismic hazards to develop failure frequencies. Acceptance is determined by comparing the failure frequencies to the DOE-1020 Performance Goals. This study concludes that: (1) If a significant number of existing isolation valves in the water distribution system are closed to dedicate the entire water system to fighting fires in specific nuclear facilities; (2) Then, the water distribution systems for WETF, RLWTF, WCRRF, and TWISP meet the PC-2 performance goal and the water distribution system for CMR is capable of surviving a 0.06g earthquake. A parametric study of the WETF water distribution system demonstrates that: (1) If a significant number of valves in the water distribution system are NOT closed to dedicate the entire water system to fighting fires in WETF; (2) Then, the water distribution system for WETF has an annual probability of failure on the order of 4 x 10 -3 that does not meet the PC-2 performance goal. Similar conclusions are expected for CMR, RLWTF, WCRRF, and TWISP. It is important to note that some of the assumptions made in deriving the results should be verified by personnel in the safety-basis office and may need to be incorporated in technical surveillance requirements in the existing authorization basis documentation if credit for availability of fire protection water is taken at the PC-2 level earthquake levels

  20. Expression and characterization of active site mutants of hevamine, a chitinase from the rubber tree Hevea brasiliensis

    Bokma, Evert; Rozeboom, Henriëtte J.; Sibbald, Mark; Dijkstra, Bauke W.; Beintema, Jaap J.

    Hevamine is a chitinase from the rubber tree Hevea brasiliensis. Its active site contains Asp125, Glu127, and Tyr183, which interact with the -1 sugar residue of the substrate. To investigate their role in catalysis, we have successfully expressed wild-type enzyme and mutants of these residues as

  1. Personality in cyberspace: personal Web sites as media for personality expressions and impressions.

    Marcus, Bernd; Machilek, Franz; Schütz, Astrid

    2006-06-01

    This research examined the personality of owners of personal Web sites based on self-reports, visitors' ratings, and the content of the Web sites. The authors compared a large sample of Web site owners with population-wide samples on the Big Five dimensions of personality. Controlling for demographic differences, the average Web site owner reported being slightly less extraverted and more open to experience. Compared with various other samples, Web site owners did not generally differ on narcissism, self-monitoring, or self-esteem, but gender differences on these traits were often smaller in Web site owners. Self-other agreement was highest with Openness to Experience, but valid judgments of all Big Five dimensions were derived from Web sites providing rich information. Visitors made use of quantifiable features of the Web site to infer personality, and the cues they utilized partly corresponded to self-reported traits. Copyright 2006 APA, all rights reserved.

  2. Brief Report: Acamprosate in Fragile X Syndrome

    Erickson, Craig A.; Mullett, Jennifer E.; McDougle, Christopher J.

    2010-01-01

    Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). We report on the first trial of acamprosate, a drug with putative mGluR5 antagonism, in three adults with FXS and autism. Medical records describing open-label treatment with acamprosate in 3 patients with FXS and a comorbid diagnosis of autistic disorder…

  3. Essays on financial fragility and regulation

    Ma, K.

    2013-01-01

    This thesis investigates various issues in regulation, with three chapters on financial fragility and banking regulation, and one chapter on competition policy. Chapter 2 studies banks’ herding driven by their need for market liquidity, highlighting a trade-off between systemic risk and liquidity

  4. Multipartnered Fertility and Depression among Fragile Families

    Turney, Kristin; Carlson, Marcia J.

    2011-01-01

    We used data from the Fragile Families and Child Wellbeing Study to examine the association between multipartnered fertility (MPF)--when parents have children with more than one partner--and depression. Random-effects models suggested that MPF is associated with a greater likelihood of depression, net of family structure and other covariates.…

  5. Comparative Erythrocytes Osmotic Fragility Test and some ...

    Erythrocytes osmotic fragility and haematological parameters of subjects with HbAS (sickle cell trait) and HbSS (sickle cell anaemia) were determined and compared with subjects with HbAA (normal adult haemoglobin), which acted as control. They were divided into three groups of 40 subjects for HbAA, 35 subjects for ...

  6. Emotion Potentiated Startle in Fragile X Syndrome

    Ballinger, Elizabeth C.; Cordeiro, Lisa; Chavez, Alyssa D.; Hagerman, Randi J.; Hessl, David

    2014-01-01

    Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We…

  7. Modeling Family Adaptation to Fragile X Syndrome

    Raspa, Melissa; Bailey, Donald, Jr.; Bann, Carla; Bishop, Ellen

    2014-01-01

    Using data from a survey of 1,099 families who have a child with Fragile X syndrome, we examined adaptation across 7 dimensions of family life: parenting knowledge, social support, social life, financial impact, well-being, quality of life, and overall impact. Results illustrate that although families report a high quality of life, they struggle…

  8. Fragile X Syndrome: An Aging Perspective

    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…

  9. Determinants of Banking System Fragility : A Regional Perspective

    Degryse, H.A.; Elahi, M.A.; Penas, M.F.

    2012-01-01

    Abstract: Banking systems are fragile not only within one country but also within and across regions. We study the role of regional banking system characteristics for regional banking system fragility. We find that regional banking system fragility reduces when banks in the region jointly hold more

  10. MicroRNA genes preferentially expressed in dendritic cells contain sites for conserved transcription factor binding motifs in their promoters

    Huynen Martijn A

    2011-06-01

    Full Text Available Abstract Background MicroRNAs (miRNAs play a fundamental role in the regulation of gene expression by translational repression or target mRNA degradation. Regulatory elements in miRNA promoters are less well studied, but may reveal a link between their expression and a specific cell type. Results To explore this link in myeloid cells, miRNA expression profiles were generated from monocytes and dendritic cells (DCs. Differences in miRNA expression among monocytes, DCs and their stimulated progeny were observed. Furthermore, putative promoter regions of miRNAs that are significantly up-regulated in DCs were screened for Transcription Factor Binding Sites (TFBSs based on TFBS motif matching score, the degree to which those TFBSs are over-represented in the promoters of the up-regulated miRNAs, and the extent of conservation of the TFBSs in mammals. Conclusions Analysis of evolutionarily conserved TFBSs in DC promoters revealed preferential clustering of sites within 500 bp upstream of the precursor miRNAs and that many mRNAs of cognate TFs of the conserved TFBSs were indeed expressed in the DCs. Taken together, our data provide evidence that selected miRNAs expressed in DCs have evolutionarily conserved TFBSs relevant to DC biology in their promoters.

  11. A Bistable Switch and Anatomical Site Control Vibrio cholerae Virulence Gene Expression in the Intestine

    Nielsen, Alex Toftgaard; Dolganov, N. A.; Rasmussen, Thomas

    2010-01-01

    A fundamental, but unanswered question in host-pathogen interactions is the timing, localization and population distribution of virulence gene expression during infection. Here, microarray and in situ single cell expression methods were used to study Vibrio cholerae growth and virulence gene...... expression during infection of the rabbit ligated ileal loop model of cholera. Genes encoding the toxin-coregulated pilus (TCP) and cholera toxin (CT) were powerfully expressed early in the infectious process in bacteria adjacent to epithelial surfaces. Increased growth was found to co......, a chemical inducer of virulence gene expression. Striking bifurcation of the population occurred during entry into stationary phase: one subpopulation continued to express tcpA, whereas the expression declined in the other subpopulation. ctxA, encoding the A subunit of CT, and toxT, encoding the proximal...

  12. Employment Impact and Financial Burden for Families of Children with Fragile X Syndrome: Findings from the National Fragile X Survey

    Ouyang, L.; Grosse, S.; Raspa, M.; Bailey, D.

    2010-01-01

    Background: The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA. Method: Using a national fragile X family survey, we analysed data on 1019 families with at least one child who had a full FXS mutation. Out-of-pocket expenditures related to fragile X were…

  13. Role of Site-Specific N-Glycans Expressed on GluA2 in the Regulation of Cell Surface Expression of AMPA-Type Glutamate Receptors.

    Yusuke Takeuchi

    Full Text Available The AMPA-type glutamate receptor (AMPAR, which is a tetrameric complex composed of four subunits (GluA1-4 with several combinations, mediates the majority of rapid excitatory synaptic transmissions in the nervous system. Cell surface expression levels of AMPAR modulate synaptic plasticity, which is considered one of the molecular bases for learning and memory formation. To date, a unique trisaccharide (HSO3-3GlcAβ1-3Galβ1-4GlcNAc, human natural killer-1 (HNK-1 carbohydrate, was found expressed specifically on N-linked glycans of GluA2 and regulated the cell surface expression of AMPAR and the spine maturation process. However, evidence that the HNK-1 epitope on N-glycans of GluA2 directly affects these phenomena is lacking. Moreover, it is thought that other N-glycans on GluA2 also have potential roles in the regulation of AMPAR functions. In the present study, using a series of mutants lacking potential N-glycosylation sites (N256, N370, N406, and N413 within GluA2, we demonstrated that the mutant lacking the N-glycan at N370 strongly suppressed the intracellular trafficking of GluA2 from the endoplasmic reticulum (ER in HEK293 cells. Cell surface expression of GluA1, which is a major subunit of AMPAR in neurons, was also suppressed by co-expression of the GluA2 N370S mutant. The N370S mutant and wild-type GluA2 were co-immunoprecipitated with GluA1, suggesting that N370S was properly associated with GluA1. Moreover, we found that N413 was the main potential site of the HNK-1 epitope that promoted the interaction of GluA2 with N-cadherin, resulting in enhanced cell surface expression of GluA2. The HNK-1 epitope on N-glycan at the N413 of GluA2 was also involved in the cell surface expression of GluA1. Thus, our data suggested that site-specific N-glycans on GluA2 regulate the intracellular trafficking and cell surface expression of AMPAR.

  14. Drift-free MPEG-4 AVC semi-fragile watermarking

    Hasnaoui, M.; Mitrea, M.

    2014-02-01

    While intra frame drifting is a concern for all types of MPEG-4 AVC compressed-domain video processing applications, it has a particular negative impact in watermarking. In order to avoid the drift drawbacks, two classes of solutions are currently considered in the literature. They try either to compensate the drift distortions at the expense of complex decoding/estimation algorithms or to restrict the insertion to the blocks which are not involved in the prediction, thus reducing the data payload. The present study follows a different approach. First, it algebraically models the drift distortion spread problem by considering the analytic expressions of the MPEG-4 AVC encoding operations. Secondly, it solves the underlying algebraic system under drift-free constraints. Finally, the advanced solution is adapted to take into account the watermarking peculiarities. The experiments consider an m-QIM semi-fragile watermarking method and a video surveillance corpus of 80 minutes. For prescribed data payload (100 bit/s), robustness (BER < 0.1 against transcoding at 50% in stream size), fragility (frame modification detection with accuracies of 1/81 from the frame size and 3s) and complexity constraints, the modified insertion results in gains in transparency of 2 dB in PSNR, of 0.4 in AAD, of 0.002 in IF, of 0.03 in SC, of 0.017 NCC and 22 in DVQ.

  15. Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

    Monyak, R E; Emerson, D; Schoenfeld, B P; Zheng, X; Chambers, D B; Rosenfelt, C; Langer, S; Hinchey, P; Choi, C H; McDonald, T V; Bolduc, F V; Sehgal, A; McBride, S M J; Jongens, T A

    2017-08-01

    Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

  16. Modification of the Creator recombination system for proteomics applications – improved expression by addition of splice sites

    Colwill, Karen; Wells, Clark D; Elder, Kelly; Goudreault, Marilyn; Hersi, Kadija; Kulkarni, Sarang; Hardy, W Rod; Pawson, Tony; Morin, Gregg B

    2006-01-01

    Background Recombinational systems have been developed to rapidly shuttle Open Reading Frames (ORFs) into multiple expression vectors in order to analyze the large number of cDNAs available in the post-genomic era. In the Creator system, an ORF introduced into a donor vector can be transferred with Cre recombinase to a library of acceptor vectors optimized for different applications. Usability of the Creator system is impacted by the ability to easily manipulate DNA, the number of acceptor vectors for downstream applications, and the level of protein expression from Creator vectors. Results To date, we have developed over 20 novel acceptor vectors that employ a variety of promoters and epitope tags commonly employed for proteomics applications and gene function analysis. We also made several enhancements to the donor vectors including addition of different multiple cloning sites to allow shuttling from pre-existing vectors and introduction of the lacZ alpha reporter gene to allow for selection. Importantly, in order to ameliorate any effects on protein expression of the loxP site between a 5' tag and ORF, we introduced a splicing event into our expression vectors. The message produced from the resulting 'Creator Splice' vector undergoes splicing in mammalian systems to remove the loxP site. Upon analysis of our Creator Splice constructs, we discovered that protein expression levels were also significantly increased. Conclusion The development of new donor and acceptor vectors has increased versatility during the cloning process and made this system compatible with a wider variety of downstream applications. The modifications introduced in our Creator Splice system were designed to remove extraneous sequences due to recombination but also aided in downstream analysis by increasing protein expression levels. As a result, we can now employ epitope tags that are detected less efficiently and reduce our assay scale to allow for higher throughput. The Creator Splice

  17. Modification of the Creator recombination system for proteomics applications--improved expression by addition of splice sites.

    Colwill, Karen; Wells, Clark D; Elder, Kelly; Goudreault, Marilyn; Hersi, Kadija; Kulkarni, Sarang; Hardy, W Rod; Pawson, Tony; Morin, Gregg B

    2006-03-06

    Recombinational systems have been developed to rapidly shuttle Open Reading Frames (ORFs) into multiple expression vectors in order to analyze the large number of cDNAs available in the post-genomic era. In the Creator system, an ORF introduced into a donor vector can be transferred with Cre recombinase to a library of acceptor vectors optimized for different applications. Usability of the Creator system is impacted by the ability to easily manipulate DNA, the number of acceptor vectors for downstream applications, and the level of protein expression from Creator vectors. To date, we have developed over 20 novel acceptor vectors that employ a variety of promoters and epitope tags commonly employed for proteomics applications and gene function analysis. We also made several enhancements to the donor vectors including addition of different multiple cloning sites to allow shuttling from pre-existing vectors and introduction of the lacZ alpha reporter gene to allow for selection. Importantly, in order to ameliorate any effects on protein expression of the loxP site between a 5' tag and ORF, we introduced a splicing event into our expression vectors. The message produced from the resulting 'Creator Splice' vector undergoes splicing in mammalian systems to remove the loxP site. Upon analysis of our Creator Splice constructs, we discovered that protein expression levels were also significantly increased. The development of new donor and acceptor vectors has increased versatility during the cloning process and made this system compatible with a wider variety of downstream applications. The modifications introduced in our Creator Splice system were designed to remove extraneous sequences due to recombination but also aided in downstream analysis by increasing protein expression levels. As a result, we can now employ epitope tags that are detected less efficiently and reduce our assay scale to allow for higher throughput. The Creator Splice system appears to be an extremely

  18. A bistable switch and anatomical site control Vibrio cholerae virulence gene expression in the intestine.

    Alex T Nielsen

    2010-09-01

    Full Text Available A fundamental, but unanswered question in host-pathogen interactions is the timing, localization and population distribution of virulence gene expression during infection. Here, microarray and in situ single cell expression methods were used to study Vibrio cholerae growth and virulence gene expression during infection of the rabbit ligated ileal loop model of cholera. Genes encoding the toxin-coregulated pilus (TCP and cholera toxin (CT were powerfully expressed early in the infectious process in bacteria adjacent to epithelial surfaces. Increased growth was found to co-localize with virulence gene expression. Significant heterogeneity in the expression of tcpA, the repeating subunit of TCP, was observed late in the infectious process. The expression of tcpA, studied in single cells in a homogeneous medium, demonstrated unimodal induction of tcpA after addition of bicarbonate, a chemical inducer of virulence gene expression. Striking bifurcation of the population occurred during entry into stationary phase: one subpopulation continued to express tcpA, whereas the expression declined in the other subpopulation. ctxA, encoding the A subunit of CT, and toxT, encoding the proximal master regulator of virulence gene expression also exhibited the bifurcation phenotype. The bifurcation phenotype was found to be reversible, epigenetic and to persist after removal of bicarbonate, features consistent with bistable switches. The bistable switch requires the positive-feedback circuit controlling ToxT expression and formation of the CRP-cAMP complex during entry into stationary phase. Key features of this bistable switch also were demonstrated in vivo, where striking heterogeneity in tcpA expression was observed in luminal fluid in later stages of the infection. When this fluid was diluted into artificial seawater, bacterial aggregates continued to express tcpA for prolonged periods of time. The bistable control of virulence gene expression points to a

  19. Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation.

    Hatziri, Aikaterini; Kalogeropoulou, Christina; Xepapadaki, Eva; Birli, Eleni; Karavia, Eleni A; Papakosta, Eugenia; Filou, Serafoula; Constantinou, Caterina; Kypreos, Kyriakos E

    2018-02-01

    Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity. In our studies APOE3 knock-in (Apoe3 knock-in ), Apoe-deficient (apoe -/- ) and brain-specific expressing APOE3 (Apoe3 brain ) mice were fed western-type diet for 12week and biochemical analyses were performed. Moreover, AAV-mediated gene transfer of APOE3 to apoe -/- mice was employed, as a means to achieve APOE3 expression selectively in periphery, since peripherally expressed APOE does not cross blood brain barrier (BBB) or blood-cerebrospinal fluid barrier (BCSFB). Our data suggest a bimodal role of APOE3 in visceral white adipose tissue (WAT) mitochondrial metabolic activation that is highly dependent on its site of expression and independent of postprandial dietary lipid deposition. Our findings indicate that brain APOE3 expression is associated with a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation, leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, peripherally expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene.

    Hessl, David; Grigsby, Jim

    2016-08-01

    Neuropsychologists have an important role in evaluating patients with fragile X-associated disorders, but most practitioners are unaware of the recently identified neurodegenerative movement disorder known as fragile X-associated tremor ataxia syndrome (FXTAS). The objective of this editorial is to orient the reader to FXTAS and highlight the importance of clinical neuropsychology in describing the fragile X premutation phenotype and the role practitioners may have in assessing and monitoring patients with or at risk for neurodegeneration. We issued a call for papers for the special issue, highlighting the primary objective of familiarizing clinical neuropsychologists with FXTAS, and with the neuropsychological phenotype of both male and female asymptomatic carriers. Eight papers are included, including an overview of the fragile X-associated disorders (Grigsby), a review of the neuroradiological and neurological aspects of FXTAS and how the disorder compares to other movement disorders (O'Keefe et al.), a perspective on the prominence of white matter disease and dementia in FXTAS (Filley), and a review of mouse models of FXTAS (Foote). There are four research papers, including one on self-reported memory problems in FXTAS (Birch et al.), and three papers focused on the neuropsychiatric aspects of the fragile X premutation, a review (Bourgeois), an examination of autism-related traits (Schneider), and a research paper on executive functioning and psychopathology (Grigsby). The issue highlights the importance of awareness of fragile X-associated disorders for neuropsychologists, an awareness that must reach beyond neurodevelopmental aspects related to fragile X syndrome into the realm of neurodegenerative disease and aging.

  1. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site.

    Antonescu, Cristina R; Viale, Agnes; Sarran, Lisa; Tschernyavsky, Sylvia J; Gonen, Mithat; Segal, Neil H; Maki, Robert G; Socci, Nicholas D; DeMatteo, Ronald P; Besmer, Peter

    2004-05-15

    Gastrointestinal stromal tumors (GISTs) are specific KIT expressing and KIT-signaling driven mesenchymal tumors of the human digestive tract, many of which have KIT-activating mutations. Previous studies have found a relatively homogeneous gene expression profile in GIST, as compared with other histological types of sarcomas. Transcriptional heterogeneity within clinically or molecularly defined subsets of GISTs has not been previously reported. We tested the hypothesis that the gene expression profile in GISTs might be related to KIT genotype and possibly to other clinicopathological factors. An HG-U133A Affymetrix chip (22,000 genes) platform was used to determine the variability of gene expression in 28 KIT-expressing GIST samples from 24 patients. A control group of six intra-abdominal leiomyosarcomas was also included for comparison. Statistical analyses (t tests) were performed to identify discriminatory gene lists among various GIST subgroups. The levels of expression of various GIST subsets were also linked to a modified version of the growth factor/KIT signaling pathway to analyze differences at various steps in signal transduction. Genes involved in KIT signaling were differentially expressed among wild-type and mutant GISTs. High gene expression of potential drug targets, such as VEGF, MCSF, and BCL2 in the wild-type group, and Mesothelin in exon 9 GISTs were found. There was a striking difference in gene expression between stomach and small bowel GISTs. This finding was validated in four separate tumors, two gastric and two intestinal, from a patient with familial GIST with a germ-line KIT W557R substitution. GISTs have heterogeneous gene expression depending on KIT genotype and tumor location, which is seen at both the genomic level and the KIT signaling pathway in particular. These findings may explain their variable clinical behavior and response to therapy.

  2. Seismic fragility of nuclear power plant components: Phase 2, Motor control center, switchboard, panelboard and power supply

    Bandyopadhyay, K.K.; Hofmayer, C.H.; Kassir, M.K.; Pepper, S.E.

    1987-12-01

    In Phase I of the Component Fragility Program, Brookhaven National Laboratory (BNL) has developed a procedure to establish the seismic fragility of nuclear power plant equipment by use of existing test data and demonstrated its application by considering two equipment pieces. In Phase II of the program, BNL has collected additional test data, and has further advanced and is applying the methodology to determine the fragility levels of selected essential equipment categories. The data evaluation of four equipment families, namely, motor control center, switchboard, panelboard and power supply has been completed. Fragility levels have been determined for various failure modes of each equipment class and the deterministic results are presented in terms of test response spectra. In addition, the test data have been analyzed for determination of the respective probabilistic fragility levels. To this end, a single g-value has been selected to approximately represent the test vibration level and a statistical analysis has been performed with the g-values corresponding to a particular failure mode. The zero period acceleration and the average spectral acceleration over a frequency range of interest are separately used as the single g-value. The resulting parameters are presented in terms of a median value, an uncertainty coefficient and a randomness coefficient. Ultimately, each fragility level is expressed in terms of a single descriptor called an HCLPF value corresponding to a high (95%) confidence of a low (5%) probability of failure. The important observations made in the process of data analysis are included in this report

  3. Fragile genomic sites are associated with origins of replication.

    Di Rienzi, Sara C; Collingwood, David; Raghuraman, M K; Brewer, Bonita J

    2009-09-09

    Genome rearrangements are mediators of evolution and disease. Such rearrangements are frequently bounded by transfer RNAs (tRNAs), transposable elements, and other repeated elements, suggesting a functional role for these elements in creating or repairing breakpoints. Though not well explored, there is evidence that origins of replication also colocalize with breakpoints. To investigate a potential correlation between breakpoints and origins, we analyzed evolutionary breakpoints defined between Saccharomyces cerevisiae and Kluyveromyces waltii and S. cerevisiae and a hypothetical ancestor of both yeasts, as well as breakpoints reported in the experimental literature. We find that origins correlate strongly with both evolutionary breakpoints and those described in the literature. Specifically, we find that origins firing earlier in S phase are more strongly correlated with breakpoints than are later-firing origins. Despite origins being located in genomic regions also bearing tRNAs and Ty elements, the correlation we observe between origins and breakpoints appears to be independent of these genomic features. This study lays the groundwork for understanding the mechanisms by which origins of replication may impact genome architecture and disease.

  4. Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders.

    Usdin, Karen; Kumari, Daman

    2015-01-01

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

  5. Fragility Analysis of Concrete Gravity Dams

    Tekie, Paulos B.; Ellingwood, Bruce R.

    2002-09-01

    Concrete gravity dams are an important part ofthe nation's infrastructure. Many dams have been in service for over 50 years, during which time important advances in the methodologies for evaluation of natural phenomena hazards have caused the design-basis events to be revised upwards, in some cases significantly. Many existing dams fail to meet these revised safety criteria and structural rehabilitation to meet newly revised criteria may be costly and difficult. A probabilistic safety analysis (PSA) provides a rational safety assessment and decision-making tool managing the various sources of uncertainty that may impact dam performance. Fragility analysis, which depicts fl%e uncertainty in the safety margin above specified hazard levels, is a fundamental tool in a PSA. This study presents a methodology for developing fragilities of concrete gravity dams to assess their performance against hydrologic and seismic hazards. Models of varying degree of complexity and sophistication were considered and compared. The methodology is illustrated using the Bluestone Dam on the New River in West Virginia, which was designed in the late 1930's. The hydrologic fragilities showed that the Eluestone Dam is unlikely to become unstable at the revised probable maximum flood (PMF), but it is likely that there will be significant cracking at the heel ofthe dam. On the other hand, the seismic fragility analysis indicated that sliding is likely, if the dam were to be subjected to a maximum credible earthquake (MCE). Moreover, there will likely be tensile cracking at the neck of the dam at this level of seismic excitation. Probabilities of relatively severe limit states appear to be only marginally affected by extremely rare events (e.g. the PMF and MCE). Moreover, the risks posed by the extreme floods and earthquakes were not balanced for the Bluestone Dam, with seismic hazard posing a relatively higher risk.

  6. Seismic fragility evaluation of unreinforced masonry walls

    Park, Y.J.; Hofmayer, C.H.; Reich, M.; Lee, S.K.

    1991-01-01

    A practical analysis scheme to evaluate the seismic fragility of unreinforced masonry walls which are used at various places in older reactor facilities is presented. Among the several failure modes for such walls, the out-of-plane bending failure is considered to be a major risk contributor in seismic PRA studies. In order to evaluate this failure mode, the use of an equivalent linear approximation method is examined based on comparisons with available test data and nonlinear time history analyses. (author)

  7. The highly fragile glass former Decalin

    Eibl, Stefan

    2009-01-01

    Systems exhibiting the glass transition can be classified by fragility. In this work we studied structural and dynamical aspects of highly fragile C 10 H 18 Decalin. Trans Decalin is locked into a pseudo-flat centrosymmetric conformation, while cis Decalin interchanges dynamically between chiral, pseudo-spherical ground states. On investigation of the phase behaviour trans Decalin was found to crystallise rapidly and cleanly; its crystal structure could be determined. From the crystal structure the dynamics of crystalline trans Decalin could be calculated using ab-initio lattice energy calculations and compared to measurements. Using neutron diffraction and molecular dynamics simulations the amorphous structure of Decalin was investigated. The difference in structure to the common molecular liquid Cumene is significant. The features of the amorphous structure of sphere-like cis Decalin show strong resemblance to the ones of Argon and metallic glasses. The dynamics of Decalin were investigated in the slightly supercooled liquid range. Using neutron scattering and optical spectroscopy, data was collected for a wide spectral range and several temperatures. The data suggests high fragility for the generic Decalin mixture, which is in agreement with the reported results. By contrast to previous estimations, an extrapolation of our data indicates cis Decalin to be only slightly less fragile than the generic mixture. Finally a lower limit to the four point susceptibility function χ 4 could be calculated and the number of correlated molecules determined. The evolution of this value as a function of T g /T and relaxation time are in agreement with literature. (author) [fr

  8. Differentially expressed genes distributed over chromosomes and implicated in certain biological processes for site insertion genetically modified rice Kemingdao.

    Liu, Zhi; Li, Yunhe; Zhao, Jie; Chen, Xiuping; Jian, Guiliang; Peng, Yufa; Qi, Fangjun

    2012-01-01

    Release of genetically modified (GM) plants has sparked off intensive debates worldwide partly because of concerns about potential adverse unintended effects of GM plants to the agro system and the safety of foods. In this study, with the aim of revealing the molecular basis for unintended effects of a single site insertion GM Kemingdao (KMD) rice transformed with a synthetic cry1Ab gene, and bridging unintended effects of KMD rice through clues of differentially expressed genes, comparative transcriptome analyses were performed for GM KMD rice and its parent rice of Xiushui11 (XS11). The results showed that 680 differentially expressed transcripts were identified from 30-day old seedlings of GM KMD rice. The absolute majority of these changed expression transcripts dispersed and located over all rice chromosomes, and existed physical distance on chromosome from the insertion site, while only two transcripts were found to be differentially expressed within the 21 genes located within 100 kb up and down-stream of the insertion site. Pathway and biology function analyses further revealed that differentially expressed transcripts of KMD rice were involved in certain biological processes, and mainly implicated in two types of pathways. One type was pathways implicated in plant stress/defense responses, which were considerably in coordination with the reported unintended effects of KMD rice, which were more susceptible to rice diseases compared to its parent rice XS11; the other type was pathways associated with amino acids metabolism. With this clue, new unintended effects for changes in amino acids synthesis of KMD rice leaves were successfully revealed. Such that an actual case was firstly provided for identification of unintended effects in GM plants by comparative transciptome analysis.

  9. Transcription factor binding site enrichment analysis predicts drivers of altered gene expression in nonalcoholic steatohepatitis

    Lake, A.D.; Chaput, A.L.; Novák, Petr; Cherrington, N.J.; Smith, C.L.

    2016-01-01

    Roč. 122, December 15 (2016), s. 62-71 ISSN 0006-2952 Institutional support: RVO:60077344 Keywords : Transcription factor * Liver * Gene expression * Bioinformatics Subject RIV: CE - Biochemistry Impact factor: 4.581, year: 2016

  10. Pancreatic hormones are expressed on the surfaces of human and rat islet cells through exocytotic sites

    Larsson, L I; Hutton, J C; Madsen, O D

    1989-01-01

    . Electron microscopy reveals the labeling to occur at sites of exocytotic granule release, involving the surfaces of extruded granule cores. The surfaces of islet cells were labeled both by polyclonal and monoclonal antibodies, excluding that receptor-interacting, anti-idiotypic hormone antibodies were...... for these results. It is concluded that the staining reflects interactions between the appropriate antibodies and exocytotic sites of hormone release....

  11. Emotion Expression on Social Networking Sites: Exploring Mood Profiles and Depression

    ELIZABETH MARY SEABROOK

    2018-01-01

    Depression can be detected from the language people use on social media. This thesis explored patterns in the way people express emotion online and how emotion patterns can be used to identify depression from status updates. Language is complex, and the emotion expressed in status updates did not clearly reflect experienced emotion at a daily level. Emotion patterns over time were more informative. For Facebook users, extreme fluctuations in the amount of negative emotion words between consec...

  12. Validation of fragility fractures in primary care electronic medical records: A population-based study.

    Martinez-Laguna, Daniel; Soria-Castro, Alberto; Carbonell-Abella, Cristina; Orozco-López, Pilar; Estrada-Laza, Pilar; Nogues, Xavier; Díez-Perez, Adolfo; Prieto-Alhambra, Daniel

    2017-11-28

    Electronic medical records databases use pre-specified lists of diagnostic codes to identify fractures. These codes, however, are not specific enough to disentangle traumatic from fragility-related fractures. We report on the proportion of fragility fractures identified in a random sample of coded fractures in SIDIAP. Patients≥50 years old with any fracture recorded in 2012 (as per pre-specified ICD-10 codes) and alive at the time of recruitment were eligible for this retrospective observational study in 6 primary care centres contributing to the SIDIAP database (www.sidiap.org). Those with previous fracture/s, non-responders, and those with dementia or a serious psychiatric disease were excluded. Data on fracture type (traumatic vs fragility), skeletal site, and basic patient characteristics were collected. Of 491/616 (79.7%) patients with a registered fracture in 2012 who were contacted, 331 (349 fractures) were included. The most common fractures were forearm (82), ribs (38), and humerus (32), and 225/349 (64.5%) were fragility fractures, with higher proportions for classic osteoporotic sites: hip, 91.7%; spine, 87.7%; and major fractures, 80.5%. This proportion was higher in women, the elderly, and patients with a previously coded diagnosis of osteoporosis. More than 4 in 5 major fractures recorded in SIDIAP are due to fragility (non-traumatic), with higher proportions for hip (92%) and vertebral (88%) fracture, and a lower proportion for fractures other than major ones. Our data support the validity of SIDIAP for the study of the epidemiology of osteoporotic fractures. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  13. Construction of permanently inducible miRNA-based expression vectors using site-specific recombinases

    Garwick-Coppens Sara E

    2011-11-01

    Full Text Available Abstract Background RNA interference (RNAi is a conserved gene silencing mechanism mediated by small inhibitory microRNAs (miRNAs. Promoter-driven miRNA expression vectors have emerged as important tools for delivering natural or artificially designed miRNAs to eukaryotic cells and organisms. Such systems can be used to query the normal or pathogenic functions of natural miRNAs or messenger RNAs, or to therapeutically silence disease genes. Results As with any molecular cloning procedure, building miRNA-based expression constructs requires a time investment and some molecular biology skills. To improve efficiency and accelerate the construction process, we developed a method to rapidly generate miRNA expression vectors using recombinases instead of more traditional cut-and-paste molecular cloning techniques. In addition to streamlining the construction process, our cloning strategy provides vectors with added versatility. In our system, miRNAs can be constitutively expressed from the U6 promoter, or inducibly expressed by Cre recombinase. We also engineered a built-in mechanism to destroy the vector with Flp recombinase, if desired. Finally, to further simplify the construction process, we developed a software package that automates the prediction and design of optimal miRNA sequences using our system. Conclusions We designed and tested a modular system to rapidly clone miRNA expression cassettes. Our strategy reduces the hands-on time required to successfully generate effective constructs, and can be implemented in labs with minimal molecular cloning expertise. This versatile system provides options that permit constitutive or inducible miRNA expression, depending upon the needs of the end user. As such, it has utility for basic or translational applications.

  14. Chondrocyte heterogeneity: immunohistologically defined variation of integrin expression at different sites in human fetal knees.

    Salter, D M; Godolphin, J L; Gourlay, M S

    1995-04-01

    During development and at maturity different forms of cartilage vary in morphology and macromolecular content. This reflects heterogeneity of chondrocyte activity, in part involving differential interactions with the adjacent extracellular matrix via specialized cell surface receptors such as integrins. We undertook an immunohistological study on a series of human fetal knee joints to assess variation in the expression of integrins by chondrocytes and potential matrix ligands in articular, epiphyseal, growth plate, and meniscal cartilage. The results show that articular chondrocytes (beta 1+, beta 5 alpha V+, alpha 1+, alpha 2+/-, alpha 5+, weakly alpha 6+, alpha V+) differed from epiphyseal (beta 1+, beta 5 alpha V+, alpha 1+/-, alpha 2+/-, alpha 5+, alpha 6+, alpha V+) growth plate (beta 1+, beta 5 alpha V+, alpha 1-, alpha 2-, alpha 5+, alpha 6+, alpha V+), and meniscal cells (beta 1+, beta 5 alpha V+, alpha 1+, strongly alpha 2+, alpha 5+, alpha 6+, alpha V+ in expression of integrin subunits. There was no expression of beta 3, beta 4, beta 6, or alpha 3 by chondrocytes. These results differ from previous reports on the expression of integrins by adult articular cartilage, where alpha 2 and alpha 6 are not seen. Variation in distribution of matrix ligands was also seen. Fibronectin, laminin and Type VI collagen were expressed in all cartilages but there was restricted expression of tenascin, ED-A and ED-B fibronectin isoforms (articular cartilage and meniscus), and vitronectin (absent from growth plate cartilage). Regulated expression of integrins by chondrocytes, associated with changes in the pericellular matrix composition, is of potential importance in control of cartilage differentiation and function in health and disease.

  15. Biological data warehousing system for identifying transcriptional regulatory sites from gene expressions of microarray data.

    Tsou, Ann-Ping; Sun, Yi-Ming; Liu, Chia-Lin; Huang, Hsien-Da; Horng, Jorng-Tzong; Tsai, Meng-Feng; Liu, Baw-Juine

    2006-07-01

    Identification of transcriptional regulatory sites plays an important role in the investigation of gene regulation. For this propose, we designed and implemented a data warehouse to integrate multiple heterogeneous biological data sources with data types such as text-file, XML, image, MySQL database model, and Oracle database model. The utility of the biological data warehouse in predicting transcriptional regulatory sites of coregulated genes was explored using a synexpression group derived from a microarray study. Both of the binding sites of known transcription factors and predicted over-represented (OR) oligonucleotides were demonstrated for the gene group. The potential biological roles of both known nucleotides and one OR nucleotide were demonstrated using bioassays. Therefore, the results from the wet-lab experiments reinforce the power and utility of the data warehouse as an approach to the genome-wide search for important transcription regulatory elements that are the key to many complex biological systems.

  16. Evaluation of structural fragilities for an IPEEE seismic probabilistic risk assessment study

    Ghiocel, D.M.; Wilson, P.R.; Stevenson, J.D.

    1995-01-01

    The paper presents the main issues and results of a structural fragility analysis for a Seismic Probabilistic Risk Assessment (SPRA) study of a nuclear power plant (NPP) in the Eastern US. The fragility evaluations were performed for the Reactor Building, Auxiliary Building, Intake Structure and Diesel Generator Building. The random seismic input is defined in terms of the Uniform Hazard Spectrum (UHS) earthquake on the NPP site anchored to a reference level of 0.40 g Zero Period Ground Acceleration (ZPGA). Because of the soft soil conditions new Soil-Structure Interaction (SSI) analyses were performed using the original finite element (stick) structural models and the complex frequency approach. The soil deposit randomness was described by the variations in both the low strain soil shear modules and in its dependence with the shear strain. The probabilistic SSI analyses were performed using digital simulation techniques. The critical failure modes for each structure are investigated and the fragility evaluations are discussed. Concluding remarks and recommendations for improving the quality of the structural fragility analyses are included

  17. Seismic fragility curves of bridge piers accounting for ground motions in Korea

    Nguyen, Duy-Duan; Lee, Tae-Hyung

    2018-04-01

    Korea is located in a slight-to-moderate seismic zone. Nevertheless, several studies pointed that the peak earthquake magnitude in the region can be reached to approximately 6.5. Accordingly, a seismic vulnerability evaluation of the existing structures accounting for ground motions in Korea is momentous. The purpose of this paper is to develop seismic fragility curves for bridge piers of a steel box girder bridge equipped with and without base isolators based on a set of ground motions recorded in Korea. A finite element simulation platform, OpenSees, is utilized to perform nonlinear time history analyses of the bridges. A series of damage states is defined based on a damage index which is expressed in terms of the column displacement ductility ratio. The fragility curves based on Korean motions were thereafter compared with the fragility curves generated using worldwide earthquakes to assess the effect of the two ground motion groups on the seismic fragility curves of the bridge piers. The results reveal that both non- and base-isolated bridge piers are less vulnerable during the Korean ground motions than that under worldwide earthquakes.

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

    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.

  19. Comparison of main-shock and aftershock fragility curves developed for New Zealand and US buildings

    Uma, S.R.; Ryu, H.; Luco, N.; Liel, A.B.; Raghunandan, M.

    2011-01-01

    Seismic risk assessment involves the development of fragility functions to express the relationship between ground motion intensity and damage potential. In evaluating the risk associated with the building inventory in a region, it is essential to capture 'actual' characteristics of the buildings and group them so that 'generic building types' can be generated for further analysis of their damage potential. Variations in building characteristics across regions/countries largely influence the resulting fragility functions, such that building models are unsuitable to be adopted for risk assessment in any other region where a different set of building is present. In this paper, for a given building type (represented in terms of height and structural system), typical New Zealand and US building models are considered to illustrate the differences in structural model parameters and their effects on resulting fragility functions for a set of main-shocks and aftershocks. From this study, the general conclusion is that the methodology and assumptions used to derive basic capacity curve parameters have a considerable influence on fragility curves.

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

    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

  1. Installation Restoration Program. Ohio Air National Guard, Toledo Express Airport, Swanton, Ohio. Site Investigation Work Plan

    1990-09-01

    Initially, cuttings from the borings and wells will be placed on plastic sheeting, covered, and left at the drilling site until a determination can be...Spwmxds Solids (K160.2) X X X X X Nitrate - Nitrate (PE3M.1) X X X X X tPhysical Caracteristics : Soil Enginering Classificatim X X X X X X X X (MQ8-84...site, soil cuttings from drilling the borings and wells will be placed on a plastic tarp and covered until samples of the soil have been screened using

  2. Msx1 is expressed in retina endothelial cells at artery branching sites

    Miguel Lopes; Olivier Goupille; Cécile Saint Cloment; Benoît Robert

    2012-01-01

    Summary Msx1 and Msx2 encode homeodomain transcription factors that play a role in several embryonic developmental processes. Previously, we have shown that in the adult mouse, Msx1lacZ is expressed in vascular smooth muscle cells (VSMCs) and pericytes, and that Msx2lacZ is also expressed in VSMCs as well as in a few endothelial cells (ECs). The mouse retina and choroid are two highly vascularized tissues. Vessel alterations in the retina are associated with several human diseases and the ret...

  3. Suppression of prolactin gene expression in GH cells correlates with site-specific DNA methylation.

    Zhang, Z X; Kumar, V; Rivera, R T; Pasion, S G; Chisholm, J; Biswas, D K

    1989-10-01

    Prolactin- (PRL) producing and nonproducing subclones of the GH line of (rat) pituitary tumor cells have been compared to elucidate the regulatory mechanisms of PRL gene expression. Particular emphasis was placed on delineating the molecular basis of the suppressed state of the PRL gene in the prolactin-nonproducing (PRL-) GH subclone (GH(1)2C1). We examined six methylatable cytosine residues (5, -CCGG- and 1, -GCGC-) within the 30-kb region of the PRL gene in these subclones. This analysis revealed that -CCGG-sequences of the transcribed region, and specifically, one in the fourth exon of the PRL gene, were heavily methylated in the PRL-, GH(1)2C1 cells. Furthermore, the inhibition of PRL gene expression in GH(1)2C1 was reversed by short-term treatment of the cells with a sublethal concentration of azacytidine (AzaC), an inhibitor of DNA methylation. The reversion of PRL gene expression by AzaC was correlated with the concurrent demethylation of the same -CCGG- sequences in the transcribed region of PRL gene. An inverse correlation between PRL gene expression and the level of methylation of the internal -C- residues in the specific -CCGG-sequence of the transcribed region of the PRL gene was demonstrated. The DNase I sensitivity of these regions of the PRL gene in PRL+, PRL-, and AzaC-treated cells was also consistent with an inverse relationship between methylation state, a higher order of structural modification, and gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Nuclear Power Plant Mechanical Component Flooding Fragility Experiments Status

    Pope, C. L. [Idaho State Univ., Pocatello, ID (United States); Savage, B. [Idaho State Univ., Pocatello, ID (United States); Johnson, B. [Idaho State Univ., Pocatello, ID (United States); Muchmore, C. [Idaho State Univ., Pocatello, ID (United States); Nichols, L. [Idaho State Univ., Pocatello, ID (United States); Roberts, G. [Idaho State Univ., Pocatello, ID (United States); Ryan, E. [Idaho State Univ., Pocatello, ID (United States); Suresh, S. [Idaho State Univ., Pocatello, ID (United States); Tahhan, A. [Idaho State Univ., Pocatello, ID (United States); Tuladhar, R. [Idaho State Univ., Pocatello, ID (United States); Wells, A. [Idaho State Univ., Pocatello, ID (United States); Smith, C. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2017-07-24

    This report describes progress on Nuclear Power Plant mechanical component flooding fragility experiments and supporting research. The progress includes execution of full scale fragility experiments using hollow-core doors, design of improvements to the Portal Evaluation Tank, equipment procurement and initial installation of PET improvements, designation of experiments exploiting the improved PET capabilities, fragility mathematical model development, Smoothed Particle Hydrodynamic simulations, wave impact simulation device research, and pipe rupture mechanics research.

  5. Treatment of Fragile X Syndrome with a Neuroactive Steroid

    2013-08-01

    Fulks JL, O’Bryhim BE et al (2010) Dopamine release and uptake impairments and behavioral alterations observed in mice that model fragile x mental...D2 dopamine receptor agonist. J Cogn Neurosci 4(1):58–68 Luo Y, Shan G et al (2010) Fragile x mental retardation protein regulates proliferation and...AD_________________ Award Number: W81XWH-11-1-0626 TITLE: Treatment of Fragile X Syndrome with a

  6. Using the Textpresso Site-Specific Recombinases Web server to identify Cre expressing mouse strains and floxed alleles.

    Condie, Brian G; Urbanski, William M

    2014-01-01

    Effective tools for searching the biomedical literature are essential for identifying reagents or mouse strains as well as for effective experimental design and informed interpretation of experimental results. We have built the Textpresso Site Specific Recombinases (Textpresso SSR) Web server to enable researchers who use mice to perform in-depth searches of a rapidly growing and complex part of the mouse literature. Our Textpresso Web server provides an interface for searching the full text of most of the peer-reviewed publications that report the characterization or use of mouse strains that express Cre or Flp recombinase. The database also contains most of the publications that describe the characterization or analysis of strains carrying conditional alleles or transgenes that can be inactivated or activated by site-specific recombinases such as Cre or Flp. Textpresso SSR complements the existing online databases that catalog Cre and Flp expression patterns by providing a unique online interface for the in-depth text mining of the site specific recombinase literature.

  7. The burden and undertreatment of fragility fractures among senior women.

    Rodrigues, Ana M; Eusébio, Mónica; Santos, Maria José; Gouveia, Nélia; Tavares, Viviana; Coelho, Pedro S; Mendes, Jorge M; Branco, Jaime C; Canhão, Helena

    2018-03-07

    Using a large population database, we showed that fragility fractures were highly prevalent in senior women and were associated with significant physical disability. However, treatment rates were low because osteoporosis treatment was not prescribed or not agreed to by the majority of women with prevalent fragility fractures. The purpose of the study is to estimate prevalence of fragility fractures (FF), risk factors, and treatment rates in senior women and to assess impact of FF on physical function and quality of life. Women aged 65 years and older from the EpiReumaPt study (2011-2013) were evaluated. Rheumatologists collected data regarding FF, clinical risk factors for fractures, and osteoporosis (OP) treatment. Health-related quality of life (EQ5D) and physical function (HAQ) were analyzed. Peripheral dual-energy X-ray absorptiometry was performed. FF was defined as any self-reported low-impact fracture that occurred after 40 years of age. Prevalence estimates of FF were calculated. Among 3877 subjects evaluated in EpiReumaPt, 884 were senior women. The estimated prevalence of FF was 20.7%. Lower leg was the most frequent fracture site reported (37.8%) followed by wrist (18.6%). Only 7.1% of the senior women reporting a prevalent FF were under treatment for OP, and 13.9% never had treatment. OP treatment was not prescribed in 47.7% of FF women, and 23.4% refused treatment. Age (OR = 2.46, 95% CI 1.11-5.47), obesity (OR = 2.05, 95% CI 1.14-3.70), and low wrist BMD (OR = 2.29; 95% CI 1.20, 4.35; p = 0.012) were positively associated with prevalent FF. A significantly higher proportion of women in the lowest quintile of wrist bone mineral density reported FF (OR = 2.29, 95% CI 1.20-4.35). FF were associated with greater physical disability (β = 0.33, 95% CI 0.13-0.51) independent of other comorbidities. FF was frequently reported among senior women as an important cause of physical disability. However, the prevalence of OP treatment was

  8. Proposed nomination of sites for site characterization and recommendation of issues for environmental assessments and site characterization plans. Technical report. Summary of issues and concerns expressed during the April-May 1983 US Department of Energy public hearings

    1983-09-01

    As required by Section 112(b)(2) of the Nuclear Waste Policy Act (Public Law 97-425), the US Department of Energy (DOE) conducted a series of nine formal public hearings during April and May 1983 in local communities in the vicinity of seven identified potentially acceptable salt sites and in the state capitals of the States of Louisiana, Mississippi, Texas, and Utah. The public hearings focused on the proposed nomination of the Vacherie Dome site in Louisiana; the Richton and Cypress Creek Salt Dome sites in Mississippi; the Deaf Smith County and Swisher County bedded salt sites in Texas; and the Davis and Lavender Canyon bedded salt sites in Utah. The issues expressed during area public hearings are summarized in this document, which serves as a digest of and as an index to the public hearing records of each of the four salt states. Specifically, almost 1100 paraphrased public hearing comments are identified and grouped into 62 subjects within the following nine general topical areas: NWTS Program Planning Process, Consultation and Cooperation, Engineering/Repository Design, Geology, Hydrology, Transportation, Public Health and Safety, Environmental Quality, and Socioeconomics

  9. Systems Fragility: The Sociology of Chaos

    2015-03-01

    shuttle explosion was found to be “a failure in the joint between the two lower segments of the right Solid Rocket Motor.” The report goes on to state...2013, http://www.bloomberg.com/news/2013-09-24/flooded-estes-park-greets- tourists -as- locals-can-t-flush html 137 Koehler, Kress, and Miller, What... market research questions about animals.166 For the purposes of this research, purposive event sampling is used to study community fragility in

  10. Seismic fragility evaluation of unreinforced masonry walls

    Park, Y.J.; Hofmayer, C.H.; Reich, M.; Lee, S.K.

    1991-01-01

    A practical analysis scheme to evaluate the seismic fragility of unreinforced masonry walls which are used to various places in older reactor facilities is presented. Among the several failure modes for such walls, the out-of-plane bending failure is considered to be a major risk contributor in seismic PRA studies. In order to evaluate this failure mode, the use of an equivalent linear approximation method is examined based on comparisons with available test data and nonlinear time history analyses. 6 refs., 4 figs., 3 tabs

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

    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.

  12. Self-Injurious Behavior and Fragile X Syndrome: Findings from the National Fragile X Survey

    Symons, Frank J.; Byiers, Breanne J.; Raspa, Melissa; Bishop, Ellen; Bailey, Donald B., Jr.

    2010-01-01

    We used National Fragile X Survey data in order to examine reported self-injurious behavior (SIB) to (a) generate lifetime and point prevalence estimates, (b) document detailed features of SIB (frequency, types, location, severity) in relation to gender, and (c) compare comorbid conditions between matched pairs (SIB vs. no SIB). Results indicate…

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

    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.

  14. Nuclear pores and perinuclear expression sites of var and ribosomal DNA genes correspond to physically distinct regions in Plasmodium falciparum.

    Guizetti, Julien; Martins, Rafael Miyazawa; Guadagnini, Stéphanie; Claes, Aurélie; Scherf, Artur

    2013-05-01

    The human malaria parasite Plasmodium falciparum modifies the erythrocyte it infects by exporting variant proteins to the host cell surface. The var gene family that codes for a large, variant adhesive surface protein called P. falciparum erythrocyte membrane protein 1 (PfEMP1) plays a particular role in this process, which is linked to pathogenesis and immune evasion. A single member of this gene family is highly transcribed while the other 59 members remain silenced. Importantly, var gene transcription occurs at a spatially restricted, but yet undefined, perinuclear site that is distinct from repressed var gene clusters. To advance our understanding of monoallelic expression, we investigated whether nuclear pores associate with the var gene expression site. To this end, we studied the nuclear pore organization during the asexual blood stage using a specific antibody directed against a subunit of the nuclear pore, P. falciparum Nup116 (PfNup116). Ring and schizont stage parasites showed highly polarized nuclear pore foci, whereas in trophozoite stage nuclear pores redistributed over the entire nuclear surface. Colocalization studies of var transcripts and anti-PfNup116 antibodies showed clear dissociation between nuclear pores and the var gene expression site in ring stage. Similar results were obtained for another differentially transcribed perinuclear gene family, the ribosomal DNA units. Furthermore, we show that in the poised state, the var gene locus is not physically linked to nuclear pores. Our results indicate that P. falciparum does form compartments of high transcriptional activity at the nuclear periphery which are, unlike the case in yeast, devoid of nuclear pores.

  15. Quantitative PET Imaging of Tissue Factor Expression Using 18F-labled Active Site Inhibited Factor VII

    Nielsen, Carsten H; Erlandsson, Maria; Jeppesen, Troels E

    2016-01-01

    Tissue factor (TF) is up regulated in many solid tumors and its expression is linked to tumor angiogenesis, invasion, metastasis and prognosis. A non-invasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII (FVII) is the natural ligand to TF. Here we...... report the development of a new PET tracer for specific imaging of TF using an (18)F-labeled derivative of FVII. METHODS: Active site inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4......-[(18)F]-fluorobenzoate ([(18)F]SFB) and purified. The corresponding product, [(18)F]FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small animal PET/CT imaging 1, 2 and 4 hours after injection. Ex vivo biodistribution was performed...

  16. Subcellular fractionation and localization studies reveal a direct interaction of the Fragile X Mental Retardation Protein (FMRP) with nucleolin

    Taha, M.S.; Nouri, K.; Milroy, L.G.; Moll, J.M.; Herrmann, C.; Brunsveld, L.; Piekorz, R.P.; Ahmadian, M.R.

    2014-01-01

    Fragile X mental Retardation Protein (FMRP) is a well-known regulator of local translation of its mRNA targets in neurons. However, despite its ubiquitous expression, the role of FMRP remains ill-defined in other cell types. In this study we investigated the subcellular distribution of FMRP and its

  17. Igs expressed by chronic lymphocytic leukemia B cells show limited binding-site structure variability.

    Marcatili, Paolo; Ghiotto, Fabio; Tenca, Claudya; Chailyan, Anna; Mazzarello, Andrea N; Yan, Xiao-Jie; Colombo, Monica; Albesiano, Emilia; Bagnara, Davide; Cutrona, Giovanna; Morabito, Fortunato; Bruno, Silvia; Ferrarini, Manlio; Chiorazzi, Nicholas; Tramontano, Anna; Fais, Franco

    2013-06-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated.

  18. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    Marcatili, P.

    2013-05-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  19. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    Marcatili, P.; Ghiotto, F.; Tenca, C.; Chailyan, A.; Mazzarello, A. N.; Yan, X.-J.; Colombo, M.; Albesiano, E.; Bagnara, D.; Cutrona, G.; Morabito, F.; Bruno, S.; Ferrarini, M.; Chiorazzi, N.; Tramontano, A.; Fais, F.

    2013-01-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  20. The kinetic fragility of natural silicate melts

    Giordano, Daniele; Dingwell, Donald B

    2003-01-01

    Newtonian viscosities of 19 multicomponent natural and synthetic silicate liquids, with variable contents of SiO 2 (41-79 wt%), Al 2 O 3 (10-19 wt%), TiO 2 (0-3 wt%), FeO tot (0-11 wt%); alkali oxides (5-17 wt%), alkaline-earth oxides (0-35 wt%), and minor oxides, obtained at ambient pressure using the high-temperature concentric cylinder, the low-temperature micropenetration, and the parallel plates techniques, have been analysed. For each silicate liquid, regression of the experimentally determined viscosities using the well known Vogel-Fulcher-Tammann (VFT) equation allowed the viscosity of all these silicates to be accurately described. The results of these fits, which provide the basis for the subsequent analysis here, permit qualitative and quantitative correlations to be made between the VFT adjustable parameters (A VFT , B VFT , and T 0 ). The values of B VFT and T 0 , calibrated via the VFT equation, are highly correlated. Kinetic fragility appears to be correlated with the number of non-bridging oxygens per tetrahedrally coordinated cation (NBO/T). This is taken to infer that melt polymerization controls melt fragility in liquid silicates. Thus NBO/T might form an useful ingredient of a structure-based model of non-Arrhenian viscosity in multicomponent silicate melts

  1. Fragility estimation for seismically isolated nuclear structures by high confidence low probability of failure values and bi-linear regression

    Carausu, A.

    1996-01-01

    A method for the fragility estimation of seismically isolated nuclear power plant structure is proposed. The relationship between the ground motion intensity parameter (e.g. peak ground velocity or peak ground acceleration) and the response of isolated structures is expressed in terms of a bi-linear regression line, whose coefficients are estimated by the least-square method in terms of available data on seismic input and structural response. The notion of high confidence low probability of failure (HCLPF) value is also used for deriving compound fragility curves for coupled subsystems. (orig.)

  2. Internal ribosomal entry site-mediated translation is important for rhythmic PERIOD1 expression.

    Kyung-Ha Lee

    Full Text Available The mouse PERIOD1 (mPER1 plays an important role in the maintenance of circadian rhythm. Translation of mPer1 is directed by both a cap-dependent process and cap-independent translation mediated by an internal ribosomal entry site (IRES in the 5' untranslated region (UTR. Here, we compared mPer1 IRES activity with other cellular IRESs. We also found critical region in mPer1 5'UTR for heterogeneous nuclear ribonucleoprotein Q (HNRNPQ binding. Deletion of HNRNPQ binding region markedly decreased IRES activity and disrupted rhythmicity. A mathematical model also suggests that rhythmic IRES-dependent translation is a key process in mPER1 oscillation. The IRES-mediated translation of mPer1 will help define the post-transcriptional regulation of the core clock genes.

  3. A thousand ways to say 'Delicious!'-Categorizing expressions of deliciousness from restaurant reviews on the social network site Yelp.

    Ariyasriwatana, Weranuj; Quiroga, Luz Marina

    2016-09-01

    This study explored expressions of deliciousness-one of the main reasons people make specific food choices over others-from restaurant reviews on Yelp, a popular social network site. Through qualitative content analysis of 205 reviews from 41 food establishments in Hawaii, we found 8 main categories of expressions of deliciousness. These eight main categories created by both concept-driven and data-driven strategies are Sense, Culinary Affair, Matter of Heart, Health, Testimonial and Endorsement, Personal Signature, Consumer, and Restaurant. Each main category was further subcategorized. This meaningful categorization might contribute to healthier eating by helping policy makers and food companies craft effective strategies for healthy eating schemes, healthy menu items, or healthy food products. Marketers of any food product can also increase their market share by utilizing these categories, subcategories, and their underlying concepts in the planning stage. Detailed examples of nudging and social marketing campaigns inspired by our findings were provided. Moreover, social network sites can better serve health conscious and hedonic consumers by personalization through improved algorithms inspired by these categories. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Evaluation of glyphosate resistance in Arabidopsis thaliana expressing an altered target site EPSPS.

    Sammons, R Douglas; You, Jinsong; Qi, Youlin; Flasinski, Stanislaw; Kavanaugh, Christina; Washam, Jeannie; Ostrander, Elizabeth; Wang, Dafu; Heck, Greg

    2018-05-01

    Glyphosate-resistant goosegrass has recently evolved and is homozygous for the double mutant of EPSPS (T 102 I, P 106 S or TIPS). These same mutations combined with EPSPS overexpression, have been used to create transgenic glyphosate-resistant crops. Arabidopsis thaliana (Wt EPSPS K i ∼ 0.5 μM) was engineered to express a variant AtEPSPS-T 102 I, P 106 A (TIPA K i = 150 μM) to determine the resistance magnitude for a more potent variant EPSPS that might evolve in weeds. Transgenic A. thaliana plants, homozygous for one, two or four copies of AtEPSPS-TIPA, had resistance (IC 50 values, R/S) as measured by seed production ranging from 4.3- to 16-fold. Plants treated in reproductive stage were male sterile with a range of R/S from 10.1- to 40.6-fold. A significant hormesis (∼ 63% gain in fresh weight) was observed for all genotypes when treated at the initiation of reproductive stage with 0.013 kg ha -1 . AtEPSPS-TIPA enzyme activity was proportional to copy number and correlated with resistance magnitude. A. thaliana, as a model weed expressing one copy of AtEPSPS-TIPA (300-fold more resistant), had only 4.3-fold resistance to glyphosate for seed production. Resistance behaved as a single dominant allele. Vegetative tissue resistance was 4.7-fold greater than reproductive tissue resistance and was linear with gene copy number. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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

    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 ...

  6. Forests, Fragility and Conflict : Overview and Case Studies

    Harwell, Emily; Farah, Douglas; Blundell, Arthur G.

    2011-01-01

    This book provides a synthesis of key themes and current knowledge about the links among forests, armed conflict, poverty, and various aspects of state fragility. The main themes addressed are: how predatory, incapable, or absent states are fragile in different ways, and their diverse relationships to forests and conflict; the mechanisms by which forests facilitate or prolong conflict, inc...

  7. Babies at Double Jeopardy: Medically Fragile Infants and Child Neglect

    Fullar, Suzanne A.

    2008-01-01

    Medically fragile infants, those born prematurely or with other complex medical or genetic problems, are at risk of long-term health and developmental problems. When a medically fragile infant comes home to a family with significant social problems such as domestic violence, mental illness, or substance abuse, the infant is at double jeopardy--at…

  8. Molecular characterization of X chromosome fragility in idiopathic ...

    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 ...

  9. Attentional Set-Shifting in Fragile X Syndrome

    Van der Molen, M. J. W.; Van der Molen, M. W.; Ridderinkhof, K. R.; Hamel, B. C. J.; Curfs, L. M. G.; Ramakers, G. J. A.

    2012-01-01

    The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the…

  10. Whole-of-Government Approaches to Fragile States in Africa

    Olsen, Gorm Rye

    2013-01-01

    For a number of years fragile states have been high on the foreign policy agendas of the USA and the EU. Both actors look upon fragile states with great concern and consider them as security threats. Officially they give priority to ‘whole-of-government approaches’ (wga) when addressing the threats...

  11. Dilemmas in counselling females with the fragile X syndrome

    B.B.A. de Vries (Bert); H.M. van den Boer-van den Berg; M.F. Niermeijer (Martinus); A. Tibben (Arend)

    1999-01-01

    textabstractThe dilemmas in counselling a mildly retarded female with the fragile X syndrome and her retarded partner are presented. The fragile X syndrome is an X linked mental retardation disorder that affects males and, often less severely, females. Affected females

  12. 21 CFR 864.6600 - Osmotic fragility test.

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Osmotic fragility test. 864.6600 Section 864.6600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Manual Hematology Devices § 864.6600 Osmotic fragility...

  13. Improved Erythrocyte Osmotic Fragility and Packed Cell Volume ...

    Improved Erythrocyte Osmotic Fragility and Packed Cell Volume following administration of Aloe barbadensis Juice Extract in Rats. ... Abstract. Aloe barbadensis is a popular house plant that has a long history of a multipurpose folk remedy. ... Keywords: osmotic fragility, packed cell volume, haemoglobin, Aloe vera ...

  14. Study on the Progress of Ecological Fragility Assessment in China

    Chen, Pei; Hou, Kang; Chang, Yue; Li, Xuxiang; Zhang, Yunwei

    2018-02-01

    The basic elements of human survival are based on the ecological environment. The development of social economic and the security of the ecological environment are closely linked and interact with each other. The fragility of the environment directly affects the stability of the regional ecosystem and the sustainable development of the ecological environment. As part of the division of the national ecological security, the assessment of ecological fragility has become a hot and difficult issue in environmental research, and researchers at home and abroad have systematically studied the causes and states of ecological fragility. The assessment of regional ecological fragility is a qualitative and quantitative analysis of the unbalanced distribution of ecological environment factors caused by human socio-economic activities or changes in ecosystems. At present, researches on ecological fragility has not formed a complete and unified index assessment system, and the unity of the assessment model has a direct impact on the accuracy of the index weights. Therefore, the discussion on selection of ecological fragility indexes and the improvement of ecological fragility assessment model is necessary, which is good for the improvement of ecological fragility assessment system in China.

  15. Usng subjective percentiles and test data for estimating fragility functions

    George, L.L.; Mensing, R.W.

    1981-01-01

    Fragility functions are cumulative distribution functions (cdfs) of strengths at failure. They are needed for reliability analyses of systems such as power generation and transmission systems. Subjective opinions supplement sparse test data for estimating fragility functions. Often the opinions are opinions on the percentiles of the fragility function. Subjective percentiles are likely to be less biased than opinions on parameters of cdfs. Solutions to several problems in the estimation of fragility functions are found for subjective percentiles and test data. How subjective percentiles should be used to estimate subjective fragility functions, how subjective percentiles should be combined with test data, how fragility functions for several failure modes should be combined into a composite fragility function, and how inherent randomness and uncertainty due to lack of knowledge should be represented are considered. Subjective percentiles are treated as independent estimates of percentiles. The following are derived: least-squares parameter estimators for normal and lognormal cdfs, based on subjective percentiles (the method is applicable to any invertible cdf); a composite fragility function for combining several failure modes; estimators of variation within and between groups of experts for nonidentically distributed subjective percentiles; weighted least-squares estimators when subjective percentiles have higher variation at higher percents; and weighted least-squares and Bayes parameter estimators based on combining subjective percentiles and test data. 4 figures, 2 tables

  16. Finiteness Marking in Boys with Fragile X Syndrome

    Sterling, Audra M.; Rice, Mabel L.; Warren, Steven F.

    2012-01-01

    Purpose: The current study investigated finiteness marking (e.g., he walk "s", he walk "ed") in boys with fragile X syndrome (FXS); the boys were grouped based on receptive vocabulary (i.e., borderline, impaired). Method: Twenty-one boys with the full mutation of fragile X, between the ages of 8 and 16 years participated. The…

  17. Seismic fragility levels of nuclear power plant equipment

    Bandyopadhyay, K.K.; Hofmayer, C.H.

    1987-01-01

    Seismic fragility levels of safety-related electrical and mechanical equipment used in nuclear power plants are discussed. The fragility level is defined as the vibration level corresponding to initiation of equipment malfunctions. The test response spectrum is used as a measure of this vibration level. The fragility phenomenon of an equipment is represented by a number of response spectra corresponding to various failure modes. Analysis methods are described for determination of the fragility level by use of existing test data. Useful conversion factors are tabulated to transform test response spectra from one damping value to another. Results are presented for switch-gears and motor control centers. The capacity levels of these equipment assemblies are observed to be limited by malfunctioning of contactors, motor starters, relays and/or switches. The applicability of the fragility levels, determined in terms of test response spectra, to Seismic Margin Studies and Probabilistic Risk Assessments is discussed and specific recommendations are provided

  18. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome.

    Li, Yue; Stockton, Michael E; Bhuiyan, Ismat; Eisinger, Brian E; Gao, Yu; Miller, Jessica L; Bhattacharyya, Anita; Zhao, Xinyu

    2016-04-27

    Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome. Copyright © 2016, American Association for the Advancement of Science.

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

    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.

  20. Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells.

    Yuping Luo

    2010-04-01

    Full Text Available Fragile X syndrome (FXS, the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP. FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs. We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3beta. Dysregulation of GSK3beta led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.

  1. ANALYSIS OF ENVIRONMENTAL FRAGILITY USING MULTI-CRITERIA ANALYSIS (MCE FOR INTEGRATED LANDSCAPE ASSESSMENT

    Abimael Cereda Junior

    2014-01-01

    Full Text Available The Geographic Information Systems brought greater possibilitie s to the representation and interpretation of the landscap e as well as the integrated a nalysis. However, this approach does not dispense technical and methodological substan tiation for achieving the computational universe. This work is grounded in ecodynamic s and empirical analysis of natural and anthr opogenic environmental Fragility a nd aims to propose and present an integrated paradigm of Multi-criteria Analysis and F uzzy Logic Model of Environmental Fragility, taking as a case study of the Basin of Monjolinho Stream in São Carlos-SP. The use of this methodology allowed for a reduct ion in the subjectivism influences of decision criteria, which factors might have its cartographic expression, respecting the complex integrated landscape.

  2. The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells.

    Zalfa, Francesca; Panasiti, Vincenzo; Carotti, Simone; Zingariello, Maria; Perrone, Giuseppe; Sancillo, Laura; Pacini, Laura; Luciani, Flavie; Roberti, Vincenzo; D'Amico, Silvia; Coppola, Rosa; Abate, Simona Osella; Rana, Rosa Alba; De Luca, Anastasia; Fiers, Mark; Melocchi, Valentina; Bianchi, Fabrizio; Farace, Maria Giulia; Achsel, Tilmann; Marine, Jean-Christophe; Morini, Sergio; Bagni, Claudia

    2017-11-16

    The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival. Reduction of FMRP in metastatic melanoma cell lines impinges on cell migration, invasion and adhesion. Next-generation sequencing in human melanoma cells revealed that FMRP regulates a large number of mRNAs involved in relevant processes of melanoma progression. Our findings suggest an association between FMRP levels and the invasive phenotype in melanoma and might open new avenues towards the discovery of novel therapeutic targets.

  3. Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins.

    Chen, Eileen; Joseph, Simpson

    2015-07-01

    Translational control is a common mechanism used to regulate gene expression and occur in bacteria to mammals. Typically in translational control, an RNA-binding protein binds to a unique sequence in the mRNA to regulate protein synthesis by the ribosomes. Alternatively, a protein may bind to or modify a translation factor to globally regulate protein synthesis by the cell. Here, we review translational control by the fragile X mental retardation protein (FMRP), the absence of which causes the neurological disease, fragile X syndrome (FXS). Copyright © 2015 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

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

    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,

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

    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.

  6. Fragile X Syndrome in a Colombian Family

    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.

  7. Ectodermal dysplasia-skin fragility syndrome

    Vijay S Adhe

    2011-01-01

    Full Text Available Ectodermal dysplasia-skin fragility (EDSF syndrome is a rare and first described inherited disorder of desmosomes. It occurs due to loss-of-function mutations in PKP1 gene resulting in poorly formed desmosomes and loss of desmosomal and epidermal integrity. We report a case of a 2-year-old Indian male child who presented with palmoplantar hyperkeratosis with fissuring, short, sparse, and easily pluckable scalp hair, nail dystrophy, and multiple erosions over the skin. Skin biopsy showed epidermal hyperplasia with widening of intercellular spaces. His developmental milestones were delayed but intelligence was normal. Echocardiography, X-ray chest, and electrocardiogram were normal. Very few cases of this syndrome have been reported in the literature. We consider this as the first case report from India.

  8. Fragility fracture risk and skeletal muscle function.

    Pérez-López, F R; Ara, I

    2016-01-01

    Low-intensity fractures are closely related with age-related musculoskeletal disorders, including osteoporosis, muscle dysfunction and sarcopenia, age-related chronic diseases, and pharmacological treatments. During the last years, a huge amount of information and recommendations has been released in relation to bone metabolism and mineral content. Muscle dysfunction and sarcopenia are highly prevalent during the second half of life, especially in older subjects. The development of sarcopenia may be slowed through healthy lifestyle changes, which include adequate dietary protein, vitamin D and mineral intakes, and regular physical activity. Prevention of falls should be integral, including correction in major involved factors in order to reduce fragility fracture, improve quality of life and appropriately focus clinical and economic resources. Therefore, to obtain better results a global approach is needed to prevent age-related fractures in frail patients that is not only centered on bone metabolism and antiresorptive drugs.

  9. Pathological Plasticity in Fragile X Syndrome

    Brandon S. Martin

    2012-01-01

    Full Text Available Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS, disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.

  10. Derivation of general expression for variance in difference in the contents of active ingredient in raw material as determined at seller's and purchaser's site

    Narasimha Murty, B.; Prahlad, B.

    2012-01-01

    Material supply from a supplier to purchaser involve weighing of the material at both the sites. It is always of interest to know whether there is any difference in the weight of the material and more importantly in the weight of the active ingredient supplied and received. This paper describes the derivation of general expression for variance in difference in the contents of active ingredient in raw material as determined at the seller's and purchaser's site. The derived expression for the variance in difference in the content of active ingredient as determined at seller's and purchaser's site is a generic one though its application is demonstrated for two raw materials

  11. An unusual internal ribosomal entry site of inverted symmetry directs expression of a potato leafroll polerovirus replication-associated protein

    Jaag, Hannah Miriam; Kawchuk, Lawrence; Rohde, Wolfgang; Fischer, Rainer; Emans, Neil; Prüfer, Dirk

    2003-01-01

    Potato leafroll polerovirus (PLRV) genomic RNA acts as a polycistronic mRNA for the production of proteins P0, P1, and P2 translated from the 5′-proximal half of the genome. Within the P1 coding region we identified a 5-kDa replication-associated protein 1 (Rap1) essential for viral multiplication. An internal ribosome entry site (IRES) with unusual structure and location was identified that regulates Rap1 translation. Core structural elements for internal ribosome entry include a conserved AUG codon and a downstream GGAGAGAGAGG motif with inverted symmetry. Reporter gene expression in potato protoplasts confirmed the internal ribosome entry function. Unlike known IRES motifs, the PLRV IRES is located completely within the coding region of Rap1 at the center of the PLRV genome. PMID:12835413

  12. Expression

    Wang-Xia Wang

    2014-02-01

    Full Text Available The miR-15/107 family comprises a group of 10 paralogous microRNAs (miRNAs, sharing a 5′ AGCAGC sequence. These miRNAs have overlapping targets. In order to characterize the expression of miR-15/107 family miRNAs, we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members, and other selected miRNAs, in 11 human tissues obtained at autopsy including the cerebral cortex, frontal cortex, primary visual cortex, thalamus, heart, lung, liver, kidney, spleen, stomach and skeletal muscle. miR-103, miR-195 and miR-497 were expressed at similar levels across various tissues, whereas miR-107 is enriched in brain samples. We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations (enriched for cortical neurons, astrocytes and microglia, respectively. In primary cultures of rat brain cells, several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system (CNS. In addition to mature miRNAs, we also examined the expression of precursors (pri-miRNAs. Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors. In summary, we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.

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

    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.

  14. Site-Specific Expression of Gelatinolytic Activity during Morphogenesis of the Secondary Palate in the Mouse Embryo

    Gkantidis, Nikolaos; Blumer, Susan; Katsaros, Christos; Graf, Daniel; Chiquet, Matthias

    2012-01-01

    Morphogenesis of the secondary palate in mammalian embryos involves two major events: first, reorientation of the two vertically oriented palatal shelves into a horizontal position above the tongue, and second, fusion of the two shelves at the midline. Genetic evidence in humans and mice indicates the involvement of matrix metalloproteinases (MMPs). As MMP expression patterns might differ from sites of activity, we used a recently developed highly sensitive in situ zymography technique to map gelatinolytic MMP activity in the developing mouse palate. At embryonic day 14.5 (E14.5), we detected strong gelatinolytic activity around the lateral epithelial folds of the nasopharyngeal cavity, which is generated as a consequence of palatal shelf elevation. Activity was concentrated in the basement membrane of the epithelial fold but extended into the adjacent mesenchyme, and increased in intensity with lateral outgrowth of the cavity at E15.5. Gelatinolytic activity at this site was not the consequence of epithelial fold formation, as it was also observed in Bmp7-deficient embryos where shelf elevation is delayed. In this case, gelatinolytic activity appeared in vertical shelves at the exact position where the epithelial fold will form during elevation. Mmp2 and Mmp14 (MT1-MMP), but not Mmp9 and Mmp13, mRNAs were expressed in the mesenchyme around the epithelial folds of the elevated palatal shelves; this was confirmed by immunostaining for MMP-2 and MT1-MMP. Weak gelatinolytic activity was also found at the midline of E14.5 palatal shelves, which increased during fusion at E15.5. Whereas MMPs have been implicated in palatal fusion before, this is the first report showing that gelatinases might contribute to tissue remodeling during early stages of palatal shelf elevation and formation of the nasopharynx. PMID:23091646

  15. Raman chemical mapping reveals site of action of HIV protease inhibitors in HPV16 E6 expressing cervical carcinoma cells.

    Kim, Dong-Hyun; Jarvis, Roger M; Allwood, J William; Batman, Gavin; Moore, Rowan E; Marsden-Edwards, Emma; Hampson, Lynne; Hampson, Ian N; Goodacre, Royston

    2010-12-01

    It has been shown that the HIV protease inhibitors indinavir and lopinavir may have activity against the human papilloma virus (HPV) type 16 inhibiting HPV E6-mediated proteasomal degradation of p53 in cultured cervical carcinoma cells. However, their mode and site of action is unknown. HPV-negative C33A cervical carcinoma cells and the same cells stably transfected with E6 (C33AE6) were exposed to indinavir and lopinavir at concentrations of 1 mM and 30 μM, respectively. The intracellular distribution of metabolites and metabolic changes induced by these treatments were investigated by Raman microspectroscopic imaging combined with the analysis of cell fractionation products by liquid chromatography-mass spectrometry (LC-MS). A uniform cellular distribution of proteins was found in drug-treated cells irrespective of cell type. Indinavir was observed to co-localise with nucleic acid in the nucleus, but only in E6 expressing cells. Principal components analysis (PCA) score maps generated on the full Raman hypercube and the corresponding PCA loadings plots revealed that the majority of metabolic variations influenced by the drug exposure within the cells were associated with changes in nucleic acids. Analysis of cell fractionation products by LC-MS confirmed that the level of indinavir in nuclear extracts was approximately eight-fold greater than in the cytoplasm. These data demonstrate that indinavir undergoes enhanced nuclear accumulation in E6-expressing cells, which suggests that this is the most likely site of action for this compound against HPV.

  16. Fragility correlates thermodynamic and kinetic properties of glass forming liquids

    Reddy, C.Narayana [Maharani’s Science College for Women, Bangalore 560001 (India); Viswanatha, R.; Chethana, B.K. [Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012 (India); Gowda, V.C.Veeranna [Government First Grade College, Jayanagara, Bangalore 560070 (India); Rao, K.J., E-mail: kalyajrao@yahoo.co.in [Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012 (India)

    2015-03-15

    Graphical abstract: The suggested new fragility parameter correlates viscosity and configurational entropy. - Highlights: • A new fragility function, F=ΔT/ΔC{sub p}×C{sub p}{sup l}/T{sub g} has been proposed. • A three parameter viscosity function using the new F reproduces Angell fragility plot. • A new ΔC{sub p} function is derived which directly relates Adam–Gibbs function with the fragility based viscosity function. - Abstract: In our earlier communication we proposed a simple fragility determining function, ([NBO]/V{sub m}{sup 3}T{sub g}), which we have now used to analyze several glass systems using available thermal data. A comparison with similar fragility determining function, ΔC{sub p}/C{sub p}{sup l}, introduced by Chryssikos et al. in their investigation of lithium borate glasses has also been performed and found to be more convenient quantity for discussing fragilities. We now propose a new function which uses both ΔC{sub p} and ΔT and which gives a numerical fragility parameter, F whose value lies between 0 and 1 for glass forming liquids. F can be calculated through the use of measured thermal parameters ΔC{sub p}, C{sub p}{sup l}, T{sub g} and T{sub m}. Use of the new fragility values in reduced viscosity equation reproduces the whole range of viscosity curves of the Angell plot. The reduced viscosity equation can be directly compared with the Adam–Gibbs viscosity equation and a heat capacity function can be formulated which reproduces satisfactorily the ΔC{sub p} versus ln(T{sub r}) curves and hence the configurational entropy.

  17. Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression.

    Peeters, Janneke G C; Vervoort, Stephin J; Tan, Sander C; Mijnheer, Gerdien; de Roock, Sytze; Vastert, Sebastiaan J; Nieuwenhuis, Edward E S; van Wijk, Femke; Prakken, Berent J; Creyghton, Menno P; Coffer, Paul J; Mokry, Michal; van Loosdregt, Jorg

    2015-09-29

    The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression

    Janneke G.C. Peeters

    2015-09-01

    Full Text Available The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4+ memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.

  19. Functional Brachyury binding sites establish a temporal read-out of gene expression in the Ciona notochord.

    Lavanya Katikala

    2013-10-01

    Full Text Available The appearance of the notochord represented a milestone in Deuterostome evolution. The notochord is necessary for the development of the chordate body plan and for the formation of the vertebral column and numerous organs. It is known that the transcription factor Brachyury is required for notochord formation in all chordates, and that it controls transcription of a large number of target genes. However, studies of the structure of the cis-regulatory modules (CRMs through which this control is exerted are complicated in vertebrates by the genomic complexity and the pan-mesodermal expression territory of Brachyury. We used the ascidian Ciona, in which the single-copy Brachyury is notochord-specific and CRMs are easily identifiable, to carry out a systematic characterization of Brachyury-downstream notochord CRMs. We found that Ciona Brachyury (Ci-Bra controls most of its targets directly, through non-palindromic binding sites that function either synergistically or individually to activate early- and middle-onset genes, respectively, while late-onset target CRMs are controlled indirectly, via transcriptional intermediaries. These results illustrate how a transcriptional regulator can efficiently shape a shallow gene regulatory network into a multi-tiered transcriptional output, and provide insights into the mechanisms that establish temporal read-outs of gene expression in a fast-developing chordate embryo.

  20. Functional Brachyury binding sites establish a temporal read-out of gene expression in the Ciona notochord.

    Katikala, Lavanya; Aihara, Hitoshi; Passamaneck, Yale J; Gazdoiu, Stefan; José-Edwards, Diana S; Kugler, Jamie E; Oda-Ishii, Izumi; Imai, Janice H; Nibu, Yutaka; Di Gregorio, Anna

    2013-10-01

    The appearance of the notochord represented a milestone in Deuterostome evolution. The notochord is necessary for the development of the chordate body plan and for the formation of the vertebral column and numerous organs. It is known that the transcription factor Brachyury is required for notochord formation in all chordates, and that it controls transcription of a large number of target genes. However, studies of the structure of the cis-regulatory modules (CRMs) through which this control is exerted are complicated in vertebrates by the genomic complexity and the pan-mesodermal expression territory of Brachyury. We used the ascidian Ciona, in which the single-copy Brachyury is notochord-specific and CRMs are easily identifiable, to carry out a systematic characterization of Brachyury-downstream notochord CRMs. We found that Ciona Brachyury (Ci-Bra) controls most of its targets directly, through non-palindromic binding sites that function either synergistically or individually to activate early- and middle-onset genes, respectively, while late-onset target CRMs are controlled indirectly, via transcriptional intermediaries. These results illustrate how a transcriptional regulator can efficiently shape a shallow gene regulatory network into a multi-tiered transcriptional output, and provide insights into the mechanisms that establish temporal read-outs of gene expression in a fast-developing chordate embryo.

  1. Invertible chaotic fragile watermarking for robust image authentication

    Sidiropoulos, Panagiotis; Nikolaidis, Nikos; Pitas, Ioannis

    2009-01-01

    Fragile watermarking is a popular method for image authentication. In such schemes, a fragile signal that is sensitive to manipulations is embedded in the image, so that it becomes undetectable after any modification of the original work. Most algorithms focus either on the ability to retrieve the original work after watermark detection (invertibility) or on detecting which image parts have been altered (localization). Furthermore, the majority of fragile watermarking schemes suffer from robustness flaws. We propose a new technique that combines localization and invertibility. Moreover, watermark dependency on the original image and the non-linear watermark embedding procedure guarantees that no malicious attacks will manage to create information leaks.

  2. Seismic fragility analysis of structural components for HFBR facilities

    Park, Y.J.; Hofmayer, C.H.

    1992-01-01

    The paper presents a summary of recently completed seismic fragility analyses of the HFBR facilities. Based on a detailed review of past PRA studies, various refinements were made regarding the strength and ductility evaluation of structural components. Available laboratory test data were analysed to evaluate the formulations used to predict the ultimate strength and deformation capacities of steel, reinforced concrete and masonry structures. The biasness and uncertainties were evaluated within the framework of the fragility evaluation methods widely accepted in the nuclear industry. A few examples of fragility calculations are also included to illustrate the use of the presented formulations

  3. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome.

    Hall, Deborah A; O'Keefe, Joan A

    2013-11-01

    This article summarizes the clinical findings, genetics, pathophysiology, and treatment of fragile X-associated tremor ataxia syndrome. The disorder occurs from a CGG repeat (55-200) expansion in the fragile X mental retardation 1 gene. It manifests clinically in kinetic tremor, gait ataxia, and executive dysfunction, usually in older men who carry the genetic abnormality. The disorder has distinct radiographic and pathologic findings. Symptomatic treatment is beneficial in some patients. The inheritance is X-linked and family members may be at risk for other fragile X-associated disorders. This information is useful to neurologists, general practitioners, and geneticists. Copyright © 2013. Published by Elsevier Inc.

  4. Fragility and cooperativity concepts in hydrogen-bonded organic glasses

    Delpouve, N., E-mail: delpouve.nicolas@gmail.com [AMME-LECAP EA 4528 International Laboratory, University of Rouen, Avenue de l' Universite BP 12, 76801 Saint Etienne du Rouvray (France); Vuillequez, A.; Saiter, A.; Youssef, B.; Saiter, J.M. [AMME-LECAP EA 4528 International Laboratory, University of Rouen, Avenue de l' Universite BP 12, 76801 Saint Etienne du Rouvray (France)

    2012-09-01

    Molecular dynamics at the glass transition of three lactose/oil glassy systems have been investigated according to the cooperativity and fragility approaches. From Donth's approach, the cooperativity length is estimated by modulated temperature calorimetric measurements. Results reveal that modification of the disaccharide by oil leads to increase the disorder degree in the lactose, the size of the cooperative domains and the fragility index. These particular hydrogen-bonded organic glasses follow the general tendency observed on organic and inorganic polymers: the higher the cooperativity length, the higher the value of the fragility index at T{sub g}.

  5. Fragility and cooperativity concepts in hydrogen-bonded organic glasses

    Delpouve, N.; Vuillequez, A.; Saiter, A.; Youssef, B.; Saiter, J.M.

    2012-01-01

    Molecular dynamics at the glass transition of three lactose/oil glassy systems have been investigated according to the cooperativity and fragility approaches. From Donth's approach, the cooperativity length is estimated by modulated temperature calorimetric measurements. Results reveal that modification of the disaccharide by oil leads to increase the disorder degree in the lactose, the size of the cooperative domains and the fragility index. These particular hydrogen-bonded organic glasses follow the general tendency observed on organic and inorganic polymers: the higher the cooperativity length, the higher the value of the fragility index at T g .

  6. Enhancement of oxidative stability of the subtilisin nattokinase by site-directed mutagenesis expressed in Escherichia coli.

    Weng, MeiZhi; Zheng, ZhongLiang; Bao, Wei; Cai, YongJun; Yin, Yan; Zou, GuoLin; Zou, GouLin

    2009-11-01

    Nattokinase (subtilisin NAT, NK) is a bacterial serine protease with strong fibrinolytic activity and it is a potent cardiovascular drug. In medical and commercial applications, however, it is susceptible to chemical oxidation, and subsequent inactivation or denaturation. Here we show that the oxidative stability of NK was substantially increased by optimizing the amino acid residues Thr(220) and Met(222), which were in the vicinity of the catalytic residue Ser(221) of the enzyme. Two nonoxidative amino acids (Ser and Ala) were introduced at these sites using site-directed mutagenesis. Active enzymes were successfully expressed in Escherichia coli with periplasmic secretion and enzymes were purified to homogeneity. The purified enzymes were analyzed with respect to oxidative stability, kinetic parameters, fibrinolytic activity and thermal stability. M222A mutant was found to have a greatly increased oxidative stability compared with wild-type enzyme and it was resistant to inactivation by more than 1 M H(2)O(2), whereas the wild-type enzyme was inactivated by 0.1 M H(2)O(2) (t(1/2) approximately 11.6 min). The other mutant (T220S) also showed an obvious increase in antioxidative ability. Molecular dynamic simulations on wild-type and T220S mutant proteins suggested that a hydrogen bond was formed between Ser(220) and Asn(155), and the spatial structure of Met(222) was changed compared with the wild-type. The present study demonstrates the feasibility of improving oxidative stability of NK by site-directed mutagenesis and shows successful protein engineering cases to improve stability of NK as a potent therapeutic agent.

  7. HCV E2 glycoprotein: mutagenesis of N-linked glycosylation sites and its effects on E2 expression and processing

    Slater-Handshy, Tiffany; Droll, Deborah A.; Fan Xiaofeng; Di Bisceglie, Adrian M.; Chambers, Thomas J.

    2004-01-01

    An expression system for analysis of the synthesis and processing of the E2 glycoprotein of a hepatitis C virus (HCV) genotype 1a strain was developed in transiently transfected cells. E2 proteins representing the entire length of the protein, including the transmembrane segment (E2) as well as two truncated versions (E2 660 and E2 715 ), were characterized for acquisition of N-linked glycans and transport to the media of transfected cells. To investigate the utilization of the 10 potential N-linked glycosylation sites on this E2 protein, a series of mutations consisting of single or multiple (two, three, four or eight) ablations of asparagine residues in the background of the E2 660 construct were analyzed. E2 660 proteins harboring single or multiple site mutations were produced at levels similar to that of wild-type protein, but secretion of the single mutants was mildly diminished, and elimination of two or more sites dramatically reduced delivery of the protein to the media. Similar results were obtained in Huh-7 cells with respect to intracellular synthesis and secretion of the mutant proteins. Analysis of oligosaccharide composition using endoglycosidase digestion revealed that all of the glycan residues on the intracellular forms of E2 660 , E2 715 , and E2 contained N-linked glycans modified into high-mannose carbohydrates, in contrast to the secreted forms, which were endo H resistant. The parental E2 660 protein could be readily detected in Huh-7 cells using anti-polyhistidine or antibody to recombinant E2. In contrast, E2 660 lacking the eight N-linked glycans was expressed but not detectable with anti-E2 antibody, and proteins lacking four glycans exhibited reduced reactivity. These experiments provide direct evidence that the presence of multiple N-linked glycans is required for the proper folding of the E2 protein in the ER and secretory pathway as well as for formation of its antigenic structure

  8. Earthquake Magnitude and Shaking Intensity Dependent Fragility Functions for Rapid Risk Assessment of Buildings

    Marie-José Nollet

    2018-01-01

    Full Text Available An integrated web application, referred to as ER2 for rapid risk evaluator, is under development for a user-friendly seismic risk assessment by the non-expert public safety community. The assessment of likely negative consequences is based on pre-populated databases of seismic, building inventory and vulnerability parameters. To further accelerate the computation for near real-time analyses, implicit building fragility curves were developed as functions of the magnitude and the intensity of the seismic shaking defined with a single intensity measure, input spectral acceleration at 1.0 s implicitly considering the epicentral distance and local soil conditions. Damage probabilities were compared with those obtained with the standard fragility functions explicitly considering epicentral distances and local site classes in addition to the earthquake magnitudes and respective intensity of the seismic shaking. Different seismic scenarios were considered first for 53 building classes common in Eastern Canada, and then a reduced number of 24 combined building classes was proposed. Comparison of results indicate that the damage predictions with implicit fragility functions for short (M ≤ 5.5 and medium strong motion duration (5.5 < M ≤ 7.5 show low variation with distance and soil class, with average error of less than 3.6%.

  9. Estimating structural collapse fragility of generic building typologies using expert judgment

    Jaiswal, Kishor S.; Wald, D.J.; Perkins, D.; Aspinall, W.P.; Kiremidjian, Anne S.; Deodatis, George; Ellingwood, Bruce R.; Frangopol, Dan M.

    2014-01-01

    The structured expert elicitation process proposed by Cooke (1991), hereafter referred to as Cooke’s approach, is applied for the first time in the realm of structural collapse-fragility assessment for selected generic construction types. Cooke’s approach works on the principle of objective calibration scoring of judgments coupled with hypothesis testing used in classical statistics. The performance-based scoring system reflects the combined measure of an expert’s informativeness about variables in the problem area under consideration, and their ability to enumerate, in a statistically accurate way through expressing their true beliefs, the quantitative uncertainties associated with their assessments. We summarize the findings of an expert elicitation workshop in which a dozen earthquake-engineering professionals from around the world were engaged to estimate seismic collapse fragility for generic construction types. Development of seismic collapse fragility functions was accomplished by combining their judgments using weights derived from Cooke’s method. Although substantial effort was needed to elicit the inputs of these experts successfully, we anticipate that the elicitation strategy described here will gain momentum in a wide variety of earthquake seismology and engineering hazard and risk analyses where physical model and data limitations are inherent and objective professional judgment can fill gaps.

  10. Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site-Inhibited Factor VII.

    Nielsen, Carsten H; Erlandsson, Maria; Jeppesen, Troels E; Jensen, Mette M; Kristensen, Lotte K; Madsen, Jacob; Petersen, Lars C; Kjaer, Andreas

    2016-01-01

    Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an (18)F-labeled derivative of factor VII. Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-(18)F-fluorobenzoate and purified. The corresponding product, (18)F-FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small-animal PET/CT imaging 1, 2, and 4 h after injection. Ex vivo biodistribution was performed after the last imaging session, and tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by enzyme-linked immunosorbent assay and correlated with the uptake of (18)F-FVIIai in the tumors measured in vivo by PET imaging. The PET images showed high uptake of (18)F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of (18)F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7 %ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of (18)F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P < 0.001). The uptake of (18)F-FVIIai measured in vivo by PET imaging correlated (r = 0.72, P < 0.02) with TF protein level measured ex vivo. (18)F-FVIIai is a promising PET tracer for

  11. Organizational changes help Benin NGO better protect fragile ...

    2016-04-28

    Apr 28, 2016 ... ... climate change adaptation, and sustainable management of fragile ecosystems. ... build community-level capacity for sustainable development through ... solution is to build new houses in more secure areas and to relocate ...

  12. Autism Is Associated with the Fragile-X Syndrome.

    Brown, W. Ted.; And Others

    1982-01-01

    The authors describe their methods for establishing the presence or absence of the fragile-X chromosome and discuss some of the clinical implications of their findings in relation to the clinical diagnosis of autism. (SW)

  13. Microaggression Expressions Submission Site

    Wenger, Robert; Ejanda, Cyndy Marie; Falcone, Brandon; Singh, Arunima

    2016-01-01

    The main objective of this project is to create a website so that those concerned with diversity related microaggressions can report, search, share, and study microaggressions. Josh Iorio, the principal faculty in the Myers-Lawson School of Construction, will serve as the client for this project. He will communicate with the College of Engineering to help them understand the effects of microaggressions on its targets and on the organizational climate of the department, helping ensure that the...

  14. Probing the ubiquinol-binding site of recombinant Sauromatum guttatum alternative oxidase expressed in E. coli membranes through site-directed mutagenesis.

    Young, Luke; May, Benjamin; Pendlebury-Watt, Alice; Shearman, Julia; Elliott, Catherine; Albury, Mary S; Shiba, Tomoo; Inaoka, Daniel Ken; Harada, Shigeharu; Kita, Kiyoshi; Moore, Anthony L

    2014-07-01

    In the present paper we have investigated the effect of mutagenesis of a number of highly conserved residues (R159, D163, L177 and L267) which we have recently shown to line the hydrophobic inhibitor/substrate cavity in the alternative oxidases (AOXs). Measurements of respiratory activity in rSgAOX expressed in Escherichia coli FN102 membranes indicate that all mutants result in a decrease in maximum activity of AOX and in some cases (D163 and L177) a decrease in the apparent Km (O2). Of particular importance was the finding that when the L177 and L267 residues, which appear to cause a bottleneck in the hydrophobic cavity, are mutated to alanine the sensitivity to AOX antagonists is reduced. When non-AOX anti-malarial inhibitors were also tested against these mutants widening the bottleneck through removal of isobutyl side chain allowed access of these bulkier inhibitors to the active-site and resulted in inhibition. Results are discussed in terms of how these mutations have altered the way in which the AOX's catalytic cycle is controlled and since maximum activity is decreased we predict that such mutations result in an increase in the steady state level of at least one O2-derived AOX intermediate. Such mutations should therefore prove to be useful in future stopped-flow and electron paramagnetic resonance experiments in attempts to understand the catalytic cycle of the alternative oxidase which may prove to be important in future rational drug design to treat diseases such as trypanosomiasis. Furthermore since single amino acid mutations in inhibitor/substrate pockets have been found to be the cause of multi-drug resistant strains of malaria, the decrease in sensitivity to main AOX antagonists observed in the L-mutants studied in this report suggests that an emergence of drug resistance to trypanosomiasis may also be possible. Therefore we suggest that the design of future AOX inhibitors should have structures that are less reliant on the orientation by the two

  15. Thermalization as an Invisibility Cloak for Fragile Quantum Superpositions

    Hahn, Walter; Fine, Boris V.

    2017-01-01

    We propose a method for protecting fragile quantum superpositions in many-particle systems from dephasing by external classical noise. We call superpositions "fragile" if dephasing occurs particularly fast, because the noise couples very differently to the superposed states. The method consists of letting a quantum superposition evolve under the internal thermalization dynamics of the system, followed by a time reversal manipulation known as Loschmidt echo. The thermalization dynamics makes t...

  16. Seismic fragility of nuclear power plant components. Phase I

    Bandyopadhyay, K.K.; Hofmayer, C.H.

    1986-06-01

    As part of the Component Fragility Research Program, sponsored by the US Nuclear Regulatory Commission, BNL is involved in establishing seismic fragility levels for various nuclear power plant equipment by identifying, collecting and analyzing existing test data from various sources. In Phase I of this program, BNL has reviewed approximately seventy test reports to collect fragility or high level test data for switchgears, motor control centers and similar electrical cabinets, valve actuators and numerous electrical devices of various manufacturers and models. This report provides an assessment and evaluation of the data collected in Phase I. The fragility data for medium voltage and low voltage switchgears and motor control centers are analyzed using the test response spectra (TRS) as a measure of the fragility level. The analysis reveals that fragility levels can best be described by a group of TRS curves corresponding to various failure modes. The lower-bound curve indicates the initiation of malfunctioning or structural damage; whereas, the upper-bound curve corresponds to overall failure of the equipment based on known failure modes. High level test data for some components are included in the report. These data indicate that some components are inherently strong and do not exhibit any failure mode even when tested at the vibration limit of a shake table. The common failure modes are identified in the report. The fragility levels determined in this report have been compared with those used in the PRA and Seismic Margin Studies. It appears that the BNL data better correlate with the HCLPF (High Confidence of a Low Probability of Failure) level used in Seismic Margin Studies and can improve this level as high as 60% for certain applications. Specific recommendations are provided for proper application of BNL fragility data to other studies

  17. Fragility: The Next Wave in Critical Infrastructure Protection

    Allan McDougall

    2009-01-01

    In North America today, we are about to embark on a significant effort to repair, or even upgrade, many aspects of our infrastructure. Many of these efforts are linked to economic recovery packages. Others are based on sheer need. The challenge for decision makers and planners involves ensuring that scarce economic resources are put to their best use. Understanding the concept of fragility plays a pivotal part in reaching that understanding.Fragility, like many other systems—particularly Info...

  18. Managing Public Finance and Procurement in Fragile and Conflicted Settings

    Porter, Doug; Andrews, Matt; Turkewitz, Joel; Wescotttz, Clay

    2011-01-01

    Discusses ways to enhance the incentives for elites to invest political capital in achieving (1) functional results through the formal public finance management (PFM) system; (2) the effectiveness of agencies responsible for services and regulating activities; and (3) better performance of civil service officials. Using the Public Expenditure and Financial Accountability (PEFA) Performance Measurement Framework, countries affected by conflict and fragility can be compared with non-fragile poo...

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

    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.

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

    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.

  1. Seismic fragility of a reinforced concrete structure

    Kurmann, Davide [Axpo Power AG, Baden (Switzerland); Proske, Dirk [Axpo Power AG, Doettingen (Switzerland); Cervenka, Jan [Cervenka Consulting, Prague (Czech Republic)

    2013-05-15

    Structures can be exposed to seismic loading. For structures of major importance, extreme seismic loadings have to be considered. The proof of safety for such loadings requires sophisticated analysis. This paper introduces an analysis method which of course still includes simplifications, but yields to a far more realistic estimation of the seismic load bearing capacity of reinforced concrete structures compared to common methods. It is based on the development of pushover curves and the application of time-histories for the dynamic model to a representative harmonic oscillator. Dynamic parameters of the oscillator, such as modal mass and damping are computed using a soil-structure-interaction analysis. Based on the pushover-curve nonlinear force-deformation-capacities are applied to the oscillator including hysteresis behaviour characteristics. The oscillator is then exposed to time-histories of several earthquakes. Based on this computation the ductility is computed. The ductility can be scaled based upon the scaling of the time-histories. Since both, the uncertainty of the earthquake by using different timehistories and the uncertainty of the structure by using characteristic and mean material values, are considered, the uncertainty of the structure under seismic loading can be explicitly represented by a fragility. (orig.)

  2. Carbon dioxide enhances fragility of ice crystals

    Qin Zhao; Buehler, Markus J

    2012-01-01

    Ice caps and glaciers cover 7% of the Earth, greater than the land area of Europe and North America combined, and play an important role in global climate. The small-scale failure mechanisms of ice fracture, however, remain largely elusive. In particular, little understanding exists about how the presence and concentration of carbon dioxide molecules, a significant component in the atmosphere, affects the propensity of ice to fracture. Here we use atomic simulations with the first-principles based ReaxFF force field capable of describing the details of chemical reactions at the tip of a crack, applied to investigate the effects of the presence of carbon dioxide molecules on ice fracture. Our result shows that increasing concentrations of carbon dioxide molecules significantly decrease the fracture toughness of the ice crystal, making it more fragile. Using enhanced molecular sampling with metadynamics we reconstruct the free energy landscape in varied chemical microenvironments and find that carbon dioxide molecules affect the bonds between water molecules at the crack tip and decrease their strength by altering the dissociation energy of hydrogen bonds. In the context of glacier dynamics our findings may provide a novel viewpoint that could aid in understanding the breakdown and melting of glaciers, suggesting that the chemical composition of the atmosphere can be critical to mediate the large-scale motion of large volumes of ice.

  3. The fragility of the Brazilian Defense Ministry

    Jorge Zaverucha

    2006-01-01

    Full Text Available The present article presents different phases that the Brazilian Defense Ministry has passed through, since its inception during Fernando Henrique Cardoso's second presidential term (1999-2002 until the current administration of Luís Inácio Lula da Silva (2003-2006, under its respective ministers of Defense. It has been seen as one of the important stages in the re-constitutionalization of the country, insofar as it establishes the submission of Armed Forces commanders to a civilian minister, and although some analysts have considered that such submission is actually achieved, we point here to the military resistance and insubordination to civil power that are the result of an authoritarian legacy. To the extent that the Ministry of Defense is unable to implement its own policies in which the military would be required to follow civilian guidance, this article concludes with considerations on the civil Defense Ministry's political and institutional fragility vis-a-vis military command. The latter has been able to retain high levels of decision making autonomy in its relationship to the Ministry and its structure.

  4. Interim Stabilisation in Fragile Security Situations

    Nat J. Colletta

    2012-09-01

    Full Text Available For more than two decades a conventional approach to security promotion has been widely applied by multilateral and bilateral agencies during war-to-peace transitions. Advocates of this approach typically recommend a combination of disarmament, demobilisation and reintegration (DDR and security sector reform (SSR to consolidate peace-making and peace-building processes (Colletta et al 2009, Muggah 2006. Notwithstanding the broad acceptance of such activities – and the theory that underlies them – there is little evidence that such interventions have contributed to any enduring solution to conflict and fragility (Muggah 2009. Indeed, analysts have come to recognise that the political, economic and social pre-conditions for DDR and SSR – including a relatively functional government, a reasonably stable labour market and a minimum level of social trust – are seldom in place. Even when these ambitious pre-requisites have been achieved, it is not clear that they are sufficient for DDR and SSR to take hold. Nevertheless, these orthodoxies persist in security promotion policy and practice.

  5. Extracellular histones induce erythrocyte fragility and anemia.

    Kordbacheh, Farzaneh; O'Meara, Connor H; Coupland, Lucy A; Lelliott, Patrick M; Parish, Christopher R

    2017-12-28

    Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity toward nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histones on erythrocyte function. We demonstrate in this study that histones promote erythrocyte aggregation, sedimentation, and using a novel in vitro shear stress model, we show that histones induce erythrocyte fragility and lysis in a concentration-dependent manner. Furthermore, histones impair erythrocyte deformability based on reduced passage of erythrocytes through an artificial spleen. These in vitro results were mirrored in vivo with the injection of histones inducing anemia within minutes of administration, with a concomitant increase in splenic hemoglobin content. Thrombocytopenia and leukopenia were also observed. These findings suggest that histones binding to erythrocytes may contribute to the elevated erythrocyte sedimentation rates observed in inflammatory conditions. Furthermore, histone-induced increases in red blood cell lysis and splenic clearance may be a significant factor in the unexplained anemias seen in critically ill patients. © 2017 by The American Society of Hematology.

  6. The Brazilian Pampa: A Fragile Biome

    Valdir Marcos Stefenon

    2009-12-01

    Full Text Available Biodiversity is one of the most fundamental properties of Nature. It underpins the stability of ecosystems, provides vast bioresources for economic use, and has important cultural significance for many people. The Pampa biome, located in the southernmost state of Brazil, Rio Grande do Sul, illustrates the direct and indirect interdependence of humans and biodiversity. The Brazilian Pampa lies within the South Temperate Zone where grasslands scattered with shrubs and trees are the dominant vegetation. The soil, originating from sedimentary rocks, often has an extremely sandy texture that makes them fragile—highly prone to water and wind erosion. Human activities have converted or degraded many areas of this biome. In this review we discuss our state-of-the-art knowledge of the diversity and the major biological features of this regions and the cultural factors that have shaped it. Our aim is to contribute toward a better understanding of the current status of this special biome and to describe how the interaction between human activities and environment affects the region, highlighting the fragility of the Brazilian Pampa.

  7. BANKING SYSTEM FRAGILITY: CASE OF THE REPUBLIC OF MOLDOVA

    Dorina CLICHICI

    2014-04-01

    Full Text Available The paper studied the determinants of Moldovan banking system fragility. It underlines the existing researches into the empirical determinants of banking fragility. The analysis revealed that there are numerous channels through which weaknesses within the macroeconomic conditions and structural characteristics might increase banking system fragility. The main macroeconomic determinants which may have an impact on Moldovan banking system fragility are: excessive domestic liquidity, pro-cyclical character of the banking system, dependence on remittances, financial dollarization. There are also several banking characteristics which play a role for Moldovan banking system fragility: the undermined intermediation function, high level of bad loans, uncertainties in the ownership structure, low presence of foreign strategic investors. The paper employed a quantitative, a qualitative and a comparative analysis using the financial soundness and structural indicators of the Moldovan banking system in order to assess the impact of various determinants on Moldovan banking system fragility. The results reveal a high degree of capitalization and liquidity of Moldovan banking system, factors which contribute and maintain the general stability of the entire financial system.

  8. Longitudinal Profiles of Adaptive Behavior in Fragile X Syndrome

    Quintin, Eve-Marie; Jo, Booil; Lightbody, Amy A.; Hazlett, Heather Cody; Piven, Joseph; Hall, Scott S.; Reiss, Allan L.

    2014-01-01

    OBJECTIVE: To examine longitudinally the adaptive behavior patterns in fragile X syndrome. METHOD: Caregivers of 275 children and adolescents with fragile X syndrome and 225 typically developing children and adolescents (2–18 years) were interviewed with the Vineland Adaptive Behavior Scales every 2 to 4 years as part of a prospective longitudinal study. RESULTS: Standard scores of adaptive behavior in people with fragile X syndrome are marked by a significant decline over time in all domains for males and in communication for females. Socialization skills are a relative strength as compared with the other domains for males with fragile X syndrome. Females with fragile X syndrome did not show a discernible pattern of developmental strengths and weaknesses. CONCLUSIONS: This is the first large-scale longitudinal study to show that the acquisition of adaptive behavior slows as individuals with fragile X syndrome age. It is imperative to ensure that assessments of adaptive behavior skills are part of intervention programs focusing on childhood and adolescence in this condition. PMID:25070318

  9. Construction and expression of hepatitis B surface antigen escape variants within the "a" determinant by site directed mutagenesis.

    Golsaz Shirazi, Forough; Amiri, Mohammad Mehdi; Mohammadi, Hamed; Bayat, Ali Ahmad; Roohi, Azam; Khoshnoodi, Jalal; Zarnani, Amir Hassan; Jeddi-Tehrani, Mahmood; Kardar, Gholam Ali; Shokri, Fazel

    2013-09-01

    The antibody response to hepatitis B surface antigen (HBsAg) controls hepatitis B virus infection. The "a" determinant of HBsAg is the most important target for protective antibody response, diagnosis and immunoprophylaxis. Mutations in this area may induce immune escape mutants and affect the performance of HBsAg assays. To construct clinically relevant recombinant mutant forms of HBsAg and assessment of their reactivity with anti-HBs monoclonal antibodies (MAbs). Wild type (wt) and mutant (mt) HBsAg genes were constructed by site directed mutagenesis and SEOing PCR. The amplified genes were inserted into pCMV6-neo plasmid and transfected in CHO cell line. The expression of wt- and mtHBsAg was assessed by commercial ELISA assays and stable cells were established and cloned by limiting dilution. The recombinant mutants were further characterized using a panel of anti-HBs monoclonal antibodies (MAbs) and the pattern of their reactivity was assessed by ELISA. Ten HBsAg mutants having single mutation within the "a" determinant including P120E, T123N, Q129H, M133L, K141E, P142S, D144A, G145R, N146S and C147S together with a wt form were successfully constructed and expressed in CHO cells. Reactivity of anti-HBs MAbs with mtHBsAgs displayed different patterns. The effect of mutations on antibody binding differed depending on the amino acid involved and its location within the ''a'' determinant. Mutation at amino acids 123 and 145 resulted in either complete loss or significant reduction of binding to all anti-HBs MAbs. Our panel of mtHBsAgs is a valuable tool for assessment of the antibody response to HBV escape mutants and may have substantial implications in HBV immunological diagnostics.

  10. Fragile X protein in newborn dried blood spots.

    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.

  11. Contrasting dynamics of fragile and non-fragile polyalcohols through the glass, and dynamical, transitions: A comparison of neutron scattering and dielectric relaxation data for sorbitol and glycerol.

    Migliardo, F; Angell, C A; Magazù, S

    2017-01-01

    Glycerol and sorbitol are glass-forming hydrogen-bonded systems characterized by intriguing properties which make these systems very interesting also from the applications point of view. The goal of this work is to relate the hydrogen-bonded features, relaxation dynamics, glass transition properties and fragility of these systems, in particular to seek insight into their very different liquid fragilities. The comparison between glycerol and sorbitol is carried out by collecting the elastic incoherent neutron scattering (EINS) intensity as a function of temperature and of the instrumental energy resolution. Intensity data vs temperature and resolution are analyzed in terms of thermal restraint and Resolution Elastic Neutron Scattering (RENS) approaches. The number of OH groups, which are related to the connecting sites, is a significant parameter both in the glass transition and in the dynamical transition. On the other hand, the disordered nature of sorbitol is confirmed by the existence of different relaxation processes. From the applications point of view, glycerol and sorbitol have remarkable bioprotectant properties which make these systems useful in different technological and industrial fields. Furthermore, polyols are rich in glassforming liquid phenomenology and highly deserving of study in their own right. The comparison of EINS and calorimetric data on glycerol and sorbitol helps provide a connection between structural relaxation, dynamical transition, glass transition, and fragility. The evaluation of the inflection point in the elastic intensity behavior as a function of temperature and instrumental energy resolution provides a confirmation of the validity of the RENS approach. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo. Copyright © 2016. Published by Elsevier B.V.

  12. Unbiased proteomics analysis demonstrates significant variability in mucosal immune factor expression depending on the site and method of collection.

    Kenzie M Birse

    Full Text Available Female genital tract secretions are commonly sampled by lavage of the ectocervix and vaginal vault or via a sponge inserted into the endocervix for evaluating inflammation status and immune factors critical for HIV microbicide and vaccine studies. This study uses a proteomics approach to comprehensively compare the efficacy of these methods, which sample from different compartments of the female genital tract, for the collection of immune factors. Matching sponge and lavage samples were collected from 10 healthy women and were analyzed by tandem mass spectrometry. Data was analyzed by a combination of differential protein expression analysis, hierarchical clustering and pathway analysis. Of the 385 proteins identified, endocervical sponge samples collected nearly twice as many unique proteins as cervicovaginal lavage (111 vs. 61 with 55% of proteins common to both (213. Each method/site identified 73 unique proteins that have roles in host immunity according to their gene ontology. Sponge samples enriched for specific inflammation pathways including acute phase response proteins (p = 3.37×10(-24 and LXR/RXR immune activation pathways (p = 8.82×10(-22 while the role IL-17A in psoriasis pathway (p = 5.98×10(-4 and the complement system pathway (p = 3.91×10(-3 were enriched in lavage samples. Many host defense factors were differentially enriched (p<0.05 between sites including known/potential antimicrobial factors (n = 21, S100 proteins (n = 9, and immune regulatory factors such as serpins (n = 7. Immunoglobulins (n = 6 were collected at comparable levels in abundance in each site although 25% of those identified were unique to sponge samples. This study demonstrates significant differences in types and quantities of immune factors and inflammation pathways collected by each sampling technique. Therefore, clinical studies that measure mucosal immune activation or factors assessing HIV transmission should utilize

  13. Comparison of the effect of hazard and response/fragility uncertainties on core melt probability uncertainty

    Mensing, R.W.

    1985-01-01

    This report proposes a method for comparing the effects of the uncertainty in probabilistic risk analysis (PRA) input parameters on the uncertainty in the predicted risks. The proposed method is applied to compare the effect of uncertainties in the descriptions of (1) the seismic hazard at a nuclear power plant site and (2) random variations in plant subsystem responses and component fragility on the uncertainty in the predicted probability of core melt. The PRA used is that developed by the Seismic Safety Margins Research Program

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

    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.

  15. Seismic fragility analysis of a nuclear building based on probabilistic seismic hazard assessment and soil-structure interaction analysis

    Gonzalez, R.; Ni, S.; Chen, R.; Han, X.M. [CANDU Energy Inc, Mississauga, Ontario (Canada); Mullin, D. [New Brunswick Power, Point Lepreau, New Brunswick (Canada)

    2016-09-15

    Seismic fragility analyses are conducted as part of seismic probabilistic safety assessment (SPSA) for nuclear facilities. Probabilistic seismic hazard assessment (PSHA) has been undertaken for a nuclear power plant in eastern Canada. Uniform Hazard Spectra (UHS), obtained from the PSHA, is characterized by high frequency content which differs from the original plant design basis earthquake spectral shape. Seismic fragility calculations for the service building of a CANDU 6 nuclear power plant suggests that the high frequency effects of the UHS can be mitigated through site response analysis with site specific geological conditions and state-of-the-art soil-structure interaction analysis. In this paper, it is shown that by performing a detailed seismic analysis using the latest technology, the conservatism embedded in the original seismic design can be quantified and the seismic capacity of the building in terms of High Confidence of Low Probability of Failure (HCLPF) can be improved. (author)

  16. EXPRESS

    Ancelin, C.; Le, P.; DeSaint-Quentin, S.; Villatte, N.

    1987-01-01

    This paper presents EXPRESS, an expert system developed for the automation of reliability studies. The first part consists in the description of the method for static thermohydraulic systems. In this step, the authors define the knowledge representation based on the two inference engines - ALOUETTE and LCR developed by EDF. They explain all the process to construct a fault tree from a topological and functional description of the system. Numerous examples are exhibited in illustration of the method. This is followed by the lessons derived from the studies performed on some safety systems of the PALUEL nuclear plant. The development of the same approach for electric power systems is described, insisting on the difference resulting from the sequential nature of these systems. Finally, they show the main advantages identified during the studies

  17. Increased synovial tissue NF-kappa B1 expression at sites adjacent to the cartilage-pannus junction in rheumatoid arthritis.

    Benito, M.J.; Murphy, E.P.; Berg, W.B. van den; Fitzgerald, O.; Bresnihan, B.

    2004-01-01

    OBJECTIVE: To compare the expression of the Rel/NF-kappa B subunits, NF-kappa B1 (p50) and RelA (p65), in paired synovial tissue samples selected from sites adjacent to and remote from the cartilage-pannus junction (CPJ) in patients with inflammatory arthritis. METHODS: Synovial tissue was selected

  18. Trabecular bone score as a skeletal fragility index in acromegaly patients.

    Hong, A R; Kim, J H; Kim, S W; Kim, S Y; Shin, C S

    2016-03-01

    Lumbar spine trabecular bone score (TBS) was significantly decreased in active acromegaly patients. TBS may be useful to assess the skeletal fragility in acromegaly in which bone mineral density (BMD) is not sufficient to represent bone strength and explain the high incidence of fragility fractures in acromegaly patients. Although the data on BMD are controversial, patients with acromegaly have an increased risk of fragility fracture. We examined the lumbar spine TBS to explain the skeletal deterioration in acromegaly patients. We included 14 men and 19 women acromegaly patients who underwent dual-energy X-ray absorptiometry at the time of diagnosis from 2000 to 2014 at Seoul National University Hospital. Ninety-nine age-, sex- and body mass index-matched controls were recruited. Biochemical parameters, lumbar spine TBS, and BMD at all sites were measured. Gonadal status was evaluated at diagnosis. Lumbar spine TBS was lower in acromegaly patients than in controls in both genders (1.345 ± 0.121 vs. 1.427 ± 0.087, P = 0.005 in men; 1.356 ± 0.082 vs. 1.431 ± 0.071, P = 0.001 in women). In contrast, BMD at all sites did not differ between the two groups. Hypogonadal acromegaly patients (men, n = 9; women, n = 12) had lower TBS values compared with controls both in men and women (all P acromegaly patients, lumbar spine TBS was lower than in women controls only (P = 0.041). Skeletal microarchitecture was deteriorated in acromegaly patients as assessed by TBS, which seems to be a consequence of growth hormone excess as well as hypogonadism, especially in women.

  19. Express-Air Screen-System to protect miners against radon exposures at small underground construction sites in old mining; Express-Wetterblenden-System zum Sofort-Schutz von Bergleuten vor Radonexpositionen bei untertaegigen Bergsicherungsarbeiten im Altbergbau

    Dehnert, J. [Saechsisches Landesamt fuer Umwelt, Landwirtschaft und Geologie (Germany). Referat Strahlenschutz; Stopp, J. [Aluminiumbau und Verwaltungs GmbH Stopp, Schneeberg (Germany); Schoenherr, B. [Bergsicherung Schneeberg GmbH (Germany)

    2016-07-01

    A new Express-Air Screen-System (EAS) for miners was developed to reduce the radon exposures of miners at small construction sites of old mining. The EAS is a lightweight, modular and reusable construction kit of interlocking telescopic aluminum tubes, plastic foils and glue foam to shut off radon rich parts of galleries in some minutes only.

  20. Assessment of clusters of transcription factor binding sites in relationship to human promoter, CpG islands and gene expression

    Sakaki Yoshiyuki

    2004-02-01

    Full Text Available Abstract Background Gene expression is regulated mainly by transcription factors (TFs that interact with regulatory cis-elements on DNA sequences. To identify functional regulatory elements, computer searching can predict TF binding sites (TFBS using position weight matrices (PWMs that represent positional base frequencies of collected experimentally determined TFBS. A disadvantage of this approach is the large output of results for genomic DNA. One strategy to identify genuine TFBS is to utilize local concentrations of predicted TFBS. It is unclear whether there is a general tendency for TFBS to cluster at promoter regions, although this is the case for certain TFBS. Also unclear is the identification of TFs that have TFBS concentrated in promoters and to what level this occurs. This study hopes to answer some of these questions. Results We developed the cluster score measure to evaluate the correlation between predicted TFBS clusters and promoter sequences for each PWM. Non-promoter sequences were used as a control. Using the cluster score, we identified a PWM group called PWM-PCP, in which TFBS clusters positively correlate with promoters, and another PWM group called PWM-NCP, in which TFBS clusters negatively correlate with promoters. The PWM-PCP group comprises 47% of the 199 vertebrate PWMs, while the PWM-NCP group occupied 11 percent. After reducing the effect of CpG islands (CGI against the clusters using partial correlation coefficients among three properties (promoter, CGI and predicted TFBS cluster, we identified two PWM groups including those strongly correlated with CGI and those not correlated with CGI. Conclusion Not all PWMs predict TFBS correlated with human promoter sequences. Two main PWM groups were identified: (1 those that show TFBS clustered in promoters associated with CGI, and (2 those that show TFBS clustered in promoters independent of CGI. Assessment of PWM matches will allow more positive interpretation of TFBS in

  1. Endoglucanase enzyme protein engineering by site-directed mutagenesis to improve the enzymatic properties and its expression in yeast

    Farnaz Nikzad Jamnani

    2013-11-01

    Full Text Available Introduction: Fossil fuel is an expensive and finite energy source. Therefore, the use of renewable energy and biofuels production has been taken into consideration. One of the most suitable raw materials for biofuels is cellulosic compounds. Only microorganisms that contain cellulose enzymes can decompose cellulose and fungus of Trichodermareesei is the most important producer of this enzyme. Methods: In this study the nucleotide sequence of endoglucanase II, which is the starter of attack to cellulose chains, synthesized from amino acid sequence of this enzyme in fungus T.reesei and based on codon usage in the host; yeast Pichiapastoris. To produce optimized enzyme and to decrease the production time and enzyme price, protein engineering will be used. There are some methods to improve the enzymatic properties like site-directed mutagenesis in which amino-acid replacement occur. In this study two mutations were induced in endoglucanase enzyme gene by PCR in which free syctein positions 169 and 393 were switched to valine and histidine respectively. Then this gene was inserted into the pPinka expression vector and cloned in Escherichia coli. The recombinant plasmids were transferred into P.pastoris competent cells with electroporation, recombinant yeasts were cultured in BMMY medium and induced with methanol. Results: The sequencing of gene proved the induction of the two mutations and the presence of recombinant enzyme was confirmed by dinitrosalicilic acid method and SDS-PAGE. Conclusion: Examination of biochemical properties revealed that the two mutations simultaneously decreased catalytic power, thermal stability and increased the affinity of enzyme and substrate.

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

    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.

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

    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.

  4. A dominant control region from the human β-globin locus conferring integration site-independent gene expression.

    D. Talbot; P. Collis; M. Antoniou (Michael); M. Vidal; F.G. Grosveld (Frank); D.R. Greaves (David)

    1989-01-01

    textabstractThe regulatory elements that determine the expression pattern of a number of eukaryotic genes expressed specifically in certain tissues have been defined and studied in detail. In general, however, the expression conferred by these elements on genes reintroduced into the genomes of cell

  5. Touch and Massage for Medically Fragile Infants

    Livingston, Karen; Beider, Shay; Kant, Alexis J.; Gallardo, Constance C.; Joseph, Michael H.

    2009-01-01

    of the infants receiving massage. Massage in a tertiary urban academic NICU continues to be an area of needed study. Future studies examining infant health outcomes, such as weight gain, decreased length of hospitalization and caregiver–infant bonding, would provide greater insight into the impact of massage for medically fragile infants. PMID:18955228

  6. Soil-Structure Interaction Effect on Fragility Curve of 3D Models of Concrete Moment-Resisting Buildings

    Ali Anvarsamarin

    2018-01-01

    Full Text Available This paper presents the probabilistic generation of collapse fragility curves for evaluating the performance of 3D, reinforced concrete (RC moment-resisting building models, considering soil-structure interaction (SSI by concentration on seismic uncertainties. It considers collapse as the loss of lateral load-resisting capacity of the building structures due to severe ground shaking and consequent large interstory drifts intensified by P-Δ effects as well as the strength and stiffness deterioration of their lateral load carrying systems. The estimation of the collapse performance of structures requires the relation between the intensity measure (IM and the probability of collapse that is determined using the generated collapse fragility curves. Considering a number of 6-, 12-, and 18-story, 3D, RC moment-resisting buildings, two scalar IMs are employed to estimate their collapse fragility curve. On the other hand, the effect of the site soil type on the collapse fragility curves was taken into account by considering the soil-structure interaction. According to the obtained results, adopting the average of spectral acceleration (Saavg intensity measure is more efficient in capturing the effect of the inherent uncertainties of the strong ground motions on the structural response parameters. In addition, considering the SSI for soil type D with shear-wave velocity of 180 m/s to 360 m/s reduces the median of intensity measure (IM = Sa(T1 of fragility curve in 6-, 12-, and 18-story buildings by 4.92%, 22.26%, and 23.03%, respectively.

  7. Seismic fragility of RC shear walls in nuclear power plant Part 1: Characterization of uncertainty in concrete constitutive model

    Syed, Sammiuddin; Gupta, Abhinav

    2015-01-01

    Highlights: • A framework is proposed for seismic fragility assessment of Reinforced Concrete structures. • Experimentally validated finite element models are used to conduct nonlinear simulations. • Critical parameters in concrete constitutive model are identified to conduct nonlinear simulations. • Uncertainties in model parameters of concrete damage plasticity model is characterized. • Closed form expressions are used to compute the damage variables and plasticity. - Abstract: This two part manuscript proposes a framework for seismic fragility assessment of reinforced concrete structures in nuclear energy facilities. The novelty of the proposed approach lies in the characterization of uncertainties in the parameters of the material constitutive model. Concrete constitutive models that comprehensively address different damage states such as tensile cracking, compression failure, stiffness degradation, and recovery of degraded stiffness due to closing of previously formed cracks under dynamic loading are generally defined in terms of a large number of variables to characterize the plasticity and damage at material level. Over the past several years, many different studies have been presented on evaluation of fragility for reinforced concrete structures using nonlinear time history simulations. However, almost all of these studies do not consider uncertainties in the parameters of a comprehensive constitutive model. Part-I of this two-part manuscript presents a study that is used to identify uncertainties associated with the critical parameters in nonlinear concrete damage plasticity model proposed by Lubliner et al. (1989. Int. J. Solids Struct., 25(3), 299) and later modified by Lee and Fenves (1998a. J. Eng. Mech., ASCE, 124(8), 892) and Lee and Fenves (1998b. Earthquake Eng. Struct. Dyn., 27(9), 937) for the purpose of seismic fragility assessment. The limitations in implementation of the damage plasticity model within a finite element framework and

  8. Seismic fragility of RC shear walls in nuclear power plant Part 1: Characterization of uncertainty in concrete constitutive model

    Syed, Sammiuddin [Department of Civil, Construction, and Environmental Engineering, North Carolina State University, 426 Mann Hall, Campus Box 7908, Raleigh, NC 27695-7908 (United States); Gupta, Abhinav, E-mail: agupta1@ncsu.edu [Department of Civil, Construction, and Environmental Engineering, North Carolina State University, 413 Mann Hall, Campus Box 7908, Raleigh, NC 27695-7908 (United States)

    2015-12-15

    Highlights: • A framework is proposed for seismic fragility assessment of Reinforced Concrete structures. • Experimentally validated finite element models are used to conduct nonlinear simulations. • Critical parameters in concrete constitutive model are identified to conduct nonlinear simulations. • Uncertainties in model parameters of concrete damage plasticity model is characterized. • Closed form expressions are used to compute the damage variables and plasticity. - Abstract: This two part manuscript proposes a framework for seismic fragility assessment of reinforced concrete structures in nuclear energy facilities. The novelty of the proposed approach lies in the characterization of uncertainties in the parameters of the material constitutive model. Concrete constitutive models that comprehensively address different damage states such as tensile cracking, compression failure, stiffness degradation, and recovery of degraded stiffness due to closing of previously formed cracks under dynamic loading are generally defined in terms of a large number of variables to characterize the plasticity and damage at material level. Over the past several years, many different studies have been presented on evaluation of fragility for reinforced concrete structures using nonlinear time history simulations. However, almost all of these studies do not consider uncertainties in the parameters of a comprehensive constitutive model. Part-I of this two-part manuscript presents a study that is used to identify uncertainties associated with the critical parameters in nonlinear concrete damage plasticity model proposed by Lubliner et al. (1989. Int. J. Solids Struct., 25(3), 299) and later modified by Lee and Fenves (1998a. J. Eng. Mech., ASCE, 124(8), 892) and Lee and Fenves (1998b. Earthquake Eng. Struct. Dyn., 27(9), 937) for the purpose of seismic fragility assessment. The limitations in implementation of the damage plasticity model within a finite element framework and

  9. Next-generation site-directed transgenesis in the malaria vector mosquito Anopheles gambiae: self-docking strains expressing germline-specific phiC31 integrase.

    Janet M Meredith

    Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and the situation is complicated due to difficulties with both existing control measures and the impact of climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. The Streptomyces phage phiC31 integrase system has been successfully adapted for site-directed transgene integration in a range of insects, thus overcoming many limitations due to size constraints and random integration associated with transposon-mediated transformation. Using this technology, we previously published the first site-directed transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 docking site at a defined genomic location. A second phase of genetic modification then achieved site-directed integration of an anti-malarial effector gene. In the current publication we report improved efficiency and utility of the phiC31 integrase system following the generation of Anopheles gambiae self-docking strains. Four independent strains, with docking sites at known locations on three different chromosome arms, were engineered to express integrase under control of the regulatory regions of the nanos gene from Anopheles gambiae. The resulting protein accumulates in the posterior oocyte to provide integrase activity at the site of germline development. Two self-docking strains, exhibiting significantly different levels of integrase expression, were assessed for site-directed transgene integration and found to demonstrate greatly improved survival and efficiency of transformation. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters to regulate their expression, enabling those offering maximum effect with minimum fitness

  10. Ectodermal dysplasia-skin fragility syndrome: A rare case report

    Subhash Kashyap

    2015-01-01

    Full Text Available Ectodermal dysplasia/skin fragility syndrome (ED-SFS is a newly described autosomal recessive disorder characterized by skin fragility and blistering, palmoplantar keratoderma, abnormal hair growth, nail dystrophy, and occasionally defective sweating. It results from mutations in the PKP1 gene encoding plakophilin 1 (PKP1, which is an important component of stratifying epithelial desmosomes and a nuclear component of many cell types. Only 12 cases of this rare genodermatosis have been reported so far. We present an unusual case of ED-SFS in a 12-year boy who was normal at birth but subsequently developed skin fragility, hair and nail deformities, abnormal dentition, palmoplantar keratoderma, and abnormal sweating but no systemic abnormality.

  11. Seismic fragilities for nuclear power plant risk studies

    Kennedy, R.P.; Ravindra, M.K.

    1983-01-01

    Seismic fragilities of critical structures and equipment are developed as families of conditional failure frequency curves plotted against peak ground acceleration. The procedure is based on available data combined with judicious extrapolation of design information on plant structures and equipment. Representative values of fragility parameters for typical modern nuclear power plants are provided. Based on the fragility evaluation for about a dozen nuclear power plants, it is proposed that unnecessary conservatism existing in current seismic design practice could be removed by properly accounting for inelastic energy absorption capabilities of structures. The paper discusses the key contributors to seismic risk and the significance of possible correlation between component failures and potential design and construction errors

  12. Fragile X syndrome in two siblings with major congenital malformations

    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.

  13. Fabrication and transfer of fragile 3D PDMS microstructures

    Karlsson, J Mikael; Haraldsson, Tommy; Carlborg, Carl Fredrik; Van der Wijngaart, Wouter; Hansson, Jonas; Russom, Aman

    2012-01-01

    We present a method for PDMS microfabrication of fragile membranes and 3D fluidic networks, using a surface modified water-dissolvable release material, poly(vinyl alcohol), as a tool for handling, transfer and release of fragile polymer microstructures. The method is well suited for the fabrication of complex multilayer microfluidic devices, here shown for a PDMS device with a thin gas permeable membrane and closely spaced holes for vertical interlayer connections fabricated in a single layer. To the authors’ knowledge, this constitutes the most advanced PDMS fabrication method for the combination of thin, fragile structures and 3D fluidics networks, and hence a considerable step in the direction of making PDMS fabrication of complex microfluidic devices a routine endeavour. (paper)

  14. Fragile X syndrome: A review of clinical management

    Lozano, Reymundo; Azarang, Atoosa; Wilaisakditipakorn, Tanaporn; Hagerman, Randi J

    2016-01-01

    Summary The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although the prevalence varies in different regions of the world. FXS is the most common inherited cause of intellectual disability and autism. The understanding of the neurobiology of FXS has led to many targeted treatments, but none have cured this disorder. The treatment of the medical problems and associated behaviors remain the most useful intervention for children with FXS. In this review, we focus on the non-pharmacological and pharmacological management of medical and behavioral problems associated with FXS as well as current recommendations for follow-up and surveillance. PMID:27672537

  15. A nonsense mutation in FMR1 causing fragile X syndrome

    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...

  16. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-10-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  17. The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; Fata, Giorgio La; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-01-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

  18. Glycogen synthase kinase-3: A promising therapeutic target for Fragile X Syndrome

    Marjelo M. Mines

    2011-11-01

    Full Text Available Recent advances in understanding the pathophysiological mechanisms contributing to Fragile X Syndrome (FXS have increased optimism that drug interventions can provide significant therapeutic benefits. FXS results from inadequate expression of functional fragile X mental retardation protein (FMRP. FMRP may have several functions, but it is most well-established as an RNA-binding protein that regulates translation, and it is by this mechanism that FMRP is capable of affecting numerous cellular processes by selectively regulating protein levels. The multiple cellular functions regulated by FMRP suggest that multiple interventions may be required for reversing the effects of deficient FMRP. Evidence that inhibitors of glycogen synthase kinase-3 (GSK3 may contribute to the therapeutic treatment of FXS is reviewed here. In the mouse model of FXS, which lacks FMRP expression (FX mice, GSK3 is hyperactive in several brain regions. Furthermore, significant improvements in several FX-related phenotypes have been obtained in FX mice following the administration of lithium, and in some case other GSK3 inhibitors. These responses include normalization of heightened audiogenic seizure susceptibility and of hyperactive locomotor behavior, enhancement of passive avoidance learning retention and of sociability behaviors, and corrections of macroorchidism, neuronal spine density, and neural plasticity measured electrophysiologically as long term depression. A pilot clinical trial of lithium in FXS patients also found improvements in several measures of behavior. Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS.

  19. Tirilazad mesylate protects stored erythrocytes against osmotic fragility.

    Epps, D E; Knechtel, T J; Bacznskyj, O; Decker, D; Guido, D M; Buxser, S E; Mathews, W R; Buffenbarger, S L; Lutzke, B S; McCall, J M

    1994-12-01

    The hypoosmotic lysis curve of freshly collected human erythrocytes is consistent with a single Gaussian error function with a mean of 46.5 +/- 0.25 mM NaCl and a standard deviation of 5.0 +/- 0.4 mM NaCl. After extended storage of RBCs under standard blood bank conditions the lysis curve conforms to the sum of two error functions instead of a possible shift in the mean and a broadening of a single error function. Thus, two distinct sub-populations with different fragilities are present instead of a single, broadly distributed population. One population is identical to the freshly collected erythrocytes, whereas the other population consists of osmotically fragile cells. The rate of generation of the new, osmotically fragile, population of cells was used to probe the hypothesis that lipid peroxidation is responsible for the induction of membrane fragility. If it is so, then the antioxidant, tirilazad mesylate (U-74,006f), should protect against this degradation of stored erythrocytes. We found that tirilazad mesylate, at 17 microM (1.5 mol% with respect to membrane lecithin), retards significantly the formation of the osmotically fragile RBCs. Concomitantly, the concentration of free hemoglobin which accumulates during storage is markedly reduced by the drug. Since the presence of the drug also decreases the amount of F2-isoprostanes formed during the storage period, an antioxidant mechanism must be operative. These results demonstrate that tirilazad mesylate significantly decreases the number of fragile erythrocytes formed during storage in the blood bank.

  20. Thermalization as an invisibility cloak for fragile quantum superpositions

    Hahn, Walter; Fine, Boris V.

    2017-07-01

    We propose a method for protecting fragile quantum superpositions in many-particle systems from dephasing by external classical noise. We call superpositions "fragile" if dephasing occurs particularly fast, because the noise couples very differently to the superposed states. The method consists of letting a quantum superposition evolve under the internal thermalization dynamics of the system, followed by a time-reversal manipulation known as Loschmidt echo. The thermalization dynamics makes the superposed states almost indistinguishable during most of the above procedure. We validate the method by applying it to a cluster of spins ½.

  1. On the pressure dependence of the fragility of glycerol

    Pawlus, S; Paluch, M; Ziolo, J [Institute of Physics, University of Silesia, Uniwersytecka 4, 40-007 Katowice (Poland); Roland, C M [Naval Research Laboratory, Chemistry Division, Code 6120, Washington, DC 20375-5342 (United States)

    2009-08-19

    This work was motivated by ostensibly contradictory results from different groups regarding the effect of pressure on the fragility of glycerol. We present new experimental data for an intermediate pressure regime showing that the fragility increases with pressure up to about 1.8 GPa, becoming invariant at higher pressures. There is no discrepancy among the various literature data taken in toto. The behavior of glycerol is quite distinct from that of normal liquids, a result of its substantial hydrogen bonding. (fast track communication)

  2. Fragility curves for bridges under differential support motions

    Konakli, Katerina

    2012-01-01

    This paper employs the notion of fragility to investigate the seismic vulnerability of bridges subjected to spatially varying support motions. Fragility curves are developed for four highway bridges in California with vastly different structural characteristics. The input in this analysis consists...... of simulated ground motion arrays with temporal and spectral nonstationarities, and consistent with prescribed spatial variation patterns. Structural damage is quantified through displacement ductility demands obtained from nonlinear time-history analysis. The potential use of the ‘equal displacement’ rule...... to approximately evaluate displacement demands from analysis of the equivalent linear systems is examined....

  3. Non-fragile multivariable PID controller design via system augmentation

    Liu, Jinrong; Lam, James; Shen, Mouquan; Shu, Zhan

    2017-07-01

    In this paper, the issue of designing non-fragile H∞ multivariable proportional-integral-derivative (PID) controllers with derivative filters is investigated. In order to obtain the controller gains, the original system is associated with an extended system such that the PID controller design can be formulated as a static output-feedback control problem. By taking the system augmentation approach, the conditions with slack matrices for solving the non-fragile H∞ multivariable PID controller gains are established. Based on the results, linear matrix inequality -based iterative algorithms are provided to compute the controller gains. Simulations are conducted to verify the effectiveness of the proposed approaches.

  4. State fragility and its regional implications for peace and stability

    Mandrup, Thomas

    of the Cold war left a security void, and the fragility, and in some instances collapse, of the state structures resulted in new state formations and new conflicts, both intra- and inter-state in nature. However, conflicts and security challenges in East Africa are due to amongst other things porous borders......, fragile states and bad governance regional in nature, and cannot be solved by the individual states alone. Regional institutions have been in a weak position dealing with these challenges, and attempts have been to strengthen the capacity of these regional institutions. This paper investigates...

  5. Mathematical Definition, Mapping, and Detection of (Anti)Fragility

    Taleb, Nassim N.; Douady, Raphael

    2012-01-01

    URL des Documents de travail : http://centredeconomiesorbonne.univ-paris1.fr/documents-de-travail/; Documents de travail du Centre d'Economie de la Sorbonne 2014.93 - ISSN : 1955-611X; We provide a mathematical definition of fragility and antifragility as negative or positive sensitivity to a semi-measure of dispersion and volatility (a variant of negative or positive "vega") and examine the link to nonlinear effects. We integrate model error (and biases) into the fragile or antifragile conte...

  6. Skeletal stem cells and their contribution to skeletal fragility

    Aldahmash, A.

    2016-01-01

    Age-related osteoporotic fractures are major health care problem worldwide and are the result of impaired bone formation, decreased bone mass and bone fragility. Bone formation is accomplished by skeletal stem cells (SSC) that are recruited to bone surfaces from bone marrow microenvironment....... This review discusses targeting SSC to enhance bone formation and to abolish age-related bone fragility in the context of using stem cells for treatment of age-related disorders. Recent studies are presented that have demonstrated that SSC exhibit impaired functions during aging due to intrinsic senescence...

  7. Fine tuning of RFX/DAF-19-regulated target gene expression through binding to multiple sites in Caenorhabditis elegans

    Chu, Jeffery S. C.; Tarailo-Graovac, Maja; Zhang, Di; Wang, Jun; Uyar, Bora; Tu, Domena; Trinh, Joanne; Baillie, David L.; Chen, Nansheng

    2011-01-01

    In humans, mutations of a growing list of regulatory factor X (RFX) target genes have been associated with devastating genetics disease conditions including ciliopathies. However, mechanisms underlying RFX transcription factors (TFs)-mediated gene expression regulation, especially differential gene expression regulation, are largely unknown. In this study, we explore the functional significance of the co-existence of multiple X-box motifs in regulating differential gene expression in Caenorha...

  8. Predictive mutagenesis of ligation-independent cloning (LIC) vectors for protein expression and site-specific chemical conjugation

    Vernet, Erik; Sauer, Jørgen; Andersen, Peter Andreas

    2011-01-01

    Ligation-independent cloning (LIC) allows for cloning of DNA constructs independent of insert restriction sites and ligases. However, any required mutations are typically introduced by additional, time-consuming steps. We present a rapid, inexpensive method for mutagenesis in the 5' LIC site...

  9. Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.

    Tabet, Ricardos; Moutin, Enora; Becker, Jérôme A J; Heintz, Dimitri; Fouillen, Laetitia; Flatter, Eric; Krężel, Wojciech; Alunni, Violaine; Koebel, Pascale; Dembélé, Doulaye; Tassone, Flora; Bardoni, Barbara; Mandel, Jean-Louis; Vitale, Nicolas; Muller, Dominique; Le Merrer, Julie; Moine, Hervé

    2016-06-28

    Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.

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

    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.

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

    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.

  12. Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

    Milani, Lili; Lundmark, Anders; Nordlund, Jessica

    2008-01-01

    To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood...

  13. LC-MS/MS confirms that COX-1 drives vascular prostacyclin whilst gene expression pattern reveals non-vascular sites of COX-2 expression.

    Nicholas S Kirkby

    Full Text Available There are two schools of thought regarding the cyclooxygenase (COX isoform active in the vasculature. Using urinary prostacyclin markers some groups have proposed that vascular COX-2 drives prostacyclin release. In contrast, we and others have found that COX-1, not COX-2, is responsible for vascular prostacyclin production. Our experiments have relied on immunoassays to detect the prostacyclin breakdown product, 6-keto-PGF1α and antibodies to detect COX-2 protein. Whilst these are standard approaches, used by many laboratories, antibody-based techniques are inherently indirect and have been criticized as limiting the conclusions that can be drawn. To address this question, we measured production of prostanoids, including 6-keto-PGF1α, by isolated vessels and in the circulation in vivo using liquid chromatography tandem mass spectrometry and found values essentially identical to those obtained by immunoassay. In addition, we determined expression from the Cox2 gene using a knockin reporter mouse in which luciferase activity reflects Cox2 gene expression. Using this we confirm the aorta to be essentially devoid of Cox2 driven expression. In contrast, thymus, renal medulla, and regions of the brain and gut expressed substantial levels of luciferase activity, which correlated well with COX-2-dependent prostanoid production. These data are consistent with the conclusion that COX-1 drives vascular prostacyclin release and puts the sparse expression of Cox2 in the vasculature in the context of the rest of the body. In doing so, we have identified the thymus, gut, brain and other tissues as target organs for consideration in developing a new understanding of how COX-2 protects the cardiovascular system.

  14. Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation

    Kamola Saydaminova

    Full Text Available Genome editing with site-specific endonucleases has implications for basic biomedical research as well as for gene therapy. We generated helper-dependent, capsid-modified adenovirus (HD-Ad5/35 vectors for zinc-finger nuclease (ZFN– or transcription activator-like effector nuclease (TALEN–mediated genome editing in human CD34+ hematopoietic stem cells (HSCs from mobilized adult donors. The production of these vectors required that ZFN and TALEN expression in HD-Ad5/35 producer 293-Cre cells was suppressed. To do this, we developed a microRNA (miRNA-based system for regulation of gene expression based on miRNA expression profiling of 293-Cre and CD34+ cells. Using miR-183-5p and miR-218-5p based regulation of transgene gene expression, we first produced an HD-Ad5/35 vector expressing a ZFN specific to the HIV coreceptor gene ccr5. We demonstrated that HD-Ad5/35.ZFNmiR vector conferred ccr5 knock out in primitive HSC (i.e., long-term culture initiating cells and NOD/SCID repopulating cells. The ccr5 gene disruption frequency achieved in engrafted HSCs found in the bone marrow of transplanted mice is clinically relevant for HIV therapy considering that these cells can give rise to multiple lineages, including all the lineages that represent targets and reservoirs for HIV. We produced a second HD-Ad5/35 vector expressing a TALEN targeting the DNase hypersensitivity region 2 (HS2 within the globin locus control region. This vector has potential for targeted gene correction in hemoglobinopathies. The miRNA regulated HD-Ad5/35 vector platform for expression of site-specific endonucleases has numerous advantages over currently used vectors as a tool for genome engineering of HSCs for therapeutic purposes.

  15. Emerging Powers and Effective Governance in Fragile States | IDRC ...

    New and emerging development organizations are providing assistance to countries experiencing tensions and challenges after periods of conflict. This research will test whether their development assistance approaches are more effective at addressing the political and social realities of fragile states than those used by ...

  16. Modeling Family Dynamics in Children with Fragile X Syndrome

    Hall, Scott S.; Burns, David D.; Reiss, Allan L.

    2007-01-01

    Few studies have examined the impact of children with genetic disorders and their unaffected siblings on family functioning. In this study, the reciprocal causal links between problem behaviors and maternal distress were investigated in 150 families containing a child with fragile X syndrome (FXS) and an unaffected sibling. Both children's…

  17. Social Cognition in Adolescent Girls with Fragile X Syndrome

    Turkstra, Lyn S.; Abbeduto, Leonard; Meulenbroek, Peter

    2014-01-01

    This study aimed to characterize social cognition, executive functions (EFs), and everyday social functioning in adolescent girls with fragile X syndrome, and identify relationships among these variables. Participants were 20 girls with FXS and 20 age-matched typically developing peers. Results showed significant between-groups differences in…

  18. Social Approach and Emotion Recognition in Fragile X Syndrome

    Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

    2014-01-01

    Evidence is emerging that individuals with Fragile X syndrome (FXS) display emotion recognition deficits, which may contribute to their significant social difficulties. The current study investigated the emotion recognition abilities, and social approachability judgments, of FXS individuals when processing emotional stimuli. Relative to…

  19. Imitation in Fragile X Syndrome: Implications for Autism

    Macedoni-Luksic, Marta; Greiss-Hess, Laura; Rogers, Sally J.; Gosar, David; Lemons-Chitwood, Kerrie; Hagerman, Randi

    2009-01-01

    To address the specific impairment of imitation in autism, the imitation abilities of 22 children with fragile X syndrome (FXS) with and without autism were compared. Based on previous research, we predicted that children with FXS and autism would have significantly more difficulty with non-meaningful imitation tasks. After controlling for…

  20. Erythrocyte Osmotic Fragility and Excitability Score in Rabbit fed ...

    olayemitoyin

    protect cells against oxidative stress in rats (Wang et al., 2000) and ... method, total red blood cell (RBC) count, total leukocyte (WBC) count .... maturative stages of the erythroblast (pluripotent stem cells) involved in cell formation (Kaur and. Kapoor, 2005). ... effect of zinc on chlorpyrifos- induced erythrocyte fragility in wistar ...

  1. Seismic fragility of ventilation stack of nuclear power plant

    Nefedov, S.S.; Yugai, T.Z.; Kalinkin, I.V.; Vizir, P.L.

    2003-01-01

    Fragility study of safety related elements is necessary step in seismic PSA of nuclear power plant (NPP). In present work fragility was analyzed after the example of the ventilation stack of NPP. Ventilation stack, considered in present work, is a separately erected construction with height of 100 m made of cast-in-place reinforced concrete. In accordance with IAEA terminology fragility of element is defined as conditional probability of its failure at given level of seismic loading. Failure of a ventilation stack was considered as development of the plastic hinge in some section of a shaft. Seismic ground acceleration a, which corresponds to failure, could be defined as limit seismic acceleration of ventilation stack [a]. Limit seismic acceleration [a] was considered as random value. Sources of its variation are connected with stochastic nature of factors determining it (properties of construction materials, soils etc.), and also with uncertainties of existing analytical techniques. Random value [a] was assumed to be distributed lognormally. Median m[a] and logarithmically standard deviation β of this distribution were defined by 'scaling method' developed by R.P. Kennedy et al. Using this values fragility curves were plotted for different levels of confidence probability. (author)

  2. Effect of road transport stress on Erthrocyte Osmotic Fragility (EOF ...

    After an overnight fast, venous blood was collected from each subject for the determination of serum cortisol, glucose concentration and erythrocyte osmotic fragility. The subjects were then transported at a speed of 65 – 75Km/h covering a distance of 180km. Thereafter venous blood was again collected (within 10 minutes) ...

  3. Intergenerational Relationships and Union Stability in Fragile Families

    Hognas, Robin S.; Carlson, Marcia J.

    2010-01-01

    Using data from the Fragile Families and Child Wellbeing Study (N = 2,656), we examined the association between intergenerational relationships and parents' union stability 5 years after a baby's birth. Results showed that more amiable relationships between parents and each partner's parents, and children's spending more time with paternal…

  4. Fragile X syndrome: Current insight | Dean | Egyptian Journal of ...

    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 ...

  5. Theory of Mind Deficits in Children with Fragile X Syndrome

    Cornish, K.; Burack, J. A.; Rahman, A.; Munir, F.; Russo, N.; Grant, C.

    2005-01-01

    Given the consistent findings of theory of mind deficits in children with autism, it would be extremely beneficial to examine the profile of theory of mind abilities in other clinical groups such as fragile X syndrome (FXS) and Down syndrome (DS). The aim of the present study was to assess whether boys with FXS are impaired in simple social…

  6. The Social Consequences of Raising Medically Fragile and ...

    2011-10-02

    Oct 2, 2011 ... who are medically fragile and/or developmentally challenged. It is an ... The overarching theme was the families' search for safety ... children. It is important for policy makers to understand the situation of such parents so ... their family members, children and families without disabilities and, service providers.

  7. Arousal Modulation in Females with Fragile X or Turner Syndrome

    Roberts, Jane; Mazzocco, Michele M. M.; Murphy, Melissa M.; Hoehn-Saric, Rudolf

    2008-01-01

    The present study was carried out to examine physiological arousal modulation (heart activity and skin conductance), across baseline and cognitive tasks, in females with fragile X or Turner syndrome and a comparison group of females with neither syndrome. Relative to the comparison group, for whom a greater increase in skin conductance was…

  8. Long term government debt, financial fragility, and sovereign default risk

    van der Kwaak, C.; van Wijnbergen, S.

    2013-01-01

    We analyze the interaction between bank rescues, financial fragility and sovereign debt discounts. To that end we set up a model that contains balance sheet constrained financial intermediaries financing both capital expenditure of intermediate goods producers and government deficits. The financial

  9. Fragile X-associated tremor/ataxia syndrome.

    Hoem, Gry; Koht, Jeanette

    2017-10-31

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

  10. Fiscal deficits, financial fragility, and the effectiveness of government policies

    Kirchner, M.; van Wijnbergen, S.

    2012-01-01

    Recent macro developments in the euro area have highlighted the interactions between fiscal policy, sovereign debt, and financial fragility. We take a structural macroeconomic model with frictions in the financial intermediation process, in line with recent research, but introduce asset choice and

  11. Noncomprehension Signaling in Males and Females with Fragile X Syndrome

    Thurman, Angela John; Kover, Sara T.; Brown, W. Ted; Harvey, Danielle J.; Abbeduto, Leonard

    2017-01-01

    Purpose: This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method: A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon…

  12. Component Fragility Research Program: Phase 1 component prioritization

    Holman, G.S.; Chou, C.K.

    1987-06-01

    Current probabilistic risk assessment (PRA) methods for nuclear power plants utilize seismic ''fragilities'' - probabilities of failure conditioned on the severity of seismic input motion - that are based largely on limited test data and on engineering judgment. Under the NRC Component Fragility Research Program (CFRP), the Lawrence Livermore National Laboratory (LLNL) has developed and demonstrated procedures for using test data to derive probabilistic fragility descriptions for mechanical and electrical components. As part of its CFRP activities, LLNL systematically identified and categorized components influencing plant safety in order to identify ''candidate'' components for future NRC testing. Plant systems relevant to safety were first identified; within each system components were then ranked according to their importance to overall system function and their anticipated seismic capacity. Highest priority for future testing was assigned to those ''very important'' components having ''low'' seismic capacity. This report describes the LLNL prioritization effort, which also included application of ''high-level'' qualification data as an alternate means of developing probabilistic fragility descriptions for PRA applications

  13. The Neuroanatomy and Neuroendocrinology of Fragile X Syndrome

    Hessl, David; Rivera, Susan M.; Reiss, Allan L.

    2004-01-01

    Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical…

  14. Infant Development in Fragile X Syndrome: Cross-Syndrome Comparisons

    Roberts, Jane E.; McCary, Lindsay M.; Shinkareva, Svetlana V.; Bailey, Donald B., Jr.

    2016-01-01

    This study examined the developmental profile of male infants with fragile X syndrome (FXS) and its divergence from typical development and development of infants at high risk for autism associated with familial recurrence (ASIBs). Participants included 174 boys ranging in age from 5 to 28 months. Cross-sectional profiles on the Mullen Scales of…

  15. Developmental Trajectories of Young Girls with Fragile X Syndrome

    Hatton, Deborah D.; Wheeler, Anne; Sideris, John; Sullivan, Kelly; Reichardt, Alison; Roberts, Jane; Clark, Renee; Bailey, Donald B., Jr.

    2009-01-01

    To describe the early phenotype of girls with full mutation fragile X, we used 54 observations of 15 girls between the ages of 6 months and 9 years to examine developmental trajectories as measured by the Battelle Development Inventory. In this sample, autistic behavior was associated with poorer developmental outcomes, primarily due to…

  16. Phonological Awareness and Reading in Boys with Fragile X Syndrome

    Adlof, Suzanne M.; Klusek, Jessica; Shinkareva, Svetlana V.; Robinson, Marissa L.; Roberts, Jane E.

    2015-01-01

    Background: Reading delays are well documented in children with fragile X syndrome (FXS), but few studies have examined linguistic precursors of reading in this population. This study examined the longitudinal development of phonological awareness and its relationship with basic reading in boys with FXS. Individual differences in genetic,…

  17. Implicit Procedural Learning in Fragile X and Down Syndrome

    Bussy, G.; Charrin, E.; Brun, A.; Curie, A.; des Portes, V.

    2011-01-01

    Background: Procedural learning refers to rule-based motor skill learning and storage. It involves the cerebellum, striatum and motor areas of the frontal lobe network. Fragile X syndrome, which has been linked with anatomical abnormalities within the striatum, may result in implicit procedural learning deficit. Methods: To address this issue, a…

  18. Reading and Phonological Skills in Boys with Fragile X Syndrome

    Klusek, Jessica; Hunt, Anna W.; Mirrett, Penny L.; Hatton, Deborah D.; Hooper, Stephen R.; Roberts, Jane E.; Bailey, Donald B.

    2015-01-01

    Although reading skills are critical for the success of individuals with intellectual disabilities, literacy has received little attention in fragile X syndrome (FXS). This study examined the literacy profile of FXS. Boys with FXS (n = 51; mean age 10.2 years) and mental age-matched boys with typical development (n = 35) participated in…

  19. Brief Report: Autism Symptoms in Infants with Fragile X Syndrome

    Roberts, Jane E.; Tonnsen, Bridgette L.; McCary, Lindsay M.; Caravella, Kelly E.; Shinkareva, Svetlana V.

    2016-01-01

    Fragile X syndrome (FXS) is the most common known genetic cause of autism spectrum disorder (ASD). Although 50-75% of children with FXS meet ASD criteria, no studies have compared ASD symptoms in infants with FXS versus other high risk groups, such as siblings of children with ASD (ASIBs). Using the Autism Observation Scale for Infants, our…

  20. Therapeutic Targets and Translational Endpoints in Fragile X Syndrome

    C.E.F. de Esch (Celine)

    2014-01-01

    markdownabstract__Abstract__ Fragile X syndrome is the most common inherited cause of intellectual disability. It is more common in boys (1 in 4000) than girls (1 in 6000). In addition to the intellectual disability patients often exhibit behavioral abnormalities including hyperactivity and

  1. Seizures in Fragile X Syndrome: Characteristics and Comorbid Diagnoses

    Berry-Kravis, Elizabeth; Raspa, Melissa; Loggin-Hester, Lisa; Bishop, Ellen; Holiday, David; Bailey, Donald B., Jr.

    2010-01-01

    A national survey of caregivers of individuals with fragile X syndrome addressed characteristics of epilepsy and co-occurring conditions. Of the 1,394 individuals (1,090 males and 304 females) with the full mutation, 14% of males and 6% of females reported seizures. Seizures were more often partial, began between ages 4 and 10 years, and were…

  2. Parenting Young Children with and without Fragile X Syndrome

    Sterling, Audra; Barnum, Leah; Skinner, Debra; Warren, Steven F.; Fleming, Kandace

    2012-01-01

    The purpose of this study was to examine maternal parenting styles across age-matched siblings using a within-family design, in which one child has Fragile X syndrome. Thirteen families participated; children were aged 16 to 71 months. Mothers completed several videotaped activities with each child separately as well as an interview. Mothers used…

  3. Seismic fragility capacity of equipment--horizontal shaft pump test

    Iijima, T.; Abe, H.; Suzuki, K.

    2005-01-01

    The current seismic fragility capacity of horizontal shaft pump is 1.6 x 9.8 m/s 2 (1.6 g), which was decided from previous vibration tests and we believe that it must have sufficient margin. The purpose of fragility capacity test is to obtain realistic seismic fragility capacity of horizontal shaft pump by vibration tests. Reactor Building Closed Cooling Water (RCW) Pump was tested as a typical horizontal shaft pump, and then bearings and liner rings were tested as important parts to evaluate critical acceleration and dispersion. Regarding RCW pump test, no damage was found, though maximum input acceleration level was 6 x 9.8 m/s 2 (6 g). Some kinds of bearings and liner rings were tested on the element test. Input load was based on seismic motion which was same with the RCW pump test, and maximum load was equivalent to over 20 times of design seismic acceleration. There was not significant damage that caused emergency stop of pump but degradation of surface roughness was found on some kinds of bearings. It would cause reduction of pump life, but such damage on bearings occurred under large seismic load condition that was equivalent to over 10 to 20 g force. Test results show that realistic fragility capacity of horizontal shaft pump would be at least four times as higher as current value which has been used for our seismic PSA. (authors)

  4. Side Effects of Minocycline Treatment in Patients with Fragile X Syndrome and Exploration of Outcome Measures

    Utari, Agustini; Chonchaiya, Weerasak; Rivera, Susan M.; Schneider, Andrea; Hagerman, Randi J.; Faradz, Sultana M. H.; Ethell, Iryna M.; Nguyen, Danh V.

    2010-01-01

    Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received…

  5. Obesity, Food Selectivity, and Physical Activity in Individuals with Fragile X Syndrome

    Raspa, Melissa; Bailey, Donald B., Jr.; Bishop, Ellen; Holiday, David; Olmsted, Murrey

    2010-01-01

    National survey data from 884 families were used to examine the overall health of children and adults with fragile X syndrome. Results indicate the rate of obesity in adults with fragile X syndrome is similar to the general population (30%). Male children with fragile X syndrome, however, had higher rates of obesity (31%) when compared with…

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

    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…

  7. Heart Activity and Autistic Behavior in Infants and Toddlers with Fragile X Syndrome

    Roberts, Jane E.; Tonnsen, Bridgette; Robinson, Ashley; Shinkareva, Svetlana V.

    2012-01-01

    The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8-40 months) and 25 age-matched…

  8. Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

    Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

    2012-01-01

    We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth…

  9. Agricultural Fragility Estimates Subjected to Volcanic Ash Fall Hazards

    Ham, H. J.; Lee, S.; Choi, S. H.; Yun, W. S.

    2015-12-01

    Agricultural Fragility Estimates Subjected to Volcanic Ash Fall Hazards Hee Jung Ham1, Seung-Hun Choi1, Woo-Seok Yun1, Sungsu Lee2 1Department of Architectural Engineering, Kangwon National University, Korea 2Division of Civil Engineering, Chungbuk National University, Korea ABSTRACT In this study, fragility functions are developed to estimate expected volcanic ash damages of the agricultural sector in Korea. The fragility functions are derived from two approaches: 1) empirical approach based on field observations of impacts to agriculture from the 2006 eruption of Merapi volcano in Indonesia and 2) the FOSM (first-order second-moment) analytical approach based on distribution and thickness of volcanic ash observed from the 1980 eruption of Mt. Saint Helens and agricultural facility specifications in Korea. Fragility function to each agricultural commodity class is presented by a cumulative distribution function of the generalized extreme value distribution. Different functions are developed to estimate production losses from outdoor and greenhouse farming. Seasonal climate influences vulnerability of each agricultural crop and is found to be a crucial component in determining fragility of agricultural commodities to an ash fall. In the study, the seasonality coefficient is established as a multiplier of fragility function to consider the seasonal vulnerability. Yields of the different agricultural commodities are obtained from Korean Statistical Information Service to create a baseline for future agricultural volcanic loss estimation. Numerically simulated examples of scenario ash fall events at Mt. Baekdu volcano are utilized to illustrate the application of the developed fragility functions. Acknowledgements This research was supported by a grant 'Development of Advanced Volcanic Disaster Response System considering Potential Volcanic Risk around Korea' [MPSS-NH-2015-81] from the Natural Hazard Mitigation Research Group, Ministry of Public Safety and Security of

  10. Testicular regulation of neuronal glucose and monocarboxylate transporter gene expression profiles in CNS metabolic sensing sites during acute and recurrent insulin-induced hypoglycemia.

    Vavaiya, Kamlesh V; Paranjape, Sachin A; Briski, Karen P

    2007-01-01

    Recurrent insulin-induced hypoglycemia (RIIH) impairs glucose counter-regulatory function in male humans and rodents and, in the latter, diminishes neuronal activation in CNS structures that monitor metabolic homeostasis, including the lateral hypothalamic area (LHA) and dorsal vagal complex (DVC). We investigated whether habituated neuronal reactivity in CNS sensing sites to hypoglycemia is correlated with modified monocarboxylate and/or glucose uptake by using quantitative real-time RT-PCR to analyze neuronal monocarboxylate transporter (MCT2) and glucose transporter variant (GLUT and GLUT4) gene expression profiles in the microdissected LHA, ventromedial nucleus hypothalamus (VMH), and DVC after one or multiple insulin injections. Because orchidectomy (ORDX) maintains uniform glycemic responses to RIIH in male rats, we also examined whether regional gene response patterns are testes dependent. In the intact male rat DVC, MCT2, GLUT3, and GLUT4 gene expression was not altered by acute hypoglycemia but was enhanced by RIIH. MCT2 and GLUT3 mRNA levels in the ORDX rat DVC did not differ among groups, but GLUT4 transcripts were progressively increased by acute and recurrent hypoglycemia. Precedent hypoglycemia decreased or increased basal MCT2 and GLUT4 gene expression, respectively, in the intact rat LHA; LHA GLUT3 transcription was augmented by RIIH in intact rats only. Acute hypoglycemia suppressed MCT2, GLUT3, and GLUT4 gene expression in the intact rat VMH, a response that was abolished by RIIH. In ORDX rats, VMH gene transcript levels were unchanged in response to one dose of insulin but were selectively diminished during RIIH. These data demonstrate site-specific, testes-dependent effects of acute and recurrent hypoglycemia on neuronal metabolic substrate transporter gene expression in characterized rat brain metabolic sensing loci and emphasize the need to assess the impact of potential alterations in glucose and lactate uptake during RIIH on general and

  11. Fragility non-hip fracture patients are at risk.

    Gosch, M; Druml, T; Nicholas, J A; Hoffmann-Weltin, Y; Roth, T; Zegg, M; Blauth, M; Kammerlander, C

    2015-01-01

    Fragility fractures are a growing worldwide health care problem. Hip fractures have been clearly associated with poor outcomes. Fragility fractures of other bones are common reasons for hospital admission and short-term disability, but specific long-term outcome studies of non-hip fragility fractures are rare. The aim of our trial was to evaluate the 1-year outcomes of non-hip fragility fracture patients. This study is a retrospective cohort review of 307 consecutive older inpatient non-hip fracture patients. Patient data for analysis included fracture location, comorbidity prevalence, pre-fracture functional status, osteoporosis treatments and sociodemographic characteristics. The main outcomes evaluated were 1-year mortality and post-fracture functional status. As compared to the expected mortality, the observed 1-year mortality was increased in the study group (17.6 vs. 12.2 %, P = 0.005). After logistic regression, three variables remained as independent risk factors for 1-year mortality among non-hip fracture patients: malnutrition (OR 3.3, CI 1.5-7.1), Charlson comorbidity index (CCI) (OR 1.3, CI 1.1-1.5) and the Parker Mobility Score (PMS) (OR 0.85, CI 0.74-0.98). CCI and PMS were independent risk factors for a high grade of dependency after 1 year. Management of osteoporosis did not significantly improve after hospitalization due to a non-hip fragility fracture. The outcomes of older non-hip fracture patients are comparable to the poor outcomes of older hip fracture patients, and appear to be primarily related to comorbidities, pre-fracture function and nutritional status. The low rate of patients on osteoporosis medications likely reflects the insufficient recognition of the importance of osteoporosis assessment and treatment in non-hip fracture patients. Increased clinical and academic attention to non-hip fracture patients is needed.

  12. Fragility fractures at Auckland City Hospital: we can do better.

    Braatvedt, Geoffrey; Wilkinson, Susan; Scott, Marilyn; Mitchell, Paul; Harris, Roger

    2017-12-01

    This study describes in detail the burden of caring for patients aged ≥ 50 years seen in one year with a fragility fracture in a large urban environment and shows that these fractures result in a long length of stay and significant mortality. Intervention to prevent further fracture was poorly done. To examine the epidemiology of fragility fracture in patients over age 50 years and record the number who received appropriate secondary prevention treatment. All patients aged ≥ 50 years presenting with a fracture during the 12 months following July 1 st 2011, to Auckland City Hospital or residing in central Auckland at the time of their fracture, were identified from hospital and Accident Compensation Corporation records. A random sample of 55% of these patient's records were reviewed to establish the type of fracture, prior fracture and falls history, and use of bisphosphonates in the 12 months before presentation. Their length of stay (LOS) by type of fracture was recorded. The use of bisphosphonate drugs in the following 12 months was obtained from centralised national records of prescriptions. 2729 patients aged ≥ 50 years presented with a fragility fracture in the central Auckland region in one year. Fifty-six percent of these patients were seen at Auckland Hospital and of these, 82% patients required admission with a mean LOS of 20 days (SD ± 24 days).The remaining 44% of patients were looked after in the private outpatient sector. Approximately 30% of the admissions were for hip fracture. Sixty-four percent of patients with a fragility fracture did not receive a potent bisphosphonate, 12% were considered not appropriate for treatment, and 24% received a potent bisphosphonate during their admission or in the next 12 months. Approximately 1 in 18 people aged ≥ 50 years presented in one year with a fragility fracture.Secondary prevention strategies were poorly implemented. Additional resources for identifying and initiating secondary fracture prevention

  13. Clinical assessment tools identify functional deficits in fragility fracture patients

    Ames TD

    2016-05-01

    Full Text Available Tyler D Ames,1 Corinne E Wee,1 Khoi M Le,1 Tiffany L Wang,1 Julie Y Bishop,2 Laura S Phieffer,2 Carmen E Quatman2 1The Ohio State University College of Medicine, 2Department of Orthopaedics, The Ohio State University Wexner Medical Center, Columbus, OH, USA Purpose: To identify inexpensive, noninvasive, portable, clinical assessment tools that can be used to assess functional performance measures that may put older patients at risk for falls such as balance, handgrip strength, and lumbopelvic control.Patients and methods: Twenty fragility fracture patients and 21 healthy control subjects were evaluated using clinical assessment tools (Nintendo Wii Balance Board [WBB], a handheld dynamometer, and an application for the Apple iPod Touch, the Level Belt that measure functional performance during activity of daily living tasks. The main outcome measurements were balance (WBB, handgrip strength (handheld dynamometer, and lumbopelvic control (iPod Touch Level Belt, which were compared between fragility fracture patients and healthy controls.Results: Fragility fracture patients had lower scores on the vertical component of the WBB Torso Twist task (P=0.042 and greater medial–lateral lumbopelvic sway during a 40 m walk (P=0.026 when compared to healthy controls. Unexpectedly, the fracture patients had significantly higher scores on the left leg (P=0.020 and total components (P=0.010 of the WBB Single Leg Stand task as well as less faults during the left Single Leg Stand task (P=0.003.Conclusion: The clinical assessment tools utilized in this study are relatively inexpensive and portable tools of performance measures capable of detecting differences in postural sway between fragility fracture patients and controls. Keywords: fall risk, geriatric fracture, Nintendo Wii Balance Board, Level Belt, fragility fracture

  14. Fragility and hysteretic creep in frictional granular jamming.

    Bandi, M M; Rivera, M K; Krzakala, F; Ecke, R E

    2013-04-01

    The granular jamming transition is experimentally investigated in a two-dimensional system of frictional, bidispersed disks subject to quasistatic, uniaxial compression without vibrational disturbances (zero granular temperature). Three primary results are presented in this experimental study. First, using disks with different static friction coefficients (μ), we experimentally verify numerical results that predict jamming onset at progressively lower packing fractions with increasing friction. Second, we show that the first compression cycle measurably differs from subsequent cycles. The first cycle is fragile-a metastable configuration with simultaneous jammed and unjammed clusters-over a small packing fraction interval (φ(1)disk displacements over the same packing fraction interval. This fragile behavior is explained through a percolation mechanism of stressed contacts where cluster growth exhibits spatial correlation with disk displacements and contributes to recent results emphasizing fragility in frictional jamming. Control experiments show that the fragile state results from the experimental incompatibility between the requirements for zero friction and zero granular temperature. Measurements with several disk materials of varying elastic moduli E and friction coefficients μ show that friction directly controls the start of the fragile state but indirectly controls the exponential pressure rise. Finally, under repetitive loading (compression) and unloading (decompression), we find the system exhibits pressure hysteresis, and the critical packing fraction φ(c) increases slowly with repetition number. This friction-induced hysteretic creep is interpreted as the granular pack's evolution from a metastable to an eventual structurally stable configuration. It is shown to depend on the quasistatic step size Δφ, which provides the only perturbative mechanism in the experimental protocol, and the friction coefficient μ, which acts to stabilize the pack.

  15. Generation of thermostable Moloney murine leukemia virus reverse transcriptase variants using site saturation mutagenesis library and cell-free protein expression system.

    Katano, Yuta; Li, Tongyang; Baba, Misato; Nakamura, Miyo; Ito, Masaaki; Kojima, Kenji; Takita, Teisuke; Yasukawa, Kiyoshi

    2017-12-01

    We attempted to increase the thermostability of Moloney murine leukemia virus (MMLV) reverse transcriptase (RT). The eight-site saturation mutagenesis libraries corresponding to Ala70-Arg469 in the whole MMLV RT (Thr24-Leu671), in each of which 1 out of 50 amino acid residues was replaced with other amino acid residue, were constructed. Seven-hundred and sixty eight MMLV RT clones were expressed using a cell-free protein expression system, and their thermostabilities were assessed by the temperature of thermal treatment at which they retained cDNA synthesis activity. One clone D200C was selected as the most thermostable variant. The highest temperature of thermal treatment at which D200C exhibited cDNA synthesis activity was 57ºC, which was higher than for WT (53ºC). Our results suggest that a combination of site saturation mutagenesis library and cell-free protein expression system might be useful for generation of thermostable MMLV RT in a short period of time for expression and selection.

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

    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.

  17. Fragile X syndrome: panoramic radiographic evaluation of dental anomalies, dental mineralization stage, and mandibular angle

    Sabbagh-Haddad, Aida; Haddad, Denise Sabbagh; Michel-Crosato, Edgard; Arita, Emiko Saito

    2016-01-01

    ABSTRACT Fragile X syndrome (FXS) is a disorder linked to the chromosome X long arm (Xq27.3), which is identified by a constriction named fragile site. It determines various changes, such as behavioral or emotional problems, learning difficulties, and intellectual disabilities. Craniofacial abnormalities such as elongated and narrow face, prominent forehead, broad nose, large and prominent ear pavilions, strabismus, and myopia are frequent characteristics. Regarding the oral aspects, deep and high-arched palate, mandibular prognathism, and malocclusion are also observed. Objective: The purpose of this study was to evaluate the dental radiographic characteristics as described in 40 records of patients with panoramic radiography. Material and Methods: The patients were in the range of 6–17 years old, and were divided into two groups (20 subjects who were compatible with the normality standard and 20 individuals diagnosed with the FXS), which were matched for gender and age. Analysis of the panoramic radiographic examination involved the evaluation of dental mineralization stage, mandibular angle size, and presence of dental anomalies in both deciduous and permanent dentitions. Results: The results of radiographic evaluation demonstrated that the chronology of tooth eruption of all third and second lower molars is anticipated in individuals with FXS (pdental anomalies. In addition, an increase was observed in the mandibular angle size in the FXS group (pdental radiographic changes is of great importance for dental surgeons to plan the treatment of these individuals. PMID:27812623

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

    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

  19. The seismic fragility analysis for multi-story steel structure in CANDU nuclear power plant

    Hwang, K.H.; Lee, B.S.; Kang, S-K.

    1996-01-01

    The Wolsong Unit 2 is a CANDU-6 type plant and is being constructed in the Wolsong site, where Design Basis Earthquake (DBE) was determined to be 0.2g. A seismic PSA for Wolsong Unit 2 is being performed as one of the conditions for the Construction Permit. One of the issues in the seismic PSA is the availability of the seismically non-qualified systems, which are located in the Turbine Building(T/B). Thus, the seismic fragility analysis for the T/B was performed to estimate the operability of the systems. The design seismic loads for the building were based on a ground response spectrum scaled down from the DBE to horizontal peak ground acceleration (pga) of 0.05g. The seismic fragility analysis for the building was performed using a factor of the safety method. It is estimated that the most critical failure is that of masonry walls and its High Confidence and Low Probability of Failure (HCLPF) capacity is 0.13g. The critical failure mode of the structure is identified to be tensile yielding failure of grip angle, and its HCLPF capacity is 0.34g. (author)

  20. Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes.

    Alfredo Panebra

    2010-07-01

    Full Text Available The beta2-adrenergic receptor (beta2AR is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions.We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5'UTR, coding, and 3'UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that beta2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. "Whole-gene" transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface beta2AR protein expression compared to the others. Agonist-promoted downregulation of beta2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression.Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of beta-agonist may be influenced by certain beta2AR haplotypes (expression phenotypes, while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes. An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where beta2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection

  1. Soil-structure interaction effects on containment fragilities and floor response spectra statistics

    Pires, J.; Reich, M.; Chokshi, N.C.

    1987-01-01

    The probability-based method for the reliability evaluation of nuclear structures developed at Brookhaven National Laboratory (BNL) is extended to include soil-structure interaction effects. A reinforced concrete containment is analyzed in order to investigate the soil-structure interaction effects on: structural fragilities; floor response spectra statistics and acceleration response correlations. To include the effect of soil flexibility on the reliability assessment the following two step approach is used. In the first step, the lumped parameter method for soil-structure interaction analysis is used together with a stick model representation of the structure in order to obtain the motions of the foundation plate. These motions, which include both translations and rotations of the foundation plate, are expressed in terms of the power-spectral density of the free-field ground excitation and the transfer function of the total acceleration response of the foundation. The second step involves a detailed finite element model of the structure subjected to the interaction motions computed from step one. Making use of the structural model and interaction motion the reliability analysis method yields the limit stat probabilities and fragility data for the structure

  2. Exposure to paper mill effluent at a site in North Central Florida elicits molecular-level changes in gene expression indicative of progesterone and androgen exposure.

    Erica K Brockmeier

    Full Text Available Endocrine disrupting compounds (EDCs are chemicals that negatively impact endocrine system function, with effluent from paper mills one example of this class of chemicals. In Florida, female Eastern mosquitofish (Gambusia holbrooki have been observed with male secondary sexual characteristics at three paper mill-impacted sites, indicative of EDC exposure, and are still found at one site on the Fenholloway River. The potential impacts that paper mill effluent exposure has on the G. holbrooki endocrine system and the stream ecosystem are unknown. The objective of this study was to use gene expression analysis to determine if exposure to an androgen receptor agonist was occurring and to couple this analysis with in vitro assays to evaluate the presence of androgen and progesterone receptor active chemicals in the Fenholloway River. Focused gene expression analyses of masculinized G. holbrooki from downstream of the Fenholloway River paper mill were indicative of androgen exposure, while genes related to reproduction indicated potential progesterone exposure. Hepatic microarray analysis revealed an increase in the expression of metabolic genes in Fenholloway River fish, with similarities in genes and biological processes compared to G. holbrooki exposed to androgens. Water samples collected downstream of the paper mill and at a reference site indicated that progesterone and androgen receptor active chemicals were present at both sites, which corroborates previous chemical analyses. Results indicate that G. holbrooki downstream of the Fenholloway River paper mill are impacted by a mixture of both androgens and progesterones. This research provides data on the mechanisms of how paper mill effluents in Florida are acting as endocrine disruptors.

  3. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

    Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Rosenfelt, Cory; Gertner, Michael J.; Campbell, Sean R.; Emerson, Danielle; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Chambers, Daniel B.; Langer, Steven; Sust, Steven; Malik, Aatika; Terlizzi, Allison M.; Liebelt, David A.; Ferreiro, David; Sharma, Ali; Koenigsberg, Eric; Choi, Richard J.; Louneva, Natalia; Arnold, Steven E.; Featherstone, Robert E.; Siegel, Steven J.; Zukin, R. Suzanne; McDonald, Thomas V.; Bolduc, Francois V.; Jongens, Thomas A.; McBride, Sean M. J.

    2016-01-01

    Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. PMID:27445731

  4. Bayesian methodology for generic seismic fragility evaluation of components in nuclear power plants

    Yamaguchi, Akira; Campbell, R.D.; Ravindra, M.K.

    1991-01-01

    Bayesian methodology for updating the seismic fragility of components in nuclear power plants is presented. The generic fragility data which have been evaluated based on the past SPSAs are combined with the seismic experience data. Although the seismic experience is limited to the acceleration range below the median capacity of the components, it has been found that the evidence is effective to update the fragility tail. In other words, the uncertainty of the fragility is reduced although the median capacity itself is not modified to a great extent. The annual frequency of failure is also reduced as a result of the updating of the fragility tail. The PDF of the seismic capacity is handled in discrete form, which enables the use of arbitrary type of prior distribution. Accordingly, the Log-N prior can be used which is consistent with the widely used fragility model. For evaluating posterior fragility parameters (A m and B U ), two methods have been proposed. Furthermore, it has been found that the importance of evidence used in the Bayesian methodology can be quantified by the entropy of the evidence. Only the events with high entropy need to be considered in the Bayesian updating of the fragility. The currently available seismic experience database for typical components can be utilized to develop the fragility tail which is contributive to the seismically-induced failure frequency. The combined use of generic fragility and seismic experience data, with the aid of Bayesian methodology, provides refined generic fragility curves which are useful for SPSA studies. (author)

  5. Impairment of Release Site Clearance within the Active Zone by Reduced SCAMP5 Expression Causes Short-Term Depression of Synaptic Release

    Daehun Park

    2018-03-01

    Full Text Available Summary: Despite being a highly enriched synaptic vesicle (SV protein and a candidate gene for autism, the physiological function of SCAMP5 remains mostly enigmatic. Here, using optical imaging and electrophysiological experiments, we demonstrate that SCAMP5 plays a critical role in release site clearance at the active zone. Truncation analysis revealed that the 2/3 loop domain of SCAMP5 directly interacts with adaptor protein 2, and this interaction is critical for its role in release site clearance. Knockdown (KD of SCAMP5 exhibited pronounced synaptic depression accompanied by a slower recovery of the SV pool. Moreover, it induced a strong frequency-dependent short-term depression of synaptic release, even under the condition of sufficient release-ready SVs. Super-resolution microscopy further proved the defects in SV protein clearance induced by KD. Thus, reduced expression of SCAMP5 may impair the efficiency of SV clearance at the active zone, and this might relate to the synaptic dysfunction observed in autism. : Park et al. show that SCAMP5 plays an important role in release site clearance during intense neuronal activity. Loss of SCAMP5 results in a traffic jam at release sites, causing aberrant short-term synaptic depression that might be associated with the synaptic dysfunction observed in autism. Keywords: secretory carrier membrane protein, SCAMP5, autism spectrum disorder, adaptor protein 2, release site clearance, presynaptic active zone, short-term depression, endocytosis, super-resolution microscopy

  6. Selectively enhanced expression of prophenoloxidase activating enzyme 1 (PPAE1 at a bacteria clearance site in the white shrimp, Litopenaeus vannamei

    Jang In-Kwon

    2011-12-01

    Full Text Available Abstract Background The prophenoloxidase-activating (PO activating system plays an important role in the crustacean innate immunity, particularly in wound healing and pathogen defense. A key member of this system is prophenoloxidase-activating enzyme (PPAE, which is the direct activator of prophenoloxidase (proPO. Despite their importance in crustacean PO activating system, the studies on them remain limited. Results Here we report on a PPAE of white shrimp, Litopenaeus vannamei (lvPPAE1, which showed 94% similarity to PPAE1 of Penaeus monodon. We found that lvPPAE1 in fluid hemocytes was down regulated after challenge by Vibrio harveyi but was enhanced when shrimps were exposed to a bacteria-rich environment for long-term. In vivo gene silence of lvPPAE1 by RNAi can significantly reduce the phenoloxidase activity (PO and increase the susceptibility of shrimps to V. harveyi. Although lvPPAE1 was down-regulated in fluid hemocytes by Vibrio challenge, its expression increased significantly in gill after bacteria injection, which is the primary bacteria-clearance tissue. Conclusion Suppressed expression in fluid hemocytes and enhanced expression in gill indicates selectively enhanced expression at the bacterial clearance site. This is a novel feature for PPAE expression. The results will contribute to our understanding of the PO activating system in crustaceans.

  7. Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression

    Peeters, Janneke G C; Vervoort, Stephin J; Tan, Sander C; Mijnheer, Gerdien; de Roock, Sytze; Vastert, Sebastiaan J.; Nieuwenhuis, Edward E S; van Wijk, Femke; Prakken, Berent J; Creyghton, Menno P; Coffer, Paul J; Mokry, Michal; van Loosdregt, Jorg

    2015-01-01

    The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation.

  8. Differential expression of bio-markers in primary non-small cell lung cancer and metastatic sites

    Gomez-Roca, C.; Besse, B.; Soria, J.C. [Department of Medicine, Institut Gustave Roussy (IGR), Villejuif (France); Raynaud, Ch.; Morat, L.; Sabatier, L.; Soria, J.C. [Laboratoire de radiobiologie et oncologie, CEA, Fontenay-aux-Roses (France); Penault-Llorca, F. [Department of Pathology Centre Jean Perrin, Institut National de la Sante et de la Recherche Medicale UMR484, Clermont-Ferrand (France); Mercier, O.; Dartevelle, Ph. [Department of Thoracic and Vascular Surgery and Heart-lung Transplantation, Marie Lannelongue Hospital, Le Pleissy-Robinson (France); Commo, F.; Taranchon, E. [Laboratory of Translational Research, IGR, Villejuif (France); Validire, P. [Department of Pathology, Institut Mutualiste Montsouris, Paris (France); Italiano, A. [Department of Medical Oncology, Centre Antoine-Lacassagne - Laboratory of Solid Tumor Genetics, Centre Hospitalier Universitaire de Nice, Nice Cedex (France)

    2009-07-01

    Introduction: The use of bio-markers to evaluate the presence of a target or to select a specific therapy is increasingly advocated. The correlation of bio-marker expression between the primary tumor and its corresponding metastasis has not yet been well documented and analyzed in patients with non-small cell lung cancer (NSCLC). Methods: The expression of epidermal growth factor receptor (EGFR), excision repair cross-complementing (ERCC1), vascular-endothelial growth factor receptor, and Ki-67 was immuno-histo-chemically analyzed in tumor samples of primary NSCLC and one corresponding metastasis in a population of 49 patients. Results: Sixteen cases (33%) displayed clear discordance in the EGFR status between the primary tumor and the metastasis, with a significant trend toward downregulation of EGFR in the metastasis (p = 0.01). The ERCC1 status was discordant in 20 cases (41%), with a trend toward overexpression in brain and adrenal metastases (p = 0.01 and p = 0.08, respectively). The vascular-endothelial growth factor receptor and Ki-67 statuses were discordant in 13 (27%) and 15 (31%) cases, respectively. No difference in expression was observed between synchronous and metachronous metastasis. Conclusion: bio-marker expression is discordant between the primary tumor and its corresponding metastasis in about one third of patients with NSCLC. These findings should be considered in the setting of clinical trials and further explored using frozen material and high-throughput techniques. (authors)

  9. 77 FR 31643 - Siltronic Corporation FAB1 Plant Including On-Site Leased Workers From Express Temporaries...

    2012-05-29

    ... Secure Solutions USA, SBM Management Services, LP, ALSCO Portland Industrial, VWR International, Inc... G4S Secure Solutions USA, SBM Management Services, LP, Alsco Portland Industrial, VWR International... workers from Express Temporaries, Aerotek Commercial Staffing, G4S Secure Solutions USA, SBM Management...

  10. [Prokaryotic expression and immunogenicity analysis of the chimeric HBcAg containing APP beta cleavage site peptide and Aβ(1-15);].

    Feng, Gai-feng; Wang, Jun-yang; Jin, Hui; Wang, Wei-xi; Qian, Yi-hua; Yang, Wei-na; Wang, Quan-ying; Yang, Guang-xiao

    2011-11-01

    To construct the recombinant prokaryotic expression plasmid pET/c-ABCSP-Aβ(15-c);, and evaluate the immunogenicity of the fusion protein expressed in E.coli. The gene fragment HBc88-144 was amplified by PCR and subcloned to pUC19. The APP beta cleavage site peptide(ABCSP) and Aβ(1-15); gene(ABCSP-Aβ(15);) was amplified by PCR and inserted downstream of HBc1-71 in pGEMEX/c1-71. After restriction enzyme digestion, c1-17-ABCSP-Aβ(15); were connected with HBc88-144, yielding the recombinant gene c-ABCSP-Aβ(15-c);. c-ABCSP-Aβ(15-c); gene was subcloned into pET-28a(+).The fusion protein expressed in transformed E.coli BL21 was induced with IPTG and analyzed by SDS-PAGE. The virus-like particles (VLP) formed by fusion protein was observed with Transmission Electron Microscope (TEM). 4 Kunming (KM) mice received intraperitoneal injection (i.p) of fusion protein VLP. The antibody was detected by indirect ELISA. The recombinant gene was confirmed by restriction enzyme digestion and DNA sequencing. After IPTG induction, fusion protein was expressed and mainly existed in the sediment of the bacterial lysate. The expression level was 40% of all the proteins in the sediment. The fusion protein could form VLP. After 5 times of immunization, the titer of anti-ABCSP and anti-Aβantibody in sera of KM mice reached up to 1:5 000 and 1:10 000 respectively, while the anti-HBc antibody was undetectable. Recombinant c-ABCSP-Aβ(15-c); gene can be expressed in E.coli. The expressed protein could form VLP and has a strong immunogenicity. This study lays the foundation for the study of AD genetic engineering vaccine.

  11. The Influence of LepR Tyrosine Site Mutations on Mouse Ovary Development and Related Gene Expression Changes

    Tu, Xiaoyu; Kuang, Zhichao; Gong, Xia; Shi, Yan; Yu, Lin; Shi, Huijuan; Wang, Jian; Sun, Zhaogui

    2015-01-01

    Leptin exerts many biological functions, such as in metabolism and reproduction, through binding to and activating the leptin receptor, LepRb, which is expressed in many regions of the brain. To better understand the roles of LepR downstream signaling pathways, Y123F mice, which expressed mutant leptin receptors with phenylalanine (F) substituted for three tyrosines (Y) (Tyr985, Tyr1077 and Tyr1138), were generated. The body weight and abdominal fat deposits of Y123F homozygous mice (HOM) were higher than those of wild-type mice (WT). HOM ovaries were atrophic and the follicles developed abnormally; however, the HOM ovaries did not exhibit polycystic phenotypes. Moreover, Y123F HOM adults had no estrous cycle and the blood estrogen concentration remained stable at a low level below detection limit of 5 pg/ml. LepR expression in HOM ovaries was higher than in WT ovaries. Using cDNA Microarrays, the mRNA expressions of 41 genes were increased, and 100 were decreased in HOM vs. WT ovaries, and many signaling pathways were evaluated to be involved significantly. The expressions of 19 genes were validated by real-time quantitative PCR, most of which were consistent with the microarray results. Thus, Y123F HOM mice were suggested as a new animal model of PCOS for research that mainly emphasizes metabolic disorders and anovulation, but not the polycystic phenotype. Meanwhile, using the model, we found that JAK-STAT and hormone biosynthesis pathways were involved in the follicular development and ovulation disorders caused by LepR deficiency in ovaries, although we could not exclude indirect actions from the brain. PMID:26529315

  12. Digestive beta-glucosidases from the wood-feeding higher termite, Nasutitermes takasagoensis: intestinal distribution, molecular characterization, and alteration in sites of expression.

    Tokuda, Gaku; Miyagi, Mio; Makiya, Hiromi; Watanabe, Hirofumi; Arakawa, Gaku

    2009-12-01

    beta-Glucosidase [EC 3.2.1.21] hydrolyzes cellobiose or cello-oligosaccharides into glucose during cellulose digestion in termites. SDS-PAGE and zymogram analyses of the digestive system in the higher termite Nasutitermes takasagoensis revealed that beta-glucosidase activity is localized in the salivary glands and midgut as dimeric glycoproteins. Degenerate PCR using primers based on the N-terminal amino acid sequences of the salivary beta-glucosidase resulted in cDNA fragments of 1.7 kb, encoding 489 amino acids with a sequence similar to glycosyl hydrolase family 1. Moreover, these primers amplified cDNA fragments from the midgut, and the deduced amino acid sequences are 87-91% identical to those of the salivary beta-glucosidases. Successful expression of the cDNAs in Escherichia coli implies that these sequences also encode functional beta-glucosidases. These results indicate that beta-glucosidases that primarily contribute to the digestive process of N. takasagoensis are produced in the midgut. Reverse transcription-PCR analysis indicated the site-specific expression of beta-glucosidase mRNAs in the salivary glands and midgut. These results suggest that termites have developed the ability to produce beta-glucosidases in the midgut, as is the case for endo-beta-1,4-glucanase, in which the site of expression has shifted from the salivary glands of lower termites to the midgut of higher termites. Copyright 2009 Elsevier Ltd. All rights reserved.

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

    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.

  14. On the importance of uncertain factors in seismic fragility assessment

    Borgonovo, E.; Zentner, I.; Pellegri, A.; Tarantola, S.; Rocquigny, E. de

    2013-01-01

    This paper addresses the definition of importance measures for helping the modeller to detect the factors on which to focus modelling activity and data collection in seismic fragility analysis. We study sensitivity measures consistent with the decision-support criteria of interest, namely, the (mean) fragility curve and the “High Confidence of Low Probability of Failure” (HCLPF) value. The importance measures are obtained analytically for the EPRI safety factor method, which is nowadays used worldwide for seismic risk assessment of nuclear plants. We illustrate and discuss the use of both variance-based and CDF-based importance measures in the application to two case studies, the first analytical and based on the EPRI method, the second numerical.

  15. Fragility and structure of Al-Cu alloy melts

    Lv Xiaoqian; Bian Xiufang; Mao Tan; Li Zhenkuan; Guo Jing; Zhao Yan

    2007-01-01

    The dynamic viscosity measurements are performed for Al-Cu alloy melts with different compositions using an oscillating-cup viscometer. The results show that the viscosities of Al-Cu alloy melts increase with the copper content increasing, and also have a correlation with the correlation radius of clusters, which is measured by the high-temperature X-ray diffractometer. It has also been found that the fragilities of superheated melts (M) of hypereutectic Al-Cu alloys increase with the copper content increasing. There exists a relationship between the fragility and the structure in Al-Cu alloy melts. The value of the M reflects the variation of activation energy for viscous flow

  16. Fragility: The Next Wave in Critical Infrastructure Protection

    Allan McDougall

    2009-01-01

    Full Text Available In North America today, we are about to embark on a significant effort to repair, or even upgrade, many aspects of our infrastructure. Many of these efforts are linked to economic recovery packages. Others are based on sheer need. The challenge for decision makers and planners involves ensuring that scarce economic resources are put to their best use. Understanding the concept of fragility plays a pivotal part in reaching that understanding.Fragility, like many other systems—particularly Information Technology (IT systems—works on the concept of subjects and objects. Subjects are those entities that seek to exploit the services (or capacity offered by the object. Objects, on the other hand, are those entities that deliver some good or service to the overall system. Of course, something may act as the object in one pairing and the subject in another pairing—they are not exclusive in nature.

  17. Mechanisms of diabetes mellitus-induced bone fragility

    Napoli, Nicola; Chandran, Manju; Pierroz, Dominique D

    2017-01-01

    The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM...... and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia......-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus....

  18. Of Men and Mice: Modeling the Fragile X Syndrome

    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

  19. Multifarious Functions of the Fragile X Mental Retardation Protein.

    Davis, Jenna K; Broadie, Kendal

    2017-10-01

    Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder (ASD), results from the loss of Fragile X mental retardation protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded its proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of its involvement in RNA, channel, and protein binding that modulate calcium signaling, activity-dependent critical period development, and the excitation-inhibition (E/I) neural circuitry balance. In this review, we contextualize 3 years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles to determine whether FMRP has a multitude of unrelated functions or whether combinatorial mechanisms can explain its multifaceted existence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Financial structure, financial development and banking fragility: International evidence

    Ruiz-Porras, Antonio

    2008-01-01

    We study the effects of financial structure and financial development on banking fragility. We develop our study by using fixed-effects panel-data regressions and by controlling the effects of certain banking indicators. We use individual and principal-components indicators of the activity, size and efficiency of intermediaries and markets. The indicators include data for 211 countries between 1990 and 2003. Our main findings suggest that banking stability is enhanced in market-based financia...

  1. The State of Synapses in Fragile X Syndrome

    Pfeiffer, Brad E.; Huber, Kimberly M.

    2009-01-01

    Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism. There is increasing evidence in both FXS and other forms of autism that alterations in synapse number, structure and function are associated and contribute to these prevalent diseases. FXS is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP. Therefore, FXS is a tractable model to understand synaptic dysfunction in cognitive disorders. FMRP is...

  2. Managing the Noodle Bowl: The Fragility of East Asian Regionalism

    Baldwin, Richard E.

    2007-01-01

    The paper argues that East Asian regionalism is fragile, since (i) each nation's industrial competitiveness depends on the smooth functioning of "Factory Asia" — in particular, on intra-regional trade; (ii) the unilateral tariff-cutting that created "Factory Asia" is not subject to WTO discipline (bindings); (iii) there is no "top-level management" to substitute for WTO discipline, i.e., to ensure that bilateral trade tensions — tensions that are inevitable in East Asia — do not spillover int...

  3. International strategies in fragile states : expanding the toolbox?

    Klotzle, Kurt

    2006-01-01

    "In recent years, international actors have taken significant strides in attempting to develop strategies and instruments that effectively address the problem of weak and failing states. On the one hand, the intensified focus on state failure has to do with general, fundamental shifts in the international security environment since the end of the Cold War. On the other hand, however, the sharpened concern with fragile states arises from the specific challenges, experiences, and interests of k...

  4. The Evaluation of Corneal Fragility After UVA/Riboflavin Crosslinking.

    Li, Zhiwei; Wang, Yumeng; Xu, Yanyun; Jhanji, Vishal; Zhang, Chunxiao; Mu, Guoying

    2017-03-01

    To evaluate the fragility of cornea after UVA/riboflavin crosslinking (CXL). Sixty New Zealand rabbits received UVA/riboflavin crosslinking treatment (wavelength 365 nm, irradiance 3.0 mW/cm, and total dose 5.4 J/cm) on right eyes. Animals were sacrificed before and immediately after treatment (day 0), day 1, 3, 7, and 28 after treatment. A 4×10 mm corneal strip for biomechanical evaluation was harvested after sacrifice. The corneal fragility was evaluated by measurement of elongation rate, whereby the elongation rate equals elongation length/baseline length. The Youngs modulus and maximal stress were 1.41±0.51 MPa and 5.56±1.84 MPa before CXL, and increased to 2.31±0.68 MPa (P=0.008) and 9.25±2.74 MPa (P=0.04), respectively, on day 0, then maintained a stable level within a 28 days follow-up. The elongation rate was 62.04±9.34% before CXL and decreased to 48.95%±8.24% (P=0.02) on day 0, then maintained a stable level within a 28 days follow-up. This study showed an increase in the corneal fragility after UVA/riboflavin crosslinking along with an increase in the corneal stiffness. A long-term follow-up should be taken to evaluate the potential deleterious effect of the increasing corneal fragility after UVA/riboflavin crosslinking.

  5. Paternal Incarceration and Father–Child Contact in Fragile Families

    Geller, Amanda

    2013-01-01

    High rates of incarceration in the United States have motivated a broad examination of the effects of parental incarceration on child well-being. Although a growing literature documents challenges facing the children of incarcerated men, most incarcerated fathers lived apart from their children before their arrest, raising questions of whether they were sufficiently involved with their families for their incarceration to affect their children. The author used the Fragile Families and Child We...

  6. Strong to fragile transition in a model of liquid silica

    Barrat, Jean-Louis; Badro, James; Gillet, Philippe

    1996-01-01

    The transport properties of an ionic model for liquid silica at high temperatures and pressure are investigated using molecular dynamics simulations. With increasing pressure, a clear change from "strong" to "fragile" behaviour (according to Angell's classification of glass-forming liquids) is observed, albeit only on the small viscosity range that can be explored in MD simulations.. This change is related to structural changes, from an almost perfect four-fold coordination to an imperfect fi...

  7. MiR-2964a-5p binding site SNP regulates ATM expression contributing to age-related cataract risk.

    Rong, Han; Gu, Shanshan; Zhang, Guowei; Kang, Lihua; Yang, Mei; Zhang, Junfang; Shen, Xinyue; Guan, Huaijin

    2017-10-17

    This study was to explore the involvement of DNA repair genes in the pathogenesis of age-related cataract (ARC). We genotyped nine single nucleotide polymorphisms (SNPs) of genes responsible to DNA double strand breaks (DSBs) in 804 ARC cases and 804 controls in a cohort of eye diseases in Chinese population and found that the ataxia telangiectasia mutated ( ATM ) gene-rs4585:G>T was significantly associated with ARC risk. An in vitro functional test found that miR-2964a-5p specifically down-regulated luciferase reporter expression and ATM expression in the cell lines transfected with rs4585 T allele compared to rs4585 G allele. The molecular assay on human tissue samples discovered that ATM expression was down-regulated in majority of ARC tissues and correlated with ATM genotypes. In addition, the Comet assay of cellular DNA damage of peripheral lymphocytes indicated that individuals carrying the G allele (GG/GT) of ATM -rs4585 had lower DNA breaks compared to individuals with TT genotype. These findings suggested that the SNP rs4585 in ATM might affect ARC risk through modulating the regulatory affinity of miR-2964a-5p. The reduced DSBs repair might be involved in ARC pathogenesis.

  8. Transforming growth factor. beta. sub 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis

    Broekelmann, T.J.; Limper, A.H.; McDonald, J.A. (Washington Univ., St. Louis, MO (United States)); Colby, T.V. (Mayo Clinic, Rochester, MN (United States))

    1991-08-01

    Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, the authors demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, they now demonstrate the presence of transforming growth factor {beta}{sub 1} (TGF-{beta}{sub 1}), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-{beta}{sub 1} may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-{beta}{sub 1} is the alveolar macrophage, and they demonstrate the expression of abundant TGF-{beta}{sub 1} mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.

  9. Fragility analysis of a seismically-isolated emergency diesel generator

    Choun, Young Sun; Choi, In Kil; Ohtori, Yasuki

    2005-01-01

    The seismic capacity of an Emergency Diesel Generator (EDG) in nuclear power plants influences the seismic safety of the plants significantly. A recent study showed that the increase of the seismic capacity of the EDG could reduce the core damage frequency (CDF) remarkably. It is known that the major failure mode of the EDG is a concrete coning failure due to the pulling out of the anchor bolts. The use of base isolators instead of anchor bolts can increase the seismic capacity of the EDG without any major problems. The fragility curves for a base-isolated EDG should be different from those for a conventional type because the major failure mode of the base-isolated EDG will not be a concrete coning one any more. The governing failure mode of the base-isolated EDG must be the damage of the isolators. This study introduces a fragility evaluation method for an isolated EDG, and evaluates the fragilities for the isolated EDG and compares them with those for the conventional one. Evaluation of the ground motion index is also carried out to determine the governing parameter suitable for representing the seismic responses of the base isolator

  10. Determination of a modal interaction correction for narrowband fragility data

    Kana, D.D.; Pomerening, D.J.

    1987-01-01

    Laboratory tests for safety equipment operation under seismic environments in nuclear power plants have typically included various motion simulations based on either successively-applied multiple narrowband waveforms or simultaneous multifrequency broadband random waveforms. However, only broadband excitations are directly applicable when equipment performance is affected by interaction between simultaneously responding modes. Therefore, a modal interaction correction factor is developed so that a narrowed response spectrum can be transformed to an approximately equivalent broadband spectrum which accounts for modal interaction effects. The approach includes study of the fragility response of a simple two-degree-of-freedom oscillator for representative narrowband and broadband excitations, and relating the two resulting fragility response spectra. It is found that multiplication of the narrowband response spectrum by an 0.7 factor produces a conservative equivalent broadband response spectrum. The results are interpreted in terms of a secondary device responding on a primary support structure, or a primary structure having two resonances. The approach is useful for updating existing test results based on narrowband spectra, developing composite spectra for similar equipment, or providing more flexibility in designing new tests, and is applicable to qualification proof test data as well as fragility data. 10 refs., 8 figs

  11. Robust-yet-fragile nature of interdependent networks

    Tan, Fei; Xia, Yongxiang; Wei, Zhi

    2015-05-01

    Interdependent networks have been shown to be extremely vulnerable based on the percolation model. Parshani et al. [Europhys. Lett. 92, 68002 (2010), 10.1209/0295-5075/92/68002] further indicated that the more intersimilar networks are, the more robust they are to random failures. When traffic load is considered, how do the coupling patterns impact cascading failures in interdependent networks? This question has been largely unexplored until now. In this paper, we address this question by investigating the robustness of interdependent Erdös-Rényi random graphs and Barabási-Albert scale-free networks under either random failures or intentional attacks. It is found that interdependent Erdös-Rényi random graphs are robust yet fragile under either random failures or intentional attacks. Interdependent Barabási-Albert scale-free networks, however, are only robust yet fragile under random failures but fragile under intentional attacks. We further analyze the interdependent communication network and power grid and achieve similar results. These results advance our understanding of how interdependency shapes network robustness.

  12. Premature ovarian failure (POF in Brazilian fragile X carriers

    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.

  13. Seismic Fragility Curves of Industrial Buildings by Using Nonlinear Analysis

    Mohamed Nazri Fadzli

    2017-01-01

    Full Text Available This study presents the steel fragility curves and performance curves of industrial buildings of different geometries. The fragility curves were obtained for different building geometries, and the performance curves were developed based on lateral load, which is affected by the geometry of the building. Three records of far-field ground motion were used for incremental dynamic analysis (IDA, and the design lateral loads for pushover analysis (POA. All designs were based on British Standard (BS 5950; however, Eurocode 8 was preferred for seismic consideration in the analysis because BS 5950 does not specify any seismic provision. The five levels of performance stated by FEMA-273, namely, operational phase, immediate occupancy, damage control, life safety, and collapse prevention (CP were used as main guidelines for evaluating structural performance. For POA, Model 2 had highest base shear, followed by Model 1 and Model 3, even though Model 2 has a smaller structure compared with Model 3. Meanwhile, the fragility curves showed that the probability of reaching or exceeding the CP level of Model 2 is the highest, followed by that of Models 1 and 3.

  14. Fragility Modeling of Aging Containment Metallic Pressure Boundaries

    Cherry, J.L.; Ellingwood, B.R.

    1999-01-01

    The containment in a nuclear power plant (NPP) provides a barrier against the release of radioactivity in the event of an accident. Corrosion that has been observed in some steel containments and liners of reinforced concrete containments has raised questions about their ability to perform this function. The performance of corroded containments during events at or beyond the design basis is impacted by numerous sources of uncertainty. A fragility model of the containment provides a relatively simple depiction of the impact of uncertainties on structural performance and a basis for decision-making in the presence of uncertainty. Moreover, it is a necessary ingredient of any time-dependent structural reliability analysis. A nonlinear finite element analysis of containment response furnishes the necessary platform to perform numerical experiments to determine containment fragility. A statistically-based sampling plan minimizes the finite element computations required to develop the fragility curve. The -percentile (or other fractile) then gives a statistically based indication of the lower bound on containment capacity, and can be used as a screening tool to determine whether more refined further analysis or tests to support service life evaluations are warranted

  15. Site-specific analysis of gene expression in early osteoarthritis using the Pond-Nuki model in dogs

    Kuroki Keiichi

    2006-10-01

    Full Text Available Abstract Background Osteoarthritis (OA is a progressive and debilitating disease that often develops from a focal lesion and may take years to clinically manifest to a complete loss of joint structure and function. Currently, there is not a cure for OA, but early diagnosis and initiation of treatment may dramatically improve the prognosis and quality of life for affected individuals. This study was designed to determine the feasibility of analyzing changes in gene expression of articular cartilage using the Pond-Nuki model two weeks after ACL-transection in dogs, and to characterize the changes observed at this time point. Methods The ACL of four dogs was completely transected arthroscopically, and the contralateral limb was used as the non-operated control. After two weeks the dogs were euthanatized and tissues harvested from the tibial plateau and femoral condyles of both limbs. Two dogs were used for histologic analysis and Mankin scoring. From the other two dogs the surface of the femoral condyle and tibial plateau were divided into four regions each, and tissues were harvested from each region for biochemical (GAG and HP and gene expression analysis. Significant changes in gene expression were determined using REST-XL, and Mann-Whitney rank sum test was used to analyze biochemical data. Significance was set at (p Results Significant differences were not observed between ACL-X and control limbs for Mankin scores or GAG and HP tissue content. Further, damage to the tissue was not observed grossly by India ink staining. However, significant changes in gene expression were observed between ACL-X and control tissues from each region analyzed, and indicate that a unique regional gene expression profile for impending ACL-X induced joint pathology may be identified in future studies. Conclusion The data obtained from this study lend credence to the research approach and model for the characterization of OA, and the identification and validation of

  16. Communication: Fast dynamics perspective on the breakdown of the Stokes-Einstein law in fragile glassformers.

    Puosi, F; Pasturel, A; Jakse, N; Leporini, D

    2018-04-07

    The breakdown of the Stokes-Einstein (SE) law in fragile glassformers is examined by Molecular-Dynamics simulations of atomic liquids and polymers and consideration of the experimental data concerning the archetypical ortho-terphenyl glassformer. All the four systems comply with the universal scaling between the viscosity (or the structural relaxation) and the Debye-Waller factor ⟨u 2 ⟩, the mean square amplitude of the particle rattling in the cage formed by the surrounding neighbors. It is found that the SE breakdown is scaled in a master curve by a reduced ⟨u 2 ⟩. Two approximated expressions of the latter, with no and one adjustable parameter, respectively, are derived.

  17. Parenting of children with Down syndrome compared to fragile X syndrome.

    Sterling, Audra; Warren, Steven F

    2018-01-01

    Children with Down syndrome (DS) and fragile X syndrome (FXS) struggle with language development. Parenting variables, such as responsiveness to children's communication attempts (Maternal Responsivity), and techniques used to support and teach appropriate behavior (Behavior Management) are known to have a significant impact on early child development. We examined these two aspects of parenting style via coded, videotaped parent-child interactions in two groups of participants matched on child age (2-5 years) and child expressive language level: mothers of children with DS and mothers of children with FXS. The mothers differed in their use of gestures and redirecting the child's attention. Overall, mothers in both groups of children appeared to adapt appropriately to their children's developmental needs.

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

    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.

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

    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

  20. Divergent expression of cytokinin biosynthesis, signaling and catabolism genes underlying differences in feeding sites induced by cyst and root-knot nematodes.

    Dowd, Carola D; Chronis, Demosthenis; Radakovic, Zoran S; Siddique, Shahid; Schmülling, Thomas; Werner, Tomáš; Kakimoto, Tatsuo; Grundler, Florian M W; Mitchum, Melissa G

    2017-10-01

    Cyst and root-knot nematodes are obligate parasites of economic importance with a remarkable ability to reprogram root cells into unique metabolically active feeding sites. Previous studies have suggested a role for cytokinin in feeding site formation induced by these two types of nematodes, but the mechanistic details have not yet been described. Using Arabidopsis as a host plant species, we conducted a comparative analysis of cytokinin genes in response to the beet cyst nematode (BCN), Heterodera schachtii, and the root-knot nematode (RKN), Meloidogyne incognita. We identified distinct differences in the expression of cytokinin biosynthesis, catabolism and signaling genes in response to infection by BCN and RKN, suggesting differential manipulation of the cytokinin pathway by these two nematode species. Furthermore, we evaluated Arabidopsis histidine kinase receptor mutant lines ahk2/3, ahk2/4 and ahk3/4 in response to RKN infection. Similar to our previous studies with BCN, these lines were significantly less susceptible to RKN without compromising nematode penetration, suggesting a requirement of cytokinin signaling in RKN feeding site formation. Moreover, an analysis of ahk double mutants using CycB1;1:GUS/ahk introgressed lines revealed contrasting differences in the cytokinin receptors mediating cell cycle activation in feeding sites induced by BCN and RKN. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

  1. Self-expression and relationship formation in high relational mobility environments: A study of dual users of American and Japanese social networking sites.

    Takemura, Kosuke; Suzuki, Satoko

    2017-06-01

    This study proposes that self-expression motivation, an aspect of independent/individualistic psychological tendencies, aids in the formation of social relationships when social relationships are open and mobile. In societies characterised by high relational mobility (e.g., North America), which creates market-like competition in social relationships, individuals must express their uniqueness and worthiness to form new social relationships. Self-expression motivation has a relatively weak effect on relationship formation in low relational mobility societies (e.g., Japan), where social relationships are generally predetermined. This hypothesis was examined and supported through a study on dual users of two social networking sites-Facebook and Mixi (the "Facebook of Japan"). As expected, relational mobility was higher on Facebook than on Mixi. Moreover, the association between self-expression motivation and the number of new friends met on Facebook/Mixi was more positive for Facebook than it was for Mixi. The social functionality of independent tendencies is then discussed. © 2015 International Union of Psychological Science.

  2. DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding.

    Zhu, Zaihua; Meng, Weida; Liu, Peiru; Zhu, Xiaoxia; Liu, Yun; Zou, Hejian

    2017-01-01

    Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo. Nuclear receptor binding protein 1 ( NRBP1 ), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data. We observed elevated NRBP1 expression in human peripheral blood mononuclear cells (PBMCs) from gout patients. In vitro luciferase reporter and protein pulldown assay results showed that DNA methylation could increase the binding of the transcription factor TFAP2A to B1, leading to suppressed gene expression. There results were further confirmed by in vivo bisulfite pyrosequencing showing that hypomethylation on B1 is associated with increased NRBP1 expression in gout patients. Hypomethylation at the promoter region of NRBP1 reduces the binding of TFAP2A and thus leads to elevated NRBP1 expression, which might contribute to the development of gout.

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

    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.

  4. Increasing our Understanding of Human Cognition Through the Study of Fragile X Syndrome

    Denise, Cook; Erin, Nuro; Keith, K. Murai

    2014-01-01

    Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 147–177, 2014 PMID:23723176

  5. Partnership for fragility bone fracture care provision and prevention program (P4Bones: study protocol for a secondary fracture prevention pragmatic controlled trial

    Gaboury Isabelle

    2013-01-01

    Full Text Available Abstract Background Fractures associated with bone fragility in older adults signal the potential for secondary fracture. Fragility fractures often precipitate further decline in health and loss of mobility, with high associated costs for patients, families, society and the healthcare system. Promptly initiating a coordinated, comprehensive pharmacological bone health and falls prevention program post-fracture may improve osteoporosis treatment compliance; and reduce rates of falls and secondary fractures, and associated morbidity, mortality and costs. Methods/design This pragmatic, controlled trial at 11 hospital sites in eight regions in Quebec, Canada, will recruit community-dwelling patients over age 50 who have sustained a fragility fracture to an intervention coordinated program or to standard care, according to the site. Site study coordinators will identify and recruit 1,596 participants for each study arm. Coordinators at intervention sites will facilitate continuity of care for bone health, and arrange fall prevention programs including physical exercise. The intervention teams include medical bone specialists, primary care physicians, pharmacists, nurses, rehabilitation clinicians, and community program organizers. The primary outcome of this study is the incidence of secondary fragility fractures within an 18-month follow-up period. Secondary outcomes include initiation and compliance with bone health medication; time to first fall and number of clinically significant falls; fall-related hospitalization and mortality; physical activity; quality of life; fragility fracture-related costs; admission to a long term care facility; participants’ perceptions of care integration, expectations and satisfaction with the program; and participants’ compliance with the fall prevention program. Finally, professionals at intervention sites will participate in focus groups to identify barriers and facilitating factors for the integrated

  6. Lead induces DNA damage and alteration of ALAD and antioxidant genes mRNA expression in construction site workers.

    Akram, Zertashia; Riaz, Sadaf; Kayani, Mahmood Akhtar; Jahan, Sarwat; Ahmad, Malik Waqar; Ullah, Muhammad Abaid; Wazir, Hizbullah; Mahjabeen, Ishrat

    2018-01-16

    Oxidative stress and DNA damage are considered as possible mechanisms involved in lead toxicity. To test this hypothesis, DNA damage and expression variations of aminolevulinic acid dehydratase (ALAD), superoxide dismutase 2 (SOD2), and 8-oxoguanine DNA glycosylase 2a (OGG1-2a) genes was studied in a cohort of 100 exposed workers and 100 controls with comet assay and real-time polymerse chain reaction (PCR). Results indicated that increased number of comets was observed in exposed workers versus controls (p gene.

  7. Different expression of MIB1 in primary site of non-Hodgkin lymphoma and its bone marrow deposits, a pilot study

    Malysz J

    2017-02-01

    Full Text Available Jozef Malysz,1 Juanita J Evans,2 Malcolm Acon-Laws,3 Michael G Bayerl,1 Michael H Creer1 1Department of Pathology, Penn State Milton S Hershey Medical Center, Hershey, PA, 2Department of Pathology, St. John Heath – Providence, Southfield, MI, USA; 3Laboratorio de Patologia Hospital Cima, San Jose, Costa Rica Abstract: Evaluation of mindbomb E3 ubiquitin protein ligase 1 (MIB1 (Ki67 proliferation index (PI in B-cell non-Hodgkin lymphomas is increasingly a common addition to classification of lymphoma and staging procedures. Clinicians relay on PI as a surrogate marker of biologic activity; however, no established guidelines have been published whether PI at the primary site of the tumor gives the same answer as evaluation of tumor in staging marrow. In our study, dual immunohistochemical staining for MIB1 and CD20 was performed on tissue from primary site and bone marrow involved by B-cell non-Hodgkin lymphoma to compare PI for each individual patient. For all patients, MIB1 expression was higher at primary tumor site as compared to staging marrow. Additional analysis was performed to investigate the degree of difference depending on lymphoma morphology. Patients with large cell lymphoma at the primary site and large cell morphology in the marrow (LCL-L, those with large cell morphology at the primary site and small cell morphology in the marrow (LCL-S, and those with small cell morphology at the primary site and small cells in the marrow (SCL-S were compared. As expected, LCL cases had a higher mean PI at the primary site when compared to SCL cases (28.5% vs 2.8%, P=0.0001. In addition, the most significant difference between medullary and extramedullary PI was observed in cases with discordant morphology (LCL-S (21% vs 1.1%, P=0.009. Our results indicate that PI of lymphoma within the bone marrow should not be used as a surrogate prognostic indicator of lymphoma biology in its primary site. Keywords: proliferation index, biologic behavior

  8. Expression, purification, crystallization and preliminary X-ray analysis of wild-type and of an active-site mutant of glyceraldehyde-3-phosphate dehydrogenase from Campylobacter jejuni

    Tourigny, David S.; Elliott, Paul R.; Edgell, Louise J.; Hudson, Gregg M.; Moody, Peter C. E.

    2010-01-01

    The cloning, expression, purification, crystallization and preliminary X-ray analysis of wild-type and of an active-site mutant of C. jejuni glyceraldehyde-3-phosphate dehydrogenase is reported. The genome of the enteric pathogen Campylobacter jejuni encodes a single glyceraldehyde-3-phosphate dehydrogenase that can utilize either NADP + or NAD + as coenzymes for the oxidative phosphorylation of glyceraldehyde-3-phosphate to 1,3-diphosphoglycerate. Here, the cloning, expression, purification, crystallization and preliminary X-ray analysis of both the wild type and an active-site mutant of the enzyme are presented. Preliminary X-ray analysis revealed that in both cases the crystals diffracted to beyond 1.9 Å resolution. The space group is shown to be I4 1 22, with unit-cell parameters a = 90.75, b = 90.75, c = 225.48 Å, α = 90.46, β = 90.46, γ = 222.79°; each asymmetric unit contains only one subunit of the tetrameric enzyme

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

    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.

  10. Data-Driven Decision Making in Fragile Contexts : Evidence from Sudan

    Hamilton, Alexander; Hammer, Craig

    2017-01-01

    Data deficiencies contribute to state fragility and exacerbate fragile states’ already limited capacity to provide basic services, public security and rule of law. The lack of robust, good quality data can also have a disabling effect on government efforts to manage political conflict, and indeed can worsen conflict, since violent settings pose substantial challenges to knowledge generation, capture and application. In short, in fragile contexts the need for reliable evidence at all levels ...

  11. Comparison of intraerythrocyte and intraleucocyte Sodium content and erythrocyte fragility in normotensive subjects

    Paci, A.; Cocci, F.; Cristofani, R.; Piras, F.; Balzan, S.; Mezzasalma, L.; Ghione; Giachetti, M.

    1988-01-01

    The Sodium content of mononuclear leucocytes and erythrocytes and the osmotic fragility of erythrocytes were measured in 22 young male volunteers before and after three days of increased Sodium intake. Analysis of variance for repeated measurements showed no significant correlations between intraleucocyte and intraerythrocyte Sodium and between intraerythrocyte Sodium and osmotic fragility. On the other hand, a highly significant relation was present between osmotic fragility and intraleucocyte Sodium before high salt intake, which disappeared after 3 days of increased salt intake

  12. Post-Traumatic Caspase-3 Expression in the Adjacent Areas of Growth Plate Injury Site: A Morphological Study

    Karin Pichler

    2013-07-01

    Full Text Available The epiphyseal plate is a hyaline cartilage plate that sits between the diaphysis and the epiphysis. The objective of this study was to determine the impact of an injury in the growth plate chondrocytes through the study of histological morphology, immunohistochemistry, histomorphometry and Western Blot analyses of the caspase-3 and cleaved PARP-1, and levels of the inflammatory cytokines, Interleukin-6 (IL-6 and Tumor Necrosis Factor alpha (TNF-α, in order to acquire more information about post-injury reactions of physeal cell turnover. In our results, morphological analysis showed that in experimental bones, neo-formed bone trabeculae—resulting from bone formation repair—invaded the growth plate and reached the metaphyseal bone tissue (bone bridge, and this could result in some growth arrest. We demonstrated, by ELISA, increased expression levels of the inflammatory cytokines IL-6 and TNF-α. Immunohistochemistry, histomorphometry and Western Blot analyses of the caspase-3 and cleaved PARP-1 showed that the physeal apoptosis rate of the experimental bones was significantly higher than that of the control ones. In conclusion, we could assume that the inflammation process causes stress to chondrocytes that will die as a biological defense mechanism, and will also increase the survival of new chondrocytes for maintaining cell homeostasis. Nevertheless, the exact stimulus leading to the increased apoptosis rate, observed after injury, needs additional research to understand the possible contribution of chondrocyte apoptosis to growth disturbance.

  13. Improved Iris Recognition through Fusion of Hamming Distance and Fragile Bit Distance.

    Hollingsworth, Karen P; Bowyer, Kevin W; Flynn, Patrick J

    2011-12-01

    The most common iris biometric algorithm represents the texture of an iris using a binary iris code. Not all bits in an iris code are equally consistent. A bit is deemed fragile if its value changes across iris codes created from different images of the same iris. Previous research has shown that iris recognition performance can be improved by masking these fragile bits. Rather than ignoring fragile bits completely, we consider what beneficial information can be obtained from the fragile bits. We find that the locations of fragile bits tend to be consistent across different iris codes of the same eye. We present a metric, called the fragile bit distance, which quantitatively measures the coincidence of the fragile bit patterns in two iris codes. We find that score fusion of fragile bit distance and Hamming distance works better for recognition than Hamming distance alone. To our knowledge, this is the first and only work to use the coincidence of fragile bit locations to improve the accuracy of matches.

  14. Development of fragility functions to estimate homelessness after an earthquake

    Brink, Susan A.; Daniell, James; Khazai, Bijan; Wenzel, Friedemann

    2014-05-01

    Immediately after an earthquake, many stakeholders need to make decisions about their response. These decisions often need to be made in a data poor environment as accurate information on the impact can take months or even years to be collected and publicized. Social fragility functions have been developed and applied to provide an estimate of the impact in terms of building damage, deaths and injuries in near real time. These rough estimates can help governments and response agencies determine what aid may be required which can improve their emergency response and facilitate planning for longer term response. Due to building damage, lifeline outages, fear of aftershocks, or other causes, people may become displaced or homeless after an earthquake. Especially in cold and dangerous locations, the rapid provision of safe emergency shelter can be a lifesaving necessity. However, immediately after an event there is little information available about the number of homeless, their locations and whether they require public shelter to aid the response agencies in decision making. In this research, we analyze homelessness after historic earthquakes using the CATDAT Damaging Earthquakes Database. CATDAT includes information on the hazard as well as the physical and social impact of over 7200 damaging earthquakes from 1900-2013 (Daniell et al. 2011). We explore the relationship of both earthquake characteristics and area characteristics with homelessness after the earthquake. We consider modelled variables such as population density, HDI, year, measures of ground motion intensity developed in Daniell (2014) over the time period from 1900-2013 as well as temperature. Using a base methodology based on that used for PAGER fatality fragility curves developed by Jaiswal and Wald (2010), but using regression through time using the socioeconomic parameters developed in Daniell et al. (2012) for "socioeconomic fragility functions", we develop a set of fragility curves that can be

  15. Preliminary Seismic Response and Fragility Analysis for DACS Cabinet

    Oh, Jinho; Kwag, Shinyoung; Lee, Jongmin; Kim, Youngki [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2013-05-15

    A DACS cabinet is installed in the main control room. The objective of this paper is to perform seismic analyses and evaluate the preliminary structural integrity and seismic capacity of the DACS cabinet. For this purpose, a 3-D finite element model of the DACS cabinet was developed and its modal analyses are carried out to analyze the dynamic characteristics. The response spectrum analyses and the related safety evaluation are then performed for the DACS cabinet subject to seismic loads. Finally, the seismic margin and seismic fragility of the DACS cabinet are investigated. A seismic analysis and preliminary structural integrity of the DACS cabinet under self weight and SSE load have been evaluated. For this purpose, 3-D finite element models of the DACS cabinet were developed. A modal analysis, response spectrum analysis, and seismic fragility analysis were then performed. From the structural analysis results, the DACS cabinet is below the structural design limit of under SSE 0.3g, and can structurally withstand until less than SSE 3g based on an evaluation of the maximum effective stresses. The HCLPF capacity for the DGRS of the SSE 0.3g is 0.55g. A modal analysis, response spectrum analysis, and seismic fragility analysis were then performed. From the structural analysis results, the DACS cabinet is below the structural design limit of under SSE 0.3g, and can structurally withstand until less than SSE 3g based on an evaluation of the maximum effective stresses. The HCLPF capacity for the DGRS of the SSE 0.3g is 0.55g. Therefore, it is concluded that the DACS cabinet was safely designed in that no damage to the preliminary structural integrity and sufficient seismic margin is expected.

  16. Preliminary Seismic Response and Fragility Analysis for DACS Cabinet

    Oh, Jinho; Kwag, Shinyoung; Lee, Jongmin; Kim, Youngki

    2013-01-01

    A DACS cabinet is installed in the main control room. The objective of this paper is to perform seismic analyses and evaluate the preliminary structural integrity and seismic capacity of the DACS cabinet. For this purpose, a 3-D finite element model of the DACS cabinet was developed and its modal analyses are carried out to analyze the dynamic characteristics. The response spectrum analyses and the related safety evaluation are then performed for the DACS cabinet subject to seismic loads. Finally, the seismic margin and seismic fragility of the DACS cabinet are investigated. A seismic analysis and preliminary structural integrity of the DACS cabinet under self weight and SSE load have been evaluated. For this purpose, 3-D finite element models of the DACS cabinet were developed. A modal analysis, response spectrum analysis, and seismic fragility analysis were then performed. From the structural analysis results, the DACS cabinet is below the structural design limit of under SSE 0.3g, and can structurally withstand until less than SSE 3g based on an evaluation of the maximum effective stresses. The HCLPF capacity for the DGRS of the SSE 0.3g is 0.55g. A modal analysis, response spectrum analysis, and seismic fragility analysis were then performed. From the structural analysis results, the DACS cabinet is below the structural design limit of under SSE 0.3g, and can structurally withstand until less than SSE 3g based on an evaluation of the maximum effective stresses. The HCLPF capacity for the DGRS of the SSE 0.3g is 0.55g. Therefore, it is concluded that the DACS cabinet was safely designed in that no damage to the preliminary structural integrity and sufficient seismic margin is expected

  17. Primary Retrograde Tibiotalocalcaneal Nailing For Fragility Ankle Fractures.

    Taylor, Benjamin C; Hansen, Dane C; Harrison, Ryan; Lucas, Douglas E; Degenova, Daniel

    2016-01-01

    Ankle fragility fractures are difficult to treat due to poor bone quality and soft tissues as well as the near ubiquitous presence of comorbidities including diabetes mellitus and peripheral neuropathy. Conventional open reduction and internal fixation in this population has been shown to lead to a significant rate of complications. Given the high rate of complications with contemporary fixation methods, the present study aims to critically evaluate the use of acute hindfoot nailing as a percutaneous fixation technique for high-risk ankle fragility fractures. In this study, we retrospectively evaluated 31 patients treated with primary retrograde tibiotalocalcaneal nail without joint preparation for a mean of 13.6 months postoperatively from an urban Level I trauma center during the years 2006-2012. Overall, there were two superficial infections (6.5%) and three deep infections (9.7%) in the series. There were 28 (90.3%) patients that went on to radiographic union at a mean of 22.2 weeks with maintenance of foot and ankle alignment. There were three cases of asymptomatic screw breakage observed at a mean of 18.3 months postoperatively, which were all treated conservatively.. This study shows that retrograde hindfoot nailing is an acceptable treatment option for treatment of ankle fragility fractures. Hindfoot nailing allows early weightbearing, limited soft tissue injury, and a relatively low rate of complications, all of which are advantages to conventional open reduction internal fixation techniques. Given these findings, larger prospective randomized trials comparing this treatment with conventional open reduction internal fixation techniques are warranted.

  18. Curcumin Reduces the Motility of Salmonella enterica Serovar Typhimurium by Binding to the Flagella, Thereby Leading to Flagellar Fragility and Shedding

    Balakrishnan, Arjun; Negi, Vidya Devi; Sakorey, Deepika; Chandra, Nagasuma

    2016-01-01

    ABSTRACT One of the important virulence properties of the pathogen is its ability to travel to a favorable environment, cross the viscous mucus barrier (intestinal barrier for enteric pathogens), and reach the epithelia to initiate pathogenesis with the help of an appendage, like flagella. Nonetheless, flagella can act as an “Achilles heel,” revealing the pathogen's presence to the host through the stimulation of innate and adaptive immune responses. We assessed whether curcumin, a dietary polyphenol, could alter the motility of Salmonella, a foodborne pathogen. It reduced the motility of Salmonella enterica serovar Typhimurium by shortening the length of the flagellar filament (from ∼8 μm to ∼5 μm) and decreasing its density (4 or 5 flagella/bacterium instead of 8 or 9 flagella/bacterium). Upon curcumin treatment, the percentage of flagellated bacteria declined from ∼84% to 59%. However, no change was detected in the expression of the flagellin gene and protein. A fluorescence binding assay demonstrated binding of curcumin to the flagellar filament. This might make the filament fragile, breaking it into smaller fragments. Computational analysis predicted the binding of curcumin, its analogues, and its degraded products to a flagellin molecule at an interface between domains D1 and D2. Site-directed mutagenesis and a fluorescence binding assay confirmed the binding of curcumin to flagellin at residues ASN120, ASP123, ASN163, SER164, ASN173, and GLN175. IMPORTANCE This work, to our knowledge the first report of its kind, examines how curcumin targets flagellar density and affects the pathogenesis of bacteria. We found that curcumin does not affect any of the flagellar synthesis genes. Instead, it binds to the flagellum and makes it fragile. It increases the torsional stress on the flagellar filament that then breaks, leaving fewer flagella around the bacteria. Flagella, which are crucial ligands for Toll-like receptor 5, are some of the most important

  19. Ageing, fragility and the reversibility window in bulk alloy glasses

    Chakravarty, S; Georgiev, D G; Boolchand, P; Micoulaut, M

    2005-01-01

    Non-reversing relaxation enthalpies (ΔH nr ) at glass transitions T g (x) in the P x Ge x Se 1-2x ternary display wide, sharp and deep global minima (∼0) in the 0.09 g s become thermally reversing. In this reversibility window, glasses are found not to age, in contrast to ageing observed for fragile glass compositions outside the window. Thermal reversibility and lack of ageing seem to be paradigms of self-organization which molecular glasses share with protein structures which repetitively and reversibly change conformation near T g and the folding temperature respectively. (letter to the editor)

  20. Detect Image Tamper by Semi-Fragile Digital Watermarking

    LIUFeilong; WANGYangsheng

    2004-01-01

    To authenticate the integrity of image while resisting some valid image processing such as JPEG compression, a semi-fragile image watermarking is described. Image name, one of the image features, has been used as the key of pseudo-random function to generate the special watermarks for the different image. Watermarks are embedded by changing the relationship between the blocks' DCT DC coefficients, and the image tamper are detected with the relationship of these DCT DC coefficients.Experimental results show that the proposed technique can resist JPEG compression, and detect image tamper in the meantime.

  1. Seismic fragility of reinforced concrete structures in nuclear facilities

    Gergely, P.

    1985-01-01

    The failure and fragility analyses of reinforced concrete structures and elements in nuclear reactor facilities within the Seismic Safety Margins Research Program (SSMRP) at the Lawrence Livermore National Laboratory are evaluated. Uncertainties in material modeling, behavior of low shear walls, and seismic risk assessment for nonlinear response receive special attention. Problems with ductility-based spectral deamplification and prediction of the stiffness of reinforced concrete walls at low stress levels are examined. It is recommended to use relatively low damping values in connection with ductility-based response reductions. The study of static nonlinear force-deflection curves is advocated for better nonlinear dynamic response predictions

  2. Why Stay Engaged with a State Deemed Fragile?

    Andersson, Magnus; Bae, Jinsun

    Based on the constructivist international relations (IR) approach, the authors study Sweden’s engagement with the DPRK as a unique case to understand motivations for engaging in a so-called fragile state. Besides having its embassy in Pyongyang and serving as a protecting power for the U.S., Sweden...... has provided capacity building programs for North Korean government officials and scholars. It has also made a consistent commitment to aid and human rights advocacy. In a nutshell, Sweden has been a facilitator between the DPRK and the outside world. Its motivations are mixed and multiple, including...

  3. Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.

    Alam, Imranul; Koller, Daniel L; Sun, Qiwei; Roeder, Ryan K; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J; Turner, Charles H; Foroud, Tatiana

    2011-05-01

    Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Copyright

  4. Fragile X syndrome: panoramic radiographic evaluation of dental anomalies, dental mineralization stage, and mandibular angle

    Aida Sabbagh-Haddad

    Full Text Available ABSTRACT Fragile X syndrome (FXS is a disorder linked to the chromosome X long arm (Xq27.3, which is identified by a constriction named fragile site. It determines various changes, such as behavioral or emotional problems, learning difficulties, and intellectual disabilities. Craniofacial abnormalities such as elongated and narrow face, prominent forehead, broad nose, large and prominent ear pavilions, strabismus, and myopia are frequent characteristics. Regarding the oral aspects, deep and high-arched palate, mandibular prognathism, and malocclusion are also observed. Objective: The purpose of this study was to evaluate the dental radiographic characteristics as described in 40 records of patients with panoramic radiography. Material and Methods: The patients were in the range of 6–17 years old, and were divided into two groups (20 subjects who were compatible with the normality standard and 20 individuals diagnosed with the FXS, which were matched for gender and age. Analysis of the panoramic radiographic examination involved the evaluation of dental mineralization stage, mandibular angle size, and presence of dental anomalies in both deciduous and permanent dentitions. Results: The results of radiographic evaluation demonstrated that the chronology of tooth eruption of all third and second lower molars is anticipated in individuals with FXS (p<0.05. In this group, supernumerary deciduous teeth (2.83%, giroversion of permanent teeth (2.31%, and partial anodontia (1.82% were the most frequent dental anomalies. In addition, an increase was observed in the mandibular angle size in the FXS group (p<0.05. Conclusion: We conclude that knowledge of dental radiographic changes is of great importance for dental surgeons to plan the treatment of these individuals.

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

    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.

  6. Transcription of lncRNA prt, clustered prt RNA sites for Mmi1 binding, and RNA polymerase II CTD phospho-sites govern the repression of pho1 gene expression under phosphate-replete conditions in fission yeast.

    Chatterjee, Debashree; Sanchez, Ana M; Goldgur, Yehuda; Shuman, Stewart; Schwer, Beate

    2016-07-01

    Expression of fission yeast Pho1 acid phosphatase is repressed during growth in phosphate-rich medium. Repression is mediated by transcription of the prt locus upstream of pho1 to produce a long noncoding (lnc) prt RNA. Repression is also governed by RNA polymerase II CTD phosphorylation status, whereby inability to place a Ser7-PO4 mark (as in S7A) derepresses Pho1 expression, and inability to place a Thr4-PO4 mark (as in T4A) hyper-represses Pho1 in phosphate replete cells. Here we find that basal pho1 expression from the prt-pho1 locus is inversely correlated with the activity of the prt promoter, which resides in a 110-nucleotide DNA segment preceding the prt transcription start site. CTD mutations S7A and T4A had no effect on the activity of the prt promoter or the pho1 promoter, suggesting that S7A and T4A affect post-initiation events in prt lncRNA synthesis that make it less and more repressive of pho1, respectively. prt lncRNA contains clusters of DSR (determinant of selective removal) sequences recognized by the YTH-domain-containing protein Mmi1. Altering the nucleobase sequence of two DSR clusters in the prt lncRNA caused hyper-repression of pho1 in phosphate replete cells, concomitant with increased levels of the prt transcript. The isolated Mmi1 YTH domain binds to RNAs with single or tandem DSR elements, to the latter in a noncooperative fashion. We report the 1.75 Å crystal structure of the Mmi1 YTH domain and provide evidence that Mmi1 recognizes DSR RNA via a binding mode distinct from that of structurally homologous YTH proteins that recognize m(6)A-modified RNA. © 2016 Chatterjee et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  7. The Role of Cultural and Identity Differences in Self-expression of Iranian Users of Social Networking Sites; A Case Study of Students of Tehran University, Amirkabir University, and Sharif University of Technology

    H. Molaei; Z. Majdizadeh

    2017-01-01

    Social media with their features such as interactivity, participatory, and user-generated content have provided a great opportunity for self-expression of the users. However, cultural differences affect the extent and modality of users’ self-expression. This study aims to investigate the modality of self-expression of Iranian users of the social networking sites. In doing so, an online survey was conducted among the students of three Iran universities: University of Tehran, Amirkabir Universi...

  8. Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

    Ferron, Laurent; Nieto-Rostro, Manuela; Cassidy, John S.; Dolphin, Annette C.

    2014-04-01

    Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.

  9. Fragile-to-strong transition in liquid silica

    Geske, Julian; Drossel, Barbara; Vogel, Michael

    2016-03-01

    We investigate anomalies in liquid silica with molecular dynamics simulations and present evidence for a fragile-to-strong transition at around 3100 K-3300 K. To this purpose, we studied the structure and dynamical properties of silica over a wide temperature range, finding four indicators of a fragile-to-strong transition. First, there is a density minimum at around 3000 K and a density maximum at 4700 K. The turning point is at 3400 K. Second, the local structure characterized by the tetrahedral order parameter changes dramatically around 3000 K from a higher-ordered, lower-density phase to a less ordered, higher-density phase. Third, the correlation time τ changes from an Arrhenius behavior below 3300 K to a Vogel-Fulcher-Tammann behavior at higher temperatures. Fourth, the Stokes-Einstein relation holds for temperatures below 3000 K, but is replaced by a fractional relation above this temperature. Furthermore, our data indicate that dynamics become again simple above 5000 K, with Arrhenius behavior and a classical Stokes-Einstein relation.

  10. Fragile-to-strong transition in liquid silica

    Julian Geske

    2016-03-01

    Full Text Available We investigate anomalies in liquid silica with molecular dynamics simulations and present evidence for a fragile-to-strong transition at around 3100 K-3300 K. To this purpose, we studied the structure and dynamical properties of silica over a wide temperature range, finding four indicators of a fragile-to-strong transition. First, there is a density minimum at around 3000 K and a density maximum at 4700 K. The turning point is at 3400 K. Second, the local structure characterized by the tetrahedral order parameter changes dramatically around 3000 K from a higher-ordered, lower-density phase to a less ordered, higher-density phase. Third, the correlation time τ changes from an Arrhenius behavior below 3300 K to a Vogel-Fulcher-Tammann behavior at higher temperatures. Fourth, the Stokes-Einstein relation holds for temperatures below 3000 K, but is replaced by a fractional relation above this temperature. Furthermore, our data indicate that dynamics become again simple above 5000 K, with Arrhenius behavior and a classical Stokes-Einstein relation.

  11. Radiology of Osteogenesis Imperfecta, Rickets and Other Bony Fragility States.

    Calder, Alistair D

    2015-01-01

    This section gives an overview of radiological findings in bony fragility states, with a special focus on osteogenesis imperfecta (OI) and rickets. Conventional radiological assessment of bone density is inaccurate and imprecise and only reliably detects severe osteopaenia. However, other aspects of bone structure and morphology can be assessed, and it is possible to distinguish between osteopaenic and osteomalacic states. OI is a heterogeneous group of disorders of type 1 collagen formation and processing that are characterised by varying degrees of bony fragility, with presentations varying from perinatal lethality to asymptomatic. Radiological diagnosis of severe forms is usually straightforward, but that of milder disease may be challenging because specific features are often absent. However, a multidisciplinary approach is usually successful. Features of OI, including Wormian bones, skull base deformities, vertebral involvement and long bone fractures and deformities, are reviewed in this section. Rickets is best defined as a disorder of the growth plate characterised by the impaired apoptosis of hypertrophied chondrocytes. Vitamin D deficiency is a common cause of rickets. The patho-anatomical basis of radiological findings in rickets is reviewed and illustrated. Rickets is frequently accompanied by hyperparathyroidism and osteomalacia. Rickets used to be classified as calciopaenic or phosphopaenic but is now referred to as parathyroid hormone or fibroblast growth factor 23 mediated, respectively [1]. The radiological features of the two forms are reviewed. © 2015 S. Karger AG, Basel.

  12. Mechanisms of diabetes mellitus-induced bone fragility.

    Napoli, Nicola; Chandran, Manju; Pierroz, Dominique D; Abrahamsen, Bo; Schwartz, Ann V; Ferrari, Serge L

    2017-04-01

    The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.

  13. Food insecurity and child behavior problems in fragile families.

    King, Christian

    2018-02-01

    Food insecurity remains a persistent problem in the United States. Several studies have shown that food insecurity is associated with child externalizing and internalizing behavior problems. However, some potential methodological limitations remain. For example, most studies use a household measure of food insecurity while there is evidence that children, especially younger ones, tend to be shielded by their parents from experiencing food insecurity. In addition, the mechanisms through which food insecurity affects children are not well understood. This study uses longitudinal data from the Fragile Families and Child Wellbeing Study to address these limitations. Fixed-effects models show that the association is even larger using a measure of child food insecurity instead of a household one. Correlated-random effects models show a large difference in child behavior problems between food secure and food insecure children due to unobserved heterogeneity. In addition, the association between child food insecurity and child externalizing behaviors remains largely unexplained while food insecurity among adults explains almost all the variation in the association with child internalizing behaviors. Food insecure children and parents are at risk of micronutrient deficiencies, which may lead to behavior problems in young children. These findings underscore the need for greater focus on reducing the risk of food insecurity, especially for children in fragile families, in order to reduce behavior problems and improve their educational attainment. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Fragility, anharmonicity and anelasticity of silver borate glasses

    Carini, Giovanni; Carini, Giuseppe; D'Angelo, Giovanna; Tripodo, Gaspare; Bartolotta, Antonio; Marco, Gaetano Di

    2006-01-01

    The fragility and the anharmonicity of (Ag 2 O) x (B 2 O 3 ) 1-x borate glasses have been quantified by measuring the change in the specific heat capacity at the glass transition temperature T g and the room-temperature thermodynamic Grueneisen parameter. Increasing the silver oxide content above X = 0.10 leads to an increase of both the parameters, showing that a growing fragility of a glass-forming liquid is predictive of an increasing overall anharmonicity of its glassy state. The attenuation and velocity of ultrasonic waves of frequencies in the range of 10-70 MHz have also been measured in silver borate glasses as a function of temperature between 1.5 and 300 K. The experimental data reveal anelastic behaviours which are governed by (i) quantum-mechanical tunnelling below 20 K (ii) thermally activated relaxations between 20 and 200 K and (iii) vibrational anharmonicity at even higher temperatures. Evaluation of tunnelling (C) and relaxation (C * ) strengths shows that C is independent of the structural changes affecting the borate network with increasing metal oxide content and is at least one order of magnitude smaller than C * . The latter observation implies that only a small fraction of the locally mobile defects are subjected to tunnelling motions

  15. Fragility assessment method of Concrete Wall Subjected to Impact Loading

    Hahm, Daegi; Shin, Sang Shup; Choi, In-Kil

    2014-01-01

    These studies have been aimed to verify and ensure the safety of the targeted walls and structures especially in the viewpoint of the deterministic approach. However, recently, the regulation and the assessment of the safety of the nuclear power plants (NPPs) against to an aircraft impact are strongly encouraged to adopt a probabilistic approach, i.e., the probabilistic risk assessment of an aircraft impact. In Korea, research to develop aircraft impact risk quantification technology was initiated in 2012 by Korea Atomic Energy Research Institute (KAERI). In this paper, for the one example of the probabilistic safety assessment approach, a method to estimate the failure probability and fragility of concrete wall subjected to impact loading caused by missiles or engine parts of aircrafts will be introduced. This method and the corresponding results will be used for the total technical roadmap and the procedure to assess the aircraft impact risk (Fig.1). A method and corresponding results of the estimation of the failure probability and fragility for a concrete wall subjected to impact loadings caused by missiles or engine parts of aircrafts was introduced. The detailed information of the target concrete wall in NPP, and the example aircraft engine model is considered safeguard information (SGI), and is not contained in this paper

  16. Atomic and electronic structures of an extremely fragile liquid.

    Kohara, Shinji; Akola, Jaakko; Patrikeev, Leonid; Ropo, Matti; Ohara, Koji; Itou, Masayoshi; Fujiwara, Akihiko; Yahiro, Jumpei; Okada, Junpei T; Ishikawa, Takehiko; Mizuno, Akitoshi; Masuno, Atsunobu; Watanabe, Yasuhiro; Usuki, Takeshi

    2014-12-18

    The structure of high-temperature liquids is an important topic for understanding the fragility of liquids. Here we report the structure of a high-temperature non-glass-forming oxide liquid, ZrO2, at an atomistic and electronic level. The Bhatia-Thornton number-number structure factor of ZrO2 does not show a first sharp diffraction peak. The atomic structure comprises ZrO5, ZrO6 and ZrO7 polyhedra with a significant contribution of edge sharing of oxygen in addition to corner sharing. The variety of large oxygen coordination and polyhedral connections with short Zr-O bond lifetimes, induced by the relatively large ionic radius of zirconium, disturbs the evolution of intermediate-range ordering, which leads to a reduced electronic band gap and increased delocalization in the ionic Zr-O bonding. The details of the chemical bonding explain the extremely low viscosity of the liquid and the absence of a first sharp diffraction peak, and indicate that liquid ZrO2 is an extremely fragile liquid.

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

    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.

  18. Deficient Sleep in Mouse Models of Fragile X Syndrome

    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.

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

    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.

  20. Risk factors for fragility fracture in Seremban district, Malaysia: a comparison of patients with fragility fracture in the orthopedic ward versus those in the outpatient department.

    Keng Yin Loh; King Hock Shong; Soo Nie Lan; Lo, Wan-Yi; Shu Yuen Woon

    2008-01-01

    Osteoporosis is a silent disease and becomes clinically significant in the presence of fragility fracture. Identifying risk factors that are associated with osteoporosis in the community is important in reducing the incidence of fragility fracture. The aim of this study is to identify risk factors associated with fragility fracture in the Seremban District of Malaysia. This is a population comparison study between orthopedic ward patients and outpatients attending a community health clinic for 6 months. Epidemiological data and the possible risk factors for osteoporosis were collected by direct interview. This study demonstrates that advancing age, low body weight, smoking, lack of regular exercise, low consumption of calcium containing foods, and using bone depleting drugs (steroids, thyroid hormone, and frusemides) are major risk factors for fragility fracture. Most of these risk factors are modifiable through effective lifestyle intervention.

  1. pMPES: A Modular Peptide Expression System for the Delivery of Antimicrobial Peptides to the Site of Gastrointestinal Infections Using Probiotics

    Kathryn Geldart

    2016-10-01

    Full Text Available Antimicrobial peptides are a promising alternative to traditional antibiotics, but their utility is limited by high production costs and poor bioavailability profiles. Bacterial production and delivery of antimicrobial peptides (AMPs directly at the site of infection may offer a path for effective therapeutic application. In this study, we have developed a vector that can be used for the production and secretion of seven antimicrobial peptides from both Escherichia coli MC1061 F’ and probiotic E.coli Nissle 1917. The vector pMPES (Modular Peptide Expression System employs the Microcin V (MccV secretion system and a powerful synthetic promoter to drive AMP production. Herein, we demonstrate the capacity of pMPES to produce inhibitory levels of MccV, Microcin L (MccL, Microcin N (McnN, Enterocin A (EntA, Enterocin P (EntP, Hiracin JM79 (HirJM79 and Enterocin B (EntB. To our knowledge, this is the first demonstration of such a broadly-applicable secretion system for AMP production. This type of modular expression system could expedite the development of sorely needed antimicrobial technologies

  2. Revision of the AESJ Standard for Seismic Probabilistic Risk Assessment (PRA). Updating requirements based on the lessons learned from the Fukushima Dai-ichi NPP Accidents (3). Fragility evaluation and outline of the updated points

    Yamaguchi, Akira; Nakamura, Susumu; Mihara, Yoshinori

    2014-01-01

    Lessons learned from Great East Japan earthquake and other new findings had been accumulated on the fragility evaluation of buildings and components. And also new analysis and evaluation method had been proposed with the advancement of recent analysis and evaluation technology. These were reflected in revision of the AESJ Standard for Seismic Probabilistic Risk Assessment (PRA). Scope of the fragility evaluation were extended to all equipment on the site, severe accident management equipment including portable equipment and earthquake concomitant incident (such as tsunami) countermeasure equipment. This article described outlines of updating points of the fragility evaluation of the AESJ Standard for Seismic PRA; (1) requirements for seismic induced other risk evaluations such as fire, inundation and tsunami, (2) simulation technology based on recent findings such as three dimensional responses of buildings / structures and its effect on equipment, (3) requirements of the fragility evaluation for various failure mode of several equipment such as severe accident management equipment, fine failure mode of buildings / structures, failures of equipment related with earthquake concomitant incidents (embankment and seawall) and spent fuel pool, and (4) requirements for the fragility evaluation of aftershocks and soil deformation due to fault displacement. (T. Tanaka)

  3. The correlation between fragility, density, and atomic interaction in glass-forming liquids

    Wang, Lijin; Guan, Pengfei, E-mail: pguan@csrc.ac.cn [Beijing Computational Science Research Center, Beijing 100193 (China); Wang, W. H. [Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China)

    2016-07-21

    The fragility that controls the temperature-dependent viscous properties of liquids as the glass transition is approached, in various glass-forming liquids with different softness of the repulsive part of atomic interactions at different densities, is investigated by molecular dynamic simulations. We show that the landscape of fragility in purely repulsive systems can be separated into three regions denoted as R{sub I,} R{sub II}, and R{sub III}, respectively, with qualitatively disparate dynamic behaviors: R{sub I} which can be described by “softness makes strong glasses,” R{sub II} where fragility is independent of softness and can only be tuned by density, and R{sub III} with constant fragility, suggesting that density plays an unexpected role for understanding the repulsive softness dependence of fragility. What is more important is that we unify the long-standing inconsistence with respect to the repulsive softness dependence of fragility by observing that a glass former can be tuned more fragile if nonperturbative attraction is added into it. Moreover, we find that the vastly dissimilar influences of attractive interaction on fragility could be estimated from the structural properties of related zero-temperature glasses.

  4. The correlation between fragility, density, and atomic interaction in glass-forming liquids

    Wang, Lijin; Guan, Pengfei; Wang, W. H.

    2016-01-01

    The fragility that controls the temperature-dependent viscous properties of liquids as the glass transition is approached, in various glass-forming liquids with different softness of the repulsive part of atomic interactions at different densities, is investigated by molecular dynamic simulations. We show that the landscape of fragility in purely repulsive systems can be separated into three regions denoted as R I, R II , and R III , respectively, with qualitatively disparate dynamic behaviors: R I which can be described by “softness makes strong glasses,” R II where fragility is independent of softness and can only be tuned by density, and R III with constant fragility, suggesting that density plays an unexpected role for understanding the repulsive softness dependence of fragility. What is more important is that we unify the long-standing inconsistence with respect to the repulsive softness dependence of fragility by observing that a glass former can be tuned more fragile if nonperturbative attraction is added into it. Moreover, we find that the vastly dissimilar influences of attractive interaction on fragility could be estimated from the structural properties of related zero-temperature glasses.

  5. Structure and management of tuberculosis control programs in fragile states--Afghanistan, DR Congo, Haiti, Somalia

    Mauch, Verena; Weil, Diana; Munim, Aayid; Boillot, Francois; Coninx, Rudi; Huseynova, Sevil; Powell, Clydette; Seita, Akihiro; Wembanyama, Henriette; van den Hof, Susan

    2010-01-01

    Health care delivery is particularly problematic in fragile states often connected with increased incidence of communicable diseases, among them tuberculosis. This article draws upon experiences in tuberculosis control in four fragile states from which four lessons learned were derived. A structured

  6. The correlation between fragility, density, and atomic interaction in glass-forming liquids.

    Wang, Lijin; Guan, Pengfei; Wang, W H

    2016-07-21

    The fragility that controls the temperature-dependent viscous properties of liquids as the glass transition is approached, in various glass-forming liquids with different softness of the repulsive part of atomic interactions at different densities, is investigated by molecular dynamic simulations. We show that the landscape of fragility in purely repulsive systems can be separated into three regions denoted as RI, RII, and RIII, respectively, with qualitatively disparate dynamic behaviors: RI which can be described by "softness makes strong glasses," RII where fragility is independent of softness and can only be tuned by density, and RIII with constant fragility, suggesting that density plays an unexpected role for understanding the repulsive softness dependence of fragility. What is more important is that we unify the long-standing inconsistence with respect to the repulsive softness dependence of fragility by observing that a glass former can be tuned more fragile if nonperturbative attraction is added into it. Moreover, we find that the vastly dissimilar influences of attractive interaction on fragility could be estimated from the structural properties of related zero-temperature glasses.

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

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

    2014-01-01

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

  8. Behavioral Assessment of Social Anxiety in Females with Turner or Fragile X Syndrome.

    Lesniak-Karpiak, Katarzyna; Mazzocco, Michele M. M.; Ross, Judith L.

    2003-01-01

    This study compared 29 females with Turner syndrome and 21 females with fragile X syndrome (ages 6-22) on a videotaped role-play interaction with 34 females in a comparison group. Three of eight behavioral measures of social skills differentiated the participant groups. Fragile-X subjects required more time to initiate interactions and Turner…

  9. Ocular Motor Indicators of Executive Dysfunction in Fragile X and Turner Syndromes

    Lasker, Adrian G.; Mazzocco, Michele M. M.; Zee, David S.

    2007-01-01

    Fragile X and Turner syndromes are two X-chromosome-related disorders associated with executive function and visual spatial deficits. In the present study, we used ocular motor paradigms to examine evidence that disruption to different neurological pathways underlies these deficits. We tested 17 females with fragile X, 19 females with Turner…

  10. Mathematics Learning Disabilities in Girls with Fragile X or Turner Syndrome during Late Elementary School

    Murphy, Melissa M.; Mazzocco, Michele M. M.

    2008-01-01

    The present study focuses on math and related skills among 32 girls with fragile X (n = 14) or Turner (n = 18) syndrome during late elementary school. Performance in each syndrome group was assessed relative to Full Scale IQ-matched comparison groups of girls from the general population (n = 32 and n = 89 for fragile X syndrome and Turner…

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

    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.

  12. Behavioral Intervention for Problem Behavior in Children with Fragile X Syndrome

    Moskowitz, Lauren J.; Carr, Edward G.; Durand, V. Mark

    2011-01-01

    Parents and professionals typically report problem behavior as a significant concern for children with fragile X syndrome. In the present study, the authors explored whether behaviorally based interventions would result in a reduction in problem behavior and an improvement in quality of life for 3 children with fragile X syndrome and their…

  13. Delineating the Profile of Autism Spectrum Disorder Characteristics in Cornelia de Lange and Fragile X Syndromes

    Moss, Joanna; Oliver, Chris; Nelson, Lisa; Richards, Caroline; Hall, Scott

    2013-01-01

    An atypical presentation of autism spectrum disorder is noted in Cornelia de Lange and Fragile X syndromes, but there are few detailed empirical descriptions. Participants in this study were individuals with Cornelia de Lange syndrome (n = 130, M age = 17.19), Fragile X syndrome (n = 182, M age = 16.94), and autism spectrum disorder (n = 142, M…

  14. Resolution of Spatial and Temporal Visual Attention in Infants with Fragile X Syndrome

    Farzin, Faraz; Rivera, Susan M.; Whitney, David

    2011-01-01

    Fragile X syndrome is the most common cause of inherited intellectual impairment and the most common single-gene cause of autism. Individuals with fragile X syndrome present with a neurobehavioural phenotype that includes selective deficits in spatiotemporal visual perception associated with neural processing in frontal-parietal networks of the…

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

    S. Zeidler (Shimriet); A.S. Pop (Andreea); I.A. Jaafar; H. De Boer (Helen); R.A.M. Buijsen (Ronald); C. de Esch (Celine); I.M. Nieuwenhuizen-Bakker; R.K. Hukema (Renate); R. Willemsen (Rob)

    2018-01-01

    textabstractIntroduction: 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

  16. Adaptive Skills, Behavior Problems, and Parenting Stress in Mothers of Boys with Fragile X Syndrome

    Sarimski, Klaus

    2010-01-01

    The relationship of temperament, atypical behaviors, and adaptive behavior of young boys with Fragile X syndrome on mothers' parenting stress was analyzed. Twenty-six boys with Fragile X syndrome (30-88 months of age) participated. The overall development of the participants was significantly delayed with a specific profile of adaptive behaviors…

  17. An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome

    Hogan-Brown, Abigail L.; Losh, Molly; Martin, Gary E.; Mueffelmann, Deborah J.

    2013-01-01

    Whereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results…

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

    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…

  19. Genetics Home Reference: fragile X-associated tremor/ataxia syndrome

    ... Share: Email Facebook Twitter Home Health Conditions FXTAS Fragile X-associated tremor/ataxia syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Fragile X-associated tremor/ataxia syndrome ( FXTAS ) is characterized by ...

  20. The Trajectory of Mathematics Skills and Working Memory Thresholds in Girls with Fragile X Syndrome

    Murphy, Melissa M.; Mazzocco, Michele M. M.

    2009-01-01

    Fragile X syndrome is a common genetic disorder associated with executive function deficits and poor mathematics achievement. In the present study, we examined changes in math performance during the elementary and middle school years in girls with fragile X syndrome, changes in the working memory loads under which children could complete a…

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

    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…

  2. Early White-Matter Abnormalities of the Ventral Frontostriatal Pathway in Fragile X Syndrome

    Haas, Brian W.; Barnea-Goraly, Naama; Lightbody, Amy A.; Patnaik, Swetapadma S.; Hoeft, Fumiko; Hazlett, Heather; Piven, Joseph; Reiss, Allan L.

    2009-01-01

    Aim: Fragile X syndrome is associated with cognitive deficits in inhibitory control and with abnormal neuronal morphology and development. Method: In this study, we used a diffusion tensor imaging (DTI) tractography approach to reconstruct white-matter fibers in the ventral frontostriatal pathway in young males with fragile X syndrome (n = 17;…

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

    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

  4. 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

    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

  5. 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

    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.

  6. Tracking development assistance for health to fragile states: 2005-2011.

    Graves, Casey M; Haakenstad, Annie; Dieleman, Joseph L

    2015-03-19

    Development assistance for health (DAH) has grown substantially, totaling more than $31.3 billion in 2013. However, the degree that countries with high concentrations of armed conflict, ethnic violence, inequality, debt, and corruption have received this health aid and how that assistance might be different from the funding provided to other countries has not been assessed. We combine DAH estimates and a multidimensional fragile states index for 2005 through 2011. We disaggregate and compare total DAH disbursed for fragile states versus stable states. Between 2005 and 2011, DAH per person in fragile countries increased at an annualized rate of 5.4%. In 2011 DAH to fragile countries totaled $6.2 billion, which is $5.05 per person. This is 43% of total DAH that is traced to a country. Comparing low-income countries, funding channeled to fragile countries was $7.22 per person while stable countries received $11.15 per person. Relative to stable countries, donors preferred to provide more funding to low-income fragile countries that have refugees or ongoing external intervention but tended to avoid providing funding to countries with political gridlock, flawed elections, or economic decline. In 2011, Ethiopia received the most health aid of all fragile countries, while the United States provided the most funds to fragile countries. In 2011, 1.2 billion people lived in fragile countries. DAH can bolster health systems and might be especially valuable in providing long-term stability in fragile environments. While external health funding to these countries has increased since 2005, it is, in per person terms, almost half as much as the DAH provided to stable countries of comparable income levels.

  7. New mechanisms and targets in the treatment of bone fragility.

    Martin, T John; Seeman, Ego

    2007-01-01

    Bone modelling and remodelling are cell-mediated processes responsible for the construction and reconstruction of the skeleton throughout life. These processes are chiefly mediated by locally generated cytokines and growth factors that regulate the differentiation, activation, work and life span of osteoblasts and osteoclasts, the cells that co-ordinate the volumes of bone resorbed and formed. In this way, the material composition and structural design of bone is regulated in accordance with its loading requirements. Abnormalities in this regulatory system compromise the material and structural determinants of bone strength producing bone fragility. Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches to prevention and treatment of bone fragility. A great deal has been learnt in the last decade. Clinical trials carried out exclusively with drugs that inhibit bone resorption have identified the importance of reducing the rate of bone remodelling and so the progression of bone fragility to achieved fracture reductions of approx. 50%. These trials have also identified limitations that should be placed upon interpretation of bone mineral density changes in relation to treatment. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. More recent research has provided the first effective anabolic therapy for bone reconstruction. Daily injections of PTH (parathyroid hormone)-(1-34) have been shown in preclinical studies and in a large clinical trial to increase bone tissue mass and reduce the risk of fractures. The action of PTH differs from that of the resorption inhibitors, but whether it is more effective in fracture reduction is not known. Understanding the cellular and molecular mechanisms of PTH action, particularly its interactions with

  8. Emerging pharmacologic treatment options for fragile X syndrome

    Schaefer, Tori L; Davenport, Matthew H; Erickson, Craig A

    2015-01-01

    Fragile X syndrome (FXS) is the most common single gene cause of intellectual disability and autism spectrum disorder. Caused by a silenced fragile X mental retardation 1 gene and the subsequent deficiency in fragile X mental retardation protein, patients with FXS experience a range of physical, behavioral, and intellectual debilitations. The FXS field, as a whole, has recently met with some challenges, as several targeted clinical trials with high expectations of success have failed to elucidate significant improvements in a variety of symptom domains. As new clinical trials in FXS are planned, there has been much discussion about the use of the commonly used clinical outcome measures, as well as study design considerations, patient stratification, and optimal age range for treatment. The evidence that modification of these drug targets and use of these failed compounds would prove to be efficacious in human clinical study were rooted in years of basic and translational research. There are questions arising as to the use of the mouse models for studying FXS treatment development. This issue is twofold: many of the symptom domains and molecular and biochemical changes assessed and indicative of efficacy in mouse model study are not easily amenable to clinical trials in people with FXS because of the intolerability of the testing paradigm or a lack of noninvasive techniques (prepulse inhibition, sensory hypersensitivity, startle reactivity, or electrophysiologic, biochemical, or structural changes in the brain); and capturing subtle yet meaningful changes in symptom domains such as sociability, anxiety, and hyperactivity in human FXS clinical trials is challenging with the currently used measures (typically parent/caregiver rating scales). Clinicians, researchers, and the pharmaceutical industry have all had to take a step back and critically evaluate the way we think about how to best optimize future investigations into pharmacologic FXS treatments. As new clinical

  9. I’m incredible—or am I? : On the socialization of fragile self-views in children

    Brummelman, E.

    2015-01-01

    I’m incredible—or am I? This is a recurring and daunting question for children with fragile self-views, whose feelings of self-worth crumble in the face of setbacks. What are the origins of children’s fragile self-views, and how can interventions reduce the fragility of children’s self-views? The

  10. Eastern Seaboard Electric Grid Fragility Maps Supporting Persistent Availability

    Walker, Kimberly A [ORNL; Weigand, Gilbert G [ORNL; Fernandez, Steven J [ORNL

    2012-11-01

    Persistently available power transmission can be disrupted by weather causing power outages with economic and social consequences. This research investigated the effects on the national power grid from a specific weather event, Hurricane Irene, that caused approximately 5.7 million customer power outages along the Eastern Seaboard in August of 2011. The objective was to describe the geographic differences in the grid s vulnerability to these events. Individual factors, such as wind speed or precipitation, were correlated with the number of outages to determine the greatest mechanism of power failure in hopes of strengthening the future power grid. The resulting fragility maps not only depicted 18 counties that were less robust than the design-standard robustness model and three counties that were more robust, but also drew new damage contours with correlated wind speeds and county features.

  11. Fragility of complexity biophysical systems by neutron scattering

    Magazu, Salvatore [Dipartimento di Fisica, Universita di Messina, P.O. Box 55, I-98166 Messina (Italy)]. E-mail: smagazu@unime.it; Migliardo, Federica [Dipartimento di Fisica, Universita di Messina, P.O. Box 55, I-98166 Messina (Italy); Bellocco, Ersilia [Dipartimento di Chimica Organica e Biologica, Universita di Messina, I-98166 Messina (Italy); Lagana, Giuseppina [Dipartimento di Chimica Organica e Biologica, Universita di Messina, I-98166 Messina (Italy); Mondelli, Claudia [CNR-INFM OGG and CRS-SOFT, c/o ILL, 6 Jules Horowitz, BP 156, 38042 Grenoble Cedex 9 (France)

    2006-11-15

    Neutron scattering is an exceptional tool to investigate structural and dynamical properties of systems of biophysical interest, such as proteins, enzymes, lipids and sugars. Moreover, elastic neutron scattering enhances the investigation of atomic motions in hydrated proteins in a wide temperature range and on the picosecond timescale. Homologous disaccharides, such as trehalose, maltose and sucrose, are cryptobiotic substances, since they allow to many organisms to undergo in a 'suspended life' state, known as cryptobiosis in extreme environmental conditions. The present paper is aimed to discuss the fragility degree of disaccharides, as evaluated of the temperature dependence of the mean square displacement by elastic neutron scattering, in order to link this feature with their bioprotective functions.

  12. The Fragile X Syndrome: Behavioral Phenotype and Learning Disabilities

    Claudia GRAU RUBIO

    2016-04-01

    Full Text Available In this article, we describe the behavioral phenotype of individuals with Fragile X Syndrome and its impact in the educational scope. This syndrome is characterized by difficulties in sensory integration, cognitive deficits (verbal reasoning, abstract/ visual and cuantitative skills, short term memory, sequential processing, attention and executive processes, language disorders (phonetic-phonologicals, semanticals, morphosyntacticals and pragmaticals and communication disorders, social anxiety, general hyperarousal, autism, non autistic social difficulties, attention deficit and hyperactivity, and learning disabilities. The behavioral phenotype is highly variable and depends on sex, age, and mutation status (full mutation or premutation. The behavioural phenotype has important repercussions in education, as it enables us to understand the learning disabilities and to develop specific intervention strategies.

  13. Mothers’ Partnership Instability and Coparenting among Fragile Families

    Cooper, Carey E.; Beck, Audrey N.; Högnäs, Robin S.; Swanson, Jodi

    2015-01-01

    Objectives The rise in nonmarital childbearing has raised concerns about coparenting among unmarried parents with increasingly complicated relationship trajectories. We address this issue by examining associations between mothers’ partnership transitions and coparenting and the moderating role of maternal race/ethnicity and child gender. Methods Data from the Fragile Families Study and ordinary least squares regression techniques are used to examine whether mothers’ partnership transitions are related to coparenting. Lagged and fixed effects models are employed to test the robustness of the findings to selection. Results Coresidential and nonresidential, dating transitions are negatively associated with coparenting, but the association is stronger for coresidential transitions than for dating transitions. Coresidential transitions are stronger predictors of coparenting for White parents than for Black parents and for parents of sons than for parents of daughters. Conclusions Policies aimed at strengthening families should emphasize relationship stability, regardless of the type of union, to promote high quality coparenting among at-risk populations. PMID:26538770

  14. Paternal Incarceration and Father–Child Contact in Fragile Families

    Geller, Amanda

    2013-01-01

    High rates of incarceration in the United States have motivated a broad examination of the effects of parental incarceration on child well-being. Although a growing literature documents challenges facing the children of incarcerated men, most incarcerated fathers lived apart from their children before their arrest, raising questions of whether they were sufficiently involved with their families for their incarceration to affect their children. The author used the Fragile Families and Child Wellbeing Study (N = 4,071) to examine father–child contact among incarcerated fathers and found that most incarcerated fathers maintained a degree of contact with their children, through either coresidence or visitation. Moreover, the results revealed robust reductions in both father–child coresidence and visitation when fathers are incarcerated—between 18% and 20% for coresidence, and 30% to 50% for the probability of visitation. The findings suggest that these reductions are driven by both incapacitation while incarcerated and union dissolution upon release. PMID:24839304

  15. Paternal Incarceration and Father-Child Contact in Fragile Families.

    Geller, Amanda

    2013-10-01

    High rates of incarceration in the United States have motivated a broad examination of the effects of parental incarceration on child well-being. Although a growing literature documents challenges facing the children of incarcerated men, most incarcerated fathers lived apart from their children before their arrest, raising questions of whether they were sufficiently involved with their families for their incarceration to affect their children. The author used the Fragile Families and Child Wellbeing Study (N = 4,071) to examine father-child contact among incarcerated fathers and found that most incarcerated fathers maintained a degree of contact with their children, through either coresidence or visitation. Moreover, the results revealed robust reductions in both father-child coresidence and visitation when fathers are incarcerated-between 18% and 20% for coresidence, and 30% to 50% for the probability of visitation. The findings suggest that these reductions are driven by both incapacitation while incarcerated and union dissolution upon release.

  16. Seismic fragility test of a 6-inch diameter pipe system

    Chen, W.P.; Onesto, A.T.; DeVita, V.

    1987-02-01

    This report contains the test results and assessments of seismic fragility tests performed on a 6-inch diameter piping system. The test was funded by the US Nuclear Regulatory Commission (NRC) and conducted by ETEC. The objective of the test was to investigate the ability of a representative nuclear piping system to withstand high level dynamic seismic and other loadings. Levels of loadings achieved during seismic testing were 20 to 30 times larger than normal elastic design evaluations to ASME Level D limits would permit. Based on failure data obtained during seismic and other dynamic testing, it was concluded that nuclear piping systems are inherently able to withstand much larger dynamic seismic loadings than permitted by current design practice criteria or predicted by the probabilistic risk assessment (PRA) methods and several proposed nonlinear methods of failure analysis

  17. Red Blood Cell Mechanical Fragility Test for Clinical Research Applications.

    Ziegler, Luke A; Olia, Salim E; Kameneva, Marina V

    2017-07-01

    Red blood cell (RBC) susceptibility to mechanically induced hemolysis, or RBC mechanical fragility (MF), is an important parameter in the characterization of erythrocyte membrane health. The rocker bead test (RBT) and associated calculated mechanical fragility index (MFI) is a simple method for the assessment of RBC MF. Requiring a minimum of 15.5 mL of blood and necessitating adjustment of hematocrit (Ht) to a "standard" value (40%), the current RBT is not suitable for use in most studies involving human subjects. To address these limitations, we propose a 6.5 mL reduced volume RBT and corresponding modified MFI (MMFI) that does not require prior Ht adjustment. This new method was assessed for i) correlation to the existing text, ii) to quantify the effect of Ht on MFI, and iii) validation by reexamining the protective effect of plasma proteins on RBC MF. The reduced volume RBT strongly correlated (r = 0.941) with the established large volume RBT at matched Hts, and an equation was developed to calculate MMFI: a numerical estimation (R 2  = 0.923) of MFI if performed with the reduced volume RBT at "standard" (40%) Ht. An inversely proportional relationship was found between plasma protein concentration and RBC MF using the MMFI-reduced volume method, supporting previous literature findings. The new reduced volume RBT and modified MFI will allow for the measurement of RBC MF in clinical and preclinical studies involving humans or small animals. © 2017 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  18. Systematic review of pharmacological treatments in fragile X syndrome

    Tejada Maria-Isabel

    2009-10-01

    Full Text Available Abstract Background Fragile X syndrome (FXS is considered the most common cause of inherited mental retardation. Affected people have mental impairment that can include Attention Deficit and/or Hyperactivity Disorder (ADHD, autism disorder, and speech and behavioural disorders. Several pharmacological interventions have been proposed to treat those impairments. Methods Systematic review of the literature and summary of the evidence from clinical controlled trials that compared at least one pharmacological treatment with placebo or other treatment in individuals with diagnosis of FXS syndrome and assessed the efficacy and/or safety of the treatments. Studies were identified by a search of PubMed, EMBASE and the Cochrane Databases using the terms fragile X and treatment. Risk of bias of the studies was assessed by using the Cochrane Collaboration criteria. Results The search identified 276 potential articles and 14 studies satisfied inclusion criteria. Of these, 10 studies on folic acid (9 with crossover design, only 1 of them with good methodological quality and low risk of bias did not find in general significant improvements. A small sample size trial assessed dextroamphetamine and methylphenidate in patients with an additional diagnosis of ADHD and found some improvements in those taking methylphenidate, but the length of follow-up was too short. Two studies on L-acetylcarnitine, showed positive effects and no side effects in patients with an additional diagnosis of ADHD. Finally, one study on patients with an additional diagnosis of autism assessed ampakine compound CX516 and found no significant differences between treatment and placebo. Regarding safety, none of the studies that assessed that area found relevant side effects, but the number of patients included was too small to detect side effects with low incidence. Conclusion Currently there is no robust evidence to support recommendations on pharmacological treatments in patients with

  19. New insights of altered lipid profile in Fragile X Syndrome.

    Artuela Çaku

    Full Text Available Fragile X Syndrome (FXS is the main genetic cause of autism and intellectual deficiency resulting the absence of the Fragile X Mental Retardation Protein (FMRP. Clinical picture is characterized by cognitive impairment associated with a broad spectrum of psychiatric comorbidities including autism spectrum disorders and attention-deficit/hyperactivity disorders. Some of these disorders have been associated with lipid abnormalities and lower cholesterol levels. Since lipids are important for neuronal development, we aim to investigate the lipid profile of French Canadian-FXS individuals and to identify the altered components of cholesterol metabolism as well as their association with clinical profile.Anthropometric data were collected from 25 FXS individuals and 26 controls. Lipid assessment included: total cholesterol (TC, triglycerides, LDL, HDL, ApoB, ApoA1, PCSK9, Lp(a and lipoprotein electrophoresis. Aberrant and adaptive behaviour of affected individuals was respectively assessed by the ABC-C and ABAS questionnaires.FXS participants had a higher body mass index as compared to controls while 38% of them had TC<10th percentile. Lower levels of LDL, HDL and apoA1 were observed in FXS group as compared to controls. However, PCSK9 levels did not differ between the two groups. As expected, PCSK9 levels correlated with total cholesterol (rs = 0.61, p = 0.001 and LDL (rs = 0.46, p = 0.014 in the control group, while no association was present in the FXS group. An inverse relationship was observed between total cholesterol and aberrant behaviour as determined by ABC-C total score.Our results showed the presence of hypocholesterolemia in French Canadian-FXS population, a condition that seems to influence their clinical phenotype. We identified for the first time a potential underlying alteration of PCSK9 function in FXS that could result from the absence of FMRP. Further investigations are warranted to better understand the association between

  20. Fragility fractures and bone remodeling in type 2 diabetes mellitus

    Tatiana O. Yalochkina

    2017-11-01

    Full Text Available Fracture risk is significantly increased in both type 1 and type 2 diabetes and individuals with diabetes experience worse fracture outcomes compared to normoglycemic individuals. Patients with T1DM have decreased bone mineral density (BMD, whereas patients with T2DM demonstrate increased BMD compared to healthy control. The latest studies show increased incidence of low-traumatic fractures in patients with T2DM instead of high bone mineral density (BMD. The risk of osteoporotic fractures in patients with T2DM can be explained by disease complications and increased risk of falls and consequent trauma. However, the most important cause of bone fragility in T2DM is the deterioration in bone microarchitecture, the mechanism of which is not completely understood. High BMD in patients with T2DM does not allow us to use dual-energy X-ray-absorptiometry as a “gold standard” test for diagnosticsof osteoporosis. Consequently,new risk factors and diagnostic algorithm as well as treatment strategy should be developed for patients with T2DM. In addition to this, some researchers considered that the group of T2DM is geterogenous and physicians might face patients with osteoporosis and mild diabetes that add very little to bone fragility; patients with osteoporosis and moderate or severe diabetes which also affects bone tissue –diabetoosteoporosis; and patients without osteoporosis but severe diabetes which cause bone tissue deterioration with the development of diabetic bone disease. New diagnostic tools and algorithm and new experimental research are needed for better understanding bone deterioration in patients with T2DM. This review summarizes our current knowledge on fracture rate, risk factors for fractures and causes of bone deterioration in subjects with T2DM.

  1. Assessing the Fragile X Syndrome Newborn Screening Landscape.

    Riley, Catharine; Wheeler, Anne

    2017-06-01

    Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability. Early identification is an important step in linking FXS individuals with appropriate and timely medical and social services. Newborn screening (NBS) is 1 approach that has been used for other conditions to facilitate early identification. A literature review was conducted to identify issues, barriers, challenges, and approaches to addressing challenges related to NBS for FXS. Search terms included: fragile X syndrome, FMR1, newborn screening, screening, and genetic testing. To supplement the literature review, 9 key informant interviews were conducted. Information gathered through these interviews supplemented what was identified in the literature. Information from both the literature review and supplemental interviews was reviewed by 3 researchers who discussed and came to consensus on thematic areas and categorization of issues. The barriers and challenges related to NBS for FXS identified in the literature and by experts and stakeholders are categorized into 5 thematic areas: public health burden, treatment, timing, screening/testing methodologies, and translating results. Summaries of these issues and barriers are provided, along with potential approaches to addressing them. The issues and barriers described in this article highlight limited areas of knowledge that need be addressed to improve our understanding of FXS and the potential benefit of NBS. The landscape of NBS for FXS could be influenced by a series of research findings over time or a larger breakthrough that demonstrates an effective targeted treatment that has to be implemented early in life. Copyright © 2017 by the American Academy of Pediatrics.

  2. Fragile X syndrome: Are signaling lipids the missing culprits?

    Tabet, Ricardos; Vitale, Nicolas; Moine, Hervé

    2016-11-01

    Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism. FXS results from the absence of FMRP, an RNA binding protein associated to ribosomes that influences the translation of specific mRNAs in post-synaptic compartments of neurons. The main molecular consequence of the absence of FMRP is an excessive translation of neuronal protein in several areas of the brain. This local protein synthesis deregulation is proposed to underlie the defect in synaptic plasticity responsible for FXS. Recent findings in neurons of the fragile X mouse model (Fmr1-KO) uncovered another consequence of the lack of FMRP: a deregulation of the diacylglycerol (DAG)/phosphatidic acid (PA) homeostasis. DAG and PA are two interconvertible lipids that influence membrane architecture and that act as essential signaling molecules that activate various downstream effectors, including master regulators of local protein synthesis and actin polymerization. As a consequence, DAG and PA govern a variety of cellular processes, including cell proliferation, vesicle/membrane trafficking and cytoskeletal organization. At the synapse, the level of these lipids is proposed to influence the synaptic activation status. FMRP appears as a master regulator of this neuronal process by controlling the translation of a diacylglycerol kinase enzyme that converts DAG into PA. The deregulated levels of DAG and PA caused by the absence of FMRP could represent a novel therapeutic target for the treatment of FXS. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

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

    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

  4. Loss of Ubr2, an E3 ubiquitin ligase, leads to chromosome fragility and impaired homologous recombinational repair

    Ouyang, Yan; Kwon, Yong Tae; An, Jee Young; Eller, Danny; Tsai, S.-C.; Diaz-Perez, Silvia; Troke, Joshua J.; Teitell, Michael A.; Marahrens, York

    2006-01-01

    The N-end rule pathway of protein degradation targets proteins with destabilizing N-terminal residues. Ubr2 is one of the E3 ubiquitin ligases of the mouse N-end rule pathway. We have previously shown that Ubr2 -/- male mice are infertile, owing to the arrest of spermatocytes between the leptotene/zygotene and pachytene of meiosis I, the failure of chromosome pairing, and subsequent apoptosis. Here, we report that mouse fibroblast cells derived from Ubr2 -/- embryos display genome instability. The frequency of chromosomal bridges and micronuclei were much higher in Ubr2 -/- fibroblasts than in +/+ controls. Metaphase chromosome spreads from Ubr2 -/- cells revealed a high incidence of spontaneous chromosomal gaps, indicating chromosomal fragility. These fragile sites were generally replicated late in S phase. Ubr2 -/- cells were hypersensitive to mitomycin C, a DNA cross-linking agent, but displayed normal sensitivity to gamma-irradiation. A reporter assay showed that Ubr2 -/- cells are significantly impaired in the homologous recombination repair of a double strand break. In contrast, Ubr2 -/- cells appeared normal in an assay for non-homologous end joining. Our results therefore unveil the role of the ubiquitin ligase Ubr2 in maintaining genome integrity and in homologous recombination repair

  5. Loss of Ubr2, an E3 ubiquitin ligase, leads to chromosome fragility and impaired homologous recombinational repair

    Ouyang, Yan [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Kwon, Yong Tae [Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261 (United States); An, Jee Young [Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261 (United States); Eller, Danny [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Tsai, S.-C. [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Diaz-Perez, Silvia [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Troke, Joshua J. [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Teitell, Michael A. [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Marahrens, York [Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States)]. E-mail: ymarahrens@mednet.ucla.edu

    2006-04-11

    The N-end rule pathway of protein degradation targets proteins with destabilizing N-terminal residues. Ubr2 is one of the E3 ubiquitin ligases of the mouse N-end rule pathway. We have previously shown that Ubr2{sup -/-} male mice are infertile, owing to the arrest of spermatocytes between the leptotene/zygotene and pachytene of meiosis I, the failure of chromosome pairing, and subsequent apoptosis. Here, we report that mouse fibroblast cells derived from Ubr2{sup -/-} embryos display genome instability. The frequency of chromosomal bridges and micronuclei were much higher in Ubr2{sup -/-} fibroblasts than in +/+ controls. Metaphase chromosome spreads from Ubr2{sup -/-} cells revealed a high incidence of spontaneous chromosomal gaps, indicating chromosomal fragility. These fragile sites were generally replicated late in S phase. Ubr2{sup -/-} cells were hypersensitive to mitomycin C, a DNA cross-linking agent, but displayed normal sensitivity to gamma-irradiation. A reporter assay showed that Ubr2{sup -/-} cells are significantly impaired in the homologous recombination repair of a double strand break. In contrast, Ubr2{sup -/-} cells appeared normal in an assay for non-homologous end joining. Our results therefore unveil the role of the ubiquitin ligase Ubr2 in maintaining genome integrity and in homologous recombination repair.

  6. The Role of Cultural and Identity Differences in Self-expression of Iranian Users of Social Networking Sites; A Case Study of Students of Tehran University, Amirkabir University, and Sharif University of Technology

    H. Molaei

    2017-12-01

    Full Text Available Social media with their features such as interactivity, participatory, and user-generated content have provided a great opportunity for self-expression of the users. However, cultural differences affect the extent and modality of users’ self-expression. This study aims to investigate the modality of self-expression of Iranian users of the social networking sites. In doing so, an online survey was conducted among the students of three Iran universities: University of Tehran, Amirkabir University of Technology, and Sharif University of Technology. A total of 371 students participated in the study. Having conducted quantitative analysis, the study results showed that women and ethnic minorities are more inclined to support their cultural differences compared to men and ethnic majority group. Supporting cultural differences was observed more among Shia religious majority group. Religious minorities expressed less tendency to create content in social networking sites and as a result support their religious identity.

  7. Structure and management of tuberculosis control programs in fragile states--Afghanistan, DR Congo, Haiti, Somalia.

    Mauch, Verena; Weil, Diana; Munim, Aayid; Boillot, Francois; Coninx, Rudi; Huseynova, Sevil; Powell, Clydette; Seita, Akihiro; Wembanyama, Henriette; van den Hof, Susan

    2010-07-01

    Health care delivery is particularly problematic in fragile states often connected with increased incidence of communicable diseases, among them tuberculosis. This article draws upon experiences in tuberculosis control in four fragile states from which four lessons learned were derived. A structured inventory to extract common themes specific for TB control in fragile states was conducted among twelve providers of technical assistance who have worked in fragile states. The themes were applied to the TB control programs of Afghanistan, DR Congo, Haiti and Somalia during the years 2000-2006. Case notifications and treatment outcomes have increased in all four countries since 2003 (treatment success rates 81-90%). Access to care and case detection however have remained insufficient (case detection rates 39-62%); There are four lessons learned: 1. TB control programs can function in fragile states. 2. National program leadership and stewardship are essential for quality and sustained TB control. 3. Partnerships with non-governmental providers are vital for continuous service delivery; 4. TB control programs in fragile states require consistent donor support. Despite challenges in management, coordination, security, logistics and funding, TB control programs can function in fragile states, but face considerable problems in access to diagnosis and treatment and therefore case detection. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Raman and DSC studies of fragility in tellurium-zinc oxide glass formers

    Stavrou, Elissaios; Kripotou, Sotiria; Raptis, Constantine; Turrell, Sylvia; Syassen, Karl

    2011-01-01

    Raman scattering and differential scanning calorimetry (DSC) measurements have been carried out in four mixed (TeO 2 ) 1-x (ZnO) x (x = 0.1, 0.2, 0.3, 0.4) glasses at high temperatures (Raman and DSC through the glass transition) and high pressures (Raman) with the aim of determining the fragility of these glass forming oxides. Four different criteria, corresponding to four parameters, were applied to assess the fragility of the glasses. From the DSC studies, we have obtained the fragility parameter m which corresponds to the slopes of Arrhenius (lnQ vs. 1/T g , were Q is the heating rate) plots, and the glass transition width ΔT g . Also, from the low-frequency Raman scattering, and in particular the boson peak intensity of the glasses at T g , we have estimated the fragility ratio r R (T g ) = I min /I max whose value serves as another (empirical) fragility criterion. Finally, from high pressure Raman measurements on the glasses, we have estimated the Grueneisen parameter γ T for each glass, which constitutes the fourth fragility parameter adopted in this work. Considering the four parameters ΔT g , m, r (T g ) and γ T and the generally accepted (empirical) fragility criteria, we conclude that the mixed tellurium-zinc oxides constitute strong-to-intermediate glass formers (copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  9. THE IMPORTANCE OF THE ERYTHROCYTES OSMOTIC FRAGILITY TEST PERFORMED IN CHILDREN WITH INDIRECT HYPERBILIRUB1NEMIA

    Ivana Stojanović

    2005-07-01

    Full Text Available The osmotic fragility test of erythrocytes is useful in the diagnosis of different types of hereditary hemolytic anemias followed with hyperbilirubinemia. Hemolytic anemias, characterized by accelerated destruction of red blood cells, are usually the consequence of many metabolic abnormalities like cellular membrane defect, erythrocyte enzymes defect or hemoglobin abnormalities – hemoglobinopathies. The object of our study was to assess the relationship between osmotic fragility test of erythrocytes and severity of indirect hyperbilirubinemia in some inherited erythrocytes’ disorders. We did the osmotic fragility test of erythrocytes by using Dacie, s method with normal values of erythrocytes hemolysis between 0,48 to 0,34% NaCl (minimal to maximal hemolysis. In hereditary spherocytosis, fragility of erythrocytes was increased (min. at 0,50 % NaCl to max. 0,44 % NaCl . In the child with β- thalassemia and cycle cell anemia erythrocytes fragility was decreased (min . at 0,42 to max. 0,32 % NaCl, that is 0,40% min. of hemolysis and 0,34% max. hemolysis in the second case. In newborn infants with high levels of indirect bilirubin in serum as a cause of physiological jaundice, the osmotic fragility test was within a normal range. Our findings point out the diagnostic value of osmotic fragility test in assessing patients with the indirect hyperbilirubinemia. This simple and important diagnostic test can be performed in small laboratories.

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

    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.

  11. The World Bank and Fragile States: Dynamics of Cooperation and Aid Structure

    Solomatin A.

    2018-03-01

    Full Text Available The eradication of extreme poverty in fragile states is one of the central problems of global governance at the present time. Development of these states is hindered by instability, weak public and social institutions or ongoing conflicts and violence. The World Bank is a key partner of fragile states, which account for almost a third of the world’s population. This article is a continuation of research exploring the evolution of conceptual and practical approaches by the World Bank to cooperation with fragile states. Its methodology is based on a multilevel analysis of the securitization of foreign aid as proposed by J. Lind and J. Howell of the London School of Economics. The main focus of this examination is on the dynamics of the change of scale and structure of the World Bank’s aid to fragile states in comparison with global armed trends of providing aid to fragile states as well. This article concludes that statements about the priority of the Bank’s work in fragile states have not yet been realized in practice. The Bank remains committed to the standard approach to working with this group of recipients, which involves serious risks. The World Bank leans toward supporting projects in fragile states which increases volatility and reduces aid predictability. This trend undermines the development potentials of recipient states. Attention is drawn to political factors influencing aid flows to fragile states and particularly to the tendency of increasing the share of aid provided to fragile states through multi donor trust funds rather than through the mechanisms of the International Development Association (IDA. This trend indicates that the Bank is no longer a central point of aid distribution to the recipients, pointing to the lack of trust of donor states in the existing mechanisms and rules of aid distribution. It also reveals the expanding role of donors’ strategic interests in the process of choosing recipients of World Bank aid.

  12. Induction of human interferon gene expression is associated with a nuclear factor that interacts with the site of the human immunodeficiency virus-enhancer

    Hiscott, J.; Alper, D.; Cohen, L.; Leblanc, J.F.; Sportza, L.; Wong, A.; Xanthoudakis, S.

    1989-01-01

    The relationship between transcription of alpha and beta interferon (IFN-α and IFN-β) genes and the interaction of IFN promoter-binding transcription factors has been examined in monoblastoid U937 cells following priming with recombinant IFN-α2 (rIFN-α2) and Sendai virus induction. Pretreatment of U937 cells with rIFN-α2 prior to Sendai virus infection increased the mRNA levels of IFN-α1, IFN-α2, and IFN-β as well as the final yield of biologically active IFN. Analysis of nuclear protein-IFN promoter DNA interactions by electrophoretic mobility-shift assays demonstrated increased factor binding to IFN-α1 and IFN-β regulatory domains, although no new induction-specific complexes were identified. On the basis of competition electrophoretic mobility-shift assay results, factors interacting with the IFN-α1 and IFN-β promoters appear to be distinct DNA-binding proteins. Hybrid promoter-chloramphenicol acetyltransferase fusion plasmids, containing either the IFN-β regulatory element or the human immunodeficiency virus enhancer element linked to the simian virus 40 promoter, were analyzed for virus and phorbol ester inducibility in epithelial and lymphoid cells, respectively. These experiments suggest that induction of IFN gene expression may be controlled in part by transcription regulatory proteins binding to an NF-κB-like site within the IFN-β promoter

  13. Genome-wide identification and tissue-specific expression analysis of nucleotide binding site-leucine rich repeat gene family in Cicer arietinum (kabuli chickpea).

    Sharma, Ranu; Rawat, Vimal; Suresh, C G

    2017-12-01

    The nucleotide binding site-leucine rich repeat (NBS-LRR) proteins play an important role in the defense mechanisms against pathogens. Using bioinformatics approach, we identified and annotated 104 NBS-LRR genes in chickpea. Phylogenetic analysis points to their diversification into two families namely TIR-NBS-LRR and non-TIR-NBS-LRR. Gene architecture revealed intron gain/loss events in this resistance gene family during their independent evolution into two families. Comparative genomics analysis elucidated its evolutionary relationship with other fabaceae species. Around 50% NBS-LRRs reside in macro-syntenic blocks underlining positional conservation along with sequence conservation of NBS-LRR genes in chickpea. Transcriptome sequencing data provided evidence for their transcription and tissue-specific expression. Four cis -regulatory elements namely WBOX, DRE, CBF, and GCC boxes, that commonly occur in resistance genes, were present in the promoter regions of these genes. Further, the findings will provide a strong background to use candidate disease resistance NBS-encoding genes and identify their specific roles in chickpea.

  14. MAdCAM-1 expressing sacral lymph node in the lymphotoxin beta-deficient mouse provides a site for immune generation following vaginal herpes simplex virus-2 infection.

    Soderberg, Kelly A; Linehan, Melissa M; Ruddle, Nancy H; Iwasaki, Akiko

    2004-08-01

    The members of the lymphotoxin (LT) family of molecules play a critical role in lymphoid organogenesis. Whereas LT alpha-deficient mice lack all lymph nodes and Peyer's patches, mice deficient in LT beta retain mesenteric lymph nodes and cervical lymph nodes, suggesting that an LT beta-independent pathway exists for the generation of mucosal lymph nodes. In this study, we describe the presence of a lymph node in LT beta-deficient mice responsible for draining the genital mucosa. In the majority of LT beta-deficient mice, a lymph node was found near the iliac artery, slightly misplaced from the site of the sacral lymph node in wild-type mice. The sacral lymph node of the LT beta-deficient mice, as well as that of the wild-type mice, expressed the mucosal addressin cell adhesion molecule-1 similar to the mesenteric lymph node. Following intravaginal infection with HSV type 2, activated dendritic cells capable of stimulating a Th1 response were found in this sacral lymph node. Furthermore, normal HSV-2-specific IgG responses were generated in the LT beta-deficient mice following intravaginal HSV-2 infection even in the absence of the spleen. Therefore, an LT beta-independent pathway exists for the development of a lymph node associated with the genital mucosa, and such a lymph node serves to generate potent immune responses against viral challenge.

  15. The Search for an Effective Therapy to Treat Fragile X Syndrome: Dream or Reality?

    Castagnola, Sara; Bardoni, Barbara; Maurin, Thomas

    2017-01-01

    Fragile X Syndrome (FXS) is the most common form of intellectual disability and a primary cause of autism. It originates from the lack of the Fragile X Mental Retardation Protein (FMRP), which is an RNA-binding protein encoded by the Fragile X Mental Retardation Gene 1 (FMR1) gene. Multiple roles have been attributed to this protein, ranging from RNA transport (from the nucleus to the cytoplasm, but also along neurites) to translational control of mRNAs. Over the last 20 years many studies ha...

  16. Influence of carbide precipitation upon hydrogen fragilization of an AISI 304 steel

    Hazarabedian, A.E.; Ovejero Garcia, J.

    1991-01-01

    The present work deals with austenitic stainless steels for a family of steels that is renowned for its high resistance to hydrogen fragilization. Nevertheless, these steels may suffer hydrogen fragilization under severe working conditions. This fact is strongly dependent on many factors -composition, grain size, other phases present, corrosion sensitivity, etc.-. While there are studies that show how intergranular corrosion is influenced by corrosion sensitivity -mainly due to carbide precipitation in grain boundaries-, there are no reports about the effect of the carbide precipitation itself on hydrogen fragilization for these steels. (Author) [es

  17. Seismic fragility analyses of nuclear power plant structures based on the recorded earthquake data in Korea

    Joe, Yang Hee; Cho, Sung Gook

    2003-01-01

    This paper briefly introduces an improved method for evaluating seismic fragilities of components of nuclear power plants in Korea. Engineering characteristics of small magnitude earthquake spectra recorded in the Korean peninsula during the last several years are also discussed in this paper. For the purpose of evaluating the effects of the recorded earthquake on the seismic fragilities of Korean nuclear power plant structures, several cases of comparative studies have been performed. The study results show that seismic fragility analysis based on the Newmark's spectra in Korea might over-estimate the seismic capacities of Korean facilities. (author)

  18. Fragility Variation of Lithium Borate Glasses Studied by Temperature-Modulated DSC

    Matsuda, Yu; Fukawa, Yasuteru; Kawashima, Mitsuru; Kojima, Seiji

    2008-02-01

    The fragility of lithium borate glass system has been investigated by Temperature-Modulated Differential Scanning Calorimetry (TMDSC). The frequency and temperature dependences of dynamic specific heat have been observed in the vicinity of a glass transition temperature Tg. It is shown that the value of the fragility index m can be determined from the temperature dependence of the α-relaxation times observed by TMDSC, when the raw phase angle is properly corrected. The composition dependence of the fragility has been also discussed.

  19. Seismic fragility analysis of the block masonry wall in nuclear power plants

    Wang, Z-L.; Pandey, M.D.; Xie, X-C.

    2014-01-01

    The evaluation of seismic fragility of a structure is an integral part in the Seismic Probabilistic Risk Analysis (SPRA). The block masonry wall, a commonly used barrier in nuclear power plants, is fairly vulnerable to failure under an earthquake. In practice, the seismic fragility of block walls is commonly evaluated using a simple deterministic approach called Conservative Deterministic Failure Margin (CDFM) method. This paper presents a more formal fragility analysis of a block wall based on rigorous probabilistic methods and the accuracy of the CDFM method is evaluated by comparison to the more rigorous FA method. (author)

  20. Identification and Investigation of Native Chromosomal Fragile Sites in the Avian Cell Line DT40

    Pentzold, Constanze

    cell systems. With the identification and investigation of CFSs in avian DT40 cells, this study reveals the genome-­‐wide evolutionary conservation of CFSs beyond the mammalian lineage for the first time. It opens the way for speculations on the beneficial existence of CFSs throughout the animal...... kingdom....