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Sample records for cis-regulatory deletion disrupting

  1. Abundant raw material for cis-regulatory evolution in humans

    Science.gov (United States)

    Rockman, Matthew V.; Wray, Gregory A.

    2002-01-01

    Changes in gene expression and regulation--due in particular to the evolution of cis-regulatory DNA sequences--may underlie many evolutionary changes in phenotypes, yet little is known about the distribution of such variation in populations. We present in this study the first survey of experimentally validated functional cis-regulatory polymorphism. These data are derived from more than 140 polymorphisms involved in the regulation of 107 genes in Homo sapiens, the eukaryote species with the most available data. We find that functional cis-regulatory variation is widespread in the human genome and that the consequent variation in gene expression is twofold or greater for 63% of the genes surveyed. Transcription factor-DNA interactions are highly polymorphic, and regulatory interactions have been gained and lost within human populations. On average, humans are heterozygous at more functional cis-regulatory sites (>16,000) than at amino acid positions (human phenotypic variation.

  2. cis-Regulatory control of the initial neurogenic pattern of onecut gene expression in the sea urchin embryo.

    Science.gov (United States)

    Barsi, Julius C; Davidson, Eric H

    2016-01-01

    Specification of the ciliated band (CB) of echinoid embryos executes three spatial functions essential for postgastrular organization. These are establishment of a band about 5 cells wide which delimits and bounds other embryonic territories; definition of a neurogenic domain within this band; and generation within it of arrays of ciliary cells that bear the special long cilia from which the structure derives its name. In Strongylocentrotus purpuratus the spatial coordinates of the future ciliated band are initially and exactly determined by the disposition of a ring of cells that transcriptionally activate the onecut homeodomain regulatory gene, beginning in blastula stage, long before the appearance of the CB per se. Thus the cis-regulatory apparatus that governs onecut expression in the blastula directly reveals the genomic sequence code by which these aspects of the spatial organization of the embryo are initially determined. We screened the entire onecut locus and its flanking region for transcriptionally active cis-regulatory elements, and by means of BAC recombineered deletions identified three separated and required cis-regulatory modules that execute different functions. The operating logic of the crucial spatial control module accounting for the spectacularly precise and beautiful early onecut expression domain depends on spatial repression. Previously predicted oral ectoderm and aboral ectoderm repressors were identified by cis-regulatory mutation as the products of goosecoid and irxa genes respectively, while the pan-ectodermal activator SoxB1 supplies a transcriptional driver function. PMID:26522848

  3. Parallel Evolution of Chordate Cis-Regulatory Code for Development

    OpenAIRE

    Doglio, Laura; Goode, Debbie K.; Maria C. Pelleri; Pauls, Stefan; Frabetti, Flavia; Shimeld, Sebastian M; Vavouri, Tanya; Elgar, Greg

    2013-01-01

    Urochordates are the closest relatives of vertebrates and at the larval stage, possess a characteristic bilateral chordate body plan. In vertebrates, the genes that orchestrate embryonic patterning are in part regulated by highly conserved non-coding elements (CNEs), yet these elements have not been identified in urochordate genomes. Consequently the evolution of the cis-regulatory code for urochordate development remains largely uncharacterised. Here, we use genome-wide comparisons between C...

  4. Twine: display and analysis of cis-regulatory modules

    OpenAIRE

    Pearson, Joseph C.; Crews, Stephen T.

    2013-01-01

    Summary: Many algorithms analyze enhancers for overrepresentation of known and novel motifs, with the goal of identifying binding sites for direct regulators of gene expression. Twine is a Java GUI with multiple graphical representations (‘Views’) of enhancer alignments that displays motifs, as IUPAC consensus sequences or position frequency matrices, in the context of phylogenetic conservation to facilitate cis-regulatory element discovery. Thresholds of phylogenetic conservation and motif s...

  5. CREME: Cis-Regulatory Module Explorer for the Human Genome

    Energy Technology Data Exchange (ETDEWEB)

    Loots, G G; Sharan, R; Ovcharenko, I; Ben-Hur, A

    2004-02-11

    The binding of transcription factors to specific regulatory sequence elements is a primary mechanism for controlling gene transcription. Eukaryotic genes are often regulated by several transcription factors, whose binding sites are tightly clustered and form cis-regulatory modules. In this paper we present a web-server, CREME, for identifying and visualizing cis-regulatory modules in the promoter regions of a given set of potentially co-regulated genes. CREME relies on a database of putative transcription factor binding sites that have been annotated across the human genome using a library of position weight matrices and evolutionary conservation with the mouse and rat genomes. A search algorithm is applied to this dataset to identify combinations of transcription factors whose binding sites tend to co-occur in close proximity in the promoter regions of the input gene set. The identified cis-regulatory modules are statistically scored and significant combinations are reported and graphically visualized. Our web-server is available at http://creme.dcode.org/.

  6. Mapping Association between Long-Range Cis-Regulatory Regions and Their Target Genes Using Comparative Genomics

    Science.gov (United States)

    Mongin, Emmanuel; Dewar, Ken; Blanchette, Mathieu

    In chordates, long-range cis-regulatory regions are involved in the control of transcription initiation (either as repressors or enhancers). They can be located as far as 1 Mb from the transcription start site of the target gene and can regulate more than one gene. Therefore, proper characterization of functional interactions between long-range cis-regulatory regions and their target genes remains problematic. We present a novel method to predict such interactions based on the analysis of rearrangements between the human and 16 other vertebrate genomes. Our method is based on the assumption that genome rearrangements that would disrupt the functional interaction between a cis-regulatory region and its target gene are likely to be deleterious. Therefore, conservation of synteny through evolution would be an indication of a functional interaction. We use our algorithm to classify a set of 1,406,084 putative associations from the human genome. This genome-wide map of interactions has many potential applications, including the selection of candidate regions prior to in vivo experimental characterization, a better characterization of regulatory regions involved in position effect diseases, and an improved understanding of the mechanisms and importance of long-range regulation.

  7. Detailed map of a cis-regulatory input function

    Science.gov (United States)

    Setty, Y.; Mayo, A. E.; Surette, M. G.; Alon, U.

    2003-06-01

    Most genes are regulated by multiple transcription factors that bind specific sites in DNA regulatory regions. These cis-regulatory regions perform a computation: the rate of transcription is a function of the active concentrations of each of the input transcription factors. Here, we used accurate gene expression measurements from living cell cultures, bearing GFP reporters, to map in detail the input function of the classic lacZYA operon of Escherichia coli, as a function of about a hundred combinations of its two inducers, cAMP and isopropyl -D-thiogalactoside (IPTG). We found an unexpectedly intricate function with four plateau levels and four thresholds. This result compares well with a mathematical model of the binding of the regulatory proteins cAMP receptor protein (CRP) and LacI to the lac regulatory region. The model is also used to demonstrate that with few mutations, the same region could encode much purer AND-like or even OR-like functions. This possibility means that the wild-type region is selected to perform an elaborate computation in setting the transcription rate. The present approach can be generally used to map the input functions of other genes.

  8. Changes in Cis-regulatory Elements during Morphological Evolution

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    Yu-Lee Paul

    2012-10-01

    Full Text Available How have animals evolved new body designs (morphological evolution? This requires explanations both for simple morphological changes, such as differences in pigmentation and hair patterns between different Drosophila populations and species, and also for more complex changes, such as differences in the forelimbs of mice and bats, and the necks of amphibians and reptiles. The genetic changes and pathways involved in these evolutionary steps require identification. Many, though not all, of these events occur by changes in cis-regulatory (enhancer elements within developmental genes. Enhancers are modular, each affecting expression in only one or a few tissues. Therefore it is possible to add, remove or alter an enhancer without producing changes in multiple tissues, and thereby avoid widespread (pleiotropic deleterious effects. Ideally, for a given step in morphological evolution it is necessary to identify (i the change in phenotype, (ii the changes in gene expression, (iii the DNA region, enhancer or otherwise, affected, (iv the mutation involved, (v the nature of the transcription or other factors that bind to this site. In practice these data are incomplete for most of the published studies upon morphological evolution. Here, the investigations are categorized according to how far these analyses have proceeded.

  9. Using hexamers to predict cis-regulatory motifs in Drosophila

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    Kibler Dennis

    2005-10-01

    Full Text Available Abstract Background Cis-regulatory modules (CRMs are short stretches of DNA that help regulate gene expression in higher eukaryotes. They have been found up to 1 megabase away from the genes they regulate and can be located upstream, downstream, and even within their target genes. Due to the difficulty of finding CRMs using biological and computational techniques, even well-studied regulatory systems may contain CRMs that have not yet been discovered. Results We present a simple, efficient method (HexDiff based only on hexamer frequencies of known CRMs and non-CRM sequence to predict novel CRMs in regulatory systems. On a data set of 16 gap and pair-rule genes containing 52 known CRMs, predictions made by HexDiff had a higher correlation with the known CRMs than several existing CRM prediction algorithms: Ahab, Cluster Buster, MSCAN, MCAST, and LWF. After combining the results of the different algorithms, 10 putative CRMs were identified and are strong candidates for future study. The hexamers used by HexDiff to distinguish between CRMs and non-CRM sequence were also analyzed and were shown to be enriched in regulatory elements. Conclusion HexDiff provides an efficient and effective means for finding new CRMs based on known CRMs, rather than known binding sites.

  10. Deciphering cis-regulatory control in inflammatory cells.

    Science.gov (United States)

    Ghisletti, Serena; Natoli, Gioacchino

    2013-01-01

    In innate immune system cells, such as macrophages and dendritic cells, deployment of inducible gene expression programmes in response to microbes and danger signals requires highly precise regulatory mechanisms. The inflammatory response has to be tailored based on both the triggering stimulus and its dose, and it has to be unfolded in a kinetically complex manner that suits the different phases of the inflammatory process. Genomic characterization of regulatory elements in this context indicated that transcriptional regulators involved in macrophage specification act as pioneer transcription factors (TFs) that generate regions of open chromatin that enable the recruitment of TFs activated in response to external inputs. Therefore, competence for responses to a specific stimulus is programmed at an early stage of differentiation by factors involved in lineage commitment and maintenance of cell identity, which are responsible for the organization of a cell-type-specific cis-regulatory repertoire. The basic functional and organizational principles that regulate inflammatory gene expression in professional cells of the innate immune system provide general paradigms on the interplay between differentiation and environmental responses. PMID:23650641

  11. Computational methods for the detection of cis-regulatory modules.

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    Van Loo, Peter; Marynen, Peter

    2009-09-01

    Metazoan transcription regulation occurs through the concerted action of multiple transcription factors that bind co-operatively to cis-regulatory modules (CRMs). The annotation of these key regulators of transcription is lagging far behind the annotation of the transcriptome itself. Here, we give an overview of existing computational methods to detect these CRMs in metazoan genomes. We subdivide these methods into three classes: CRM scanners screen sequences for CRMs based on predefined models that often consist of multiple position weight matrices (PWMs). CRM builders construct models of similar CRMs controlling a set of co-regulated or co-expressed genes. CRM genome screeners screen sequences or complete genomes for CRMs as homotypic or heterotypic clusters of binding sites for any combination of transcription factors. We believe that CRM scanners are currently the most advanced methods, although their applicability is limited. Finally, we argue that CRM builders that make use of PWM libraries will benefit greatly from future advances and will prove to be most instrumental for the annotation of regulatory regions in metazoan genomes. PMID:19498042

  12. The search for cis-regulatory driver mutations in cancer genomes

    OpenAIRE

    Poulos, Rebecca C.; Sloane, Mathew A; Hesson, Luke B; Wong, Jason W. H.

    2015-01-01

    With the advent of high-throughput and relatively inexpensive whole-genome sequencing technology, the focus of cancer research has begun to shift toward analyses of somatic mutations in non-coding cis-regulatory elements of the cancer genome. Cis-regulatory elements play an important role in gene regulation, with mutations in these elements potentially resulting in changes to the expression of linked genes. The recent discoveries of recurrent TERT promoter mutations in melanoma, and recurrent...

  13. Cis-regulatory Evolution of Chalcone-Synthase Expression in the Genus Arabidopsis

    OpenAIRE

    de Meaux, J. (Juliette); Pop, A.(National Institute for Physics and Nuclear Engineering, Bucharest, Romania); Mitchell-Olds, T.

    2006-01-01

    The contribution of cis-regulation to adaptive evolutionary change is believed to be essential, yet little is known about the evolutionary rules that govern regulatory sequences. Here, we characterize the short-term evolutionary dynamics of a cis-regulatory region within and among two closely related species, A. lyrata and A. halleri, and compare our findings to A. thaliana. We focused on the cis-regulatory region of chalcone synthase (CHS), a key enzyme involved in the synthesis of plant sec...

  14. Shared Enhancer Activity in the Limbs and Phallus and Functional Divergence of a Limb-Genital cis-Regulatory Element in Snakes.

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    Infante, Carlos R; Mihala, Alexandra G; Park, Sungdae; Wang, Jialiang S; Johnson, Kenji K; Lauderdale, James D; Menke, Douglas B

    2015-10-12

    The amniote phallus and limbs differ dramatically in their morphologies but share patterns of signaling and gene expression in early development. Thus far, the extent to which genital and limb transcriptional networks also share cis-regulatory elements has remained unexplored. We show that many limb enhancers are retained in snake genomes, suggesting that these elements may function in non-limb tissues. Consistent with this, our analysis of cis-regulatory activity in mice and Anolis lizards reveals that patterns of enhancer activity in embryonic limbs and genitalia overlap heavily. In mice, deletion of HLEB, an enhancer of Tbx4, produces defects in hindlimbs and genitalia, establishing the importance of this limb-genital enhancer for development of these different appendages. Further analyses demonstrate that the HLEB of snakes has lost hindlimb enhancer function while retaining genital activity. Our findings identify roles for Tbx4 in genital development and highlight deep similarities in cis-regulatory activity between limbs and genitalia. PMID:26439399

  15. The search for cis-regulatory driver mutations in cancer genomes.

    Science.gov (United States)

    Poulos, Rebecca C; Sloane, Mathew A; Hesson, Luke B; Wong, Jason W H

    2015-10-20

    With the advent of high-throughput and relatively inexpensive whole-genome sequencing technology, the focus of cancer research has begun to shift toward analyses of somatic mutations in non-coding cis-regulatory elements of the cancer genome. Cis-regulatory elements play an important role in gene regulation, with mutations in these elements potentially resulting in changes to the expression of linked genes. The recent discoveries of recurrent TERT promoter mutations in melanoma, and recurrent mutations that create a super-enhancer regulating TAL1 expression in T-cell acute lymphoblastic leukaemia (T-ALL), have sparked significant interest in the search for other somatic cis-regulatory mutations driving cancer development. In this review, we look more closely at the TERT promoter and TAL1 enhancer alterations and use these examples to ask whether other cis-regulatory mutations may play a role in cancer susceptibility. In doing so, we make observations from the data emerging from recent research in this field, and describe the experimental and analytical approaches which could be adopted in the hope of better uncovering the true functional significance of somatic cis-regulatory mutations in cancer. PMID:26356674

  16. cis-Regulatory and Protein Evolution in Orthologous and Duplicate Genes

    OpenAIRE

    Castillo-Davis, Cristian I.; Hartl, Daniel L.; Achaz, Guillaume

    2004-01-01

    The relationship between protein and regulatory sequence evolution is a central question in molecular evolution. It is currently not known to what extent changes in gene expression are coupled with the evolution of protein coding sequences, or whether these changes differ among orthologs (species homologs) and paralogs (duplicate genes). Here, we develop a method to measure the extent of functionally relevant cis-regulatory sequence change in homologous genes, and validate it using microarray...

  17. Genome-wide de novo prediction of cis-regulatory binding sites in prokaryotes

    OpenAIRE

    Zhang, Shaoqiang; Xu, Minli; Li, Shan; Su, Zhengchang

    2009-01-01

    Although cis-regulatory binding sites (CRBSs) are at least as important as the coding sequences in a genome, our general understanding of them in most sequenced genomes is very limited due to the lack of efficient and accurate experimental and computational methods for their characterization, which has largely hindered our understanding of many important biological processes. In this article, we describe a novel algorithm for genome-wide de novo prediction of CRBSs with high accuracy. We desi...

  18. Computational and molecular dissection of an X-box cis-Regulatory module

    OpenAIRE

    Warrington, Timothy Burton

    2015-01-01

    Ciliopathies are a class of human diseases marked by dysfunction of the cellular organelle, cilia. While many of the molecular components that make up cilia have been identified and studied, comparatively little is understood about the transcriptional regulation of genes encoding these components. The conserved transcription factor Regulatory Factor X (RFX)/DAF-19, which acts through binding to the cis-regulatory motif known as X-box, has been shown to regulate ciliary genes in many animals f...

  19. Studying the functional conservation of cis-regulatory modules and their transcriptional output

    OpenAIRE

    Bailey Timothy L; Bauer Denis C

    2008-01-01

    Abstract Background Cis-regulatory modules (CRMs) are distinct, genomic regions surrounding the target gene that can independently activate the promoter to drive transcription. The activation of a CRM is controlled by the binding of a certain combination of transcription factors (TFs). It would be of great benefit if the transcriptional output mediated by a specific CRM could be predicted. Of equal benefit would be identifying in silico a specific CRM as the driver of the expression in a spec...

  20. Deletion of the secretory vesicle proteins IA-2 and IA-2β disrupts circadian rhythms of cardiovascular and physical activity

    OpenAIRE

    Kim, Soo Mi; Power, Andrea; Brown, Timothy M.; Constance, Cara M.; Coon, Steven L.; Nishimura, Takuya; Hirai, Hiroki; Cai, Tao; Eisner, Christoph; David R Weaver; Piggins, Hugh D.; Klein, David C.; Schnermann, Jürgen; Notkins, Abner L.

    2009-01-01

    Targeted deletion of IA-2 and IA-2β, major autoantigens in type 1 diabetes and transmembrane secretory vesicle proteins, results in impaired secretion of hormones and neurotransmitters. In the present study, we evaluated the effect of these deletions on daily rhythms in blood pressure, heart rate, core body temperature, and spontaneous physical and neuronal activity. We found that deletion of both IA-2 and IA-2β profoundly disrupts the usual diurnal variation of each of these parameters, wher...

  1. An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers.

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    Daniel Savic

    Full Text Available Genome-wide association studies (GWAS have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D, implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition.

  2. Bounded search for de novo identification of degenerate cis-regulatory elements

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    Khetani Radhika S

    2006-05-01

    Full Text Available Abstract Background The identification of statistically overrepresented sequences in the upstream regions of coregulated genes should theoretically permit the identification of potential cis-regulatory elements. However, in practice many cis-regulatory elements are highly degenerate, precluding the use of an exhaustive word-counting strategy for their identification. While numerous methods exist for inferring base distributions using a position weight matrix, recent studies suggest that the independence assumptions inherent in the model, as well as the inability to reach a global optimum, limit this approach. Results In this paper, we report PRISM, a degenerate motif finder that leverages the relationship between the statistical significance of a set of binding sites and that of the individual binding sites. PRISM first identifies overrepresented, non-degenerate consensus motifs, then iteratively relaxes each one into a high-scoring degenerate motif. This approach requires no tunable parameters, thereby lending itself to unbiased performance comparisons. We therefore compare PRISM's performance against nine popular motif finders on 28 well-characterized S. cerevisiae regulons. PRISM consistently outperforms all other programs. Finally, we use PRISM to predict the binding sites of uncharacterized regulons. Our results support a proposed mechanism of action for the yeast cell-cycle transcription factor Stb1, whose binding site has not been determined experimentally. Conclusion The relationship between statistical measures of the binding sites and the set as a whole leads to a simple means of identifying the diverse range of cis-regulatory elements to which a protein binds. This approach leverages the advantages of word-counting, in that position dependencies are implicitly accounted for and local optima are more easily avoided. While we sacrifice guaranteed optimality to prevent the exponential blowup of exhaustive search, we prove that the error

  3. Identification of a cis-regulatory element by transient analysis of co-ordinately regulated genes

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    Allan Andrew C

    2008-07-01

    Full Text Available Abstract Background Transcription factors (TFs co-ordinately regulate target genes that are dispersed throughout the genome. This co-ordinate regulation is achieved, in part, through the interaction of transcription factors with conserved cis-regulatory motifs that are in close proximity to the target genes. While much is known about the families of transcription factors that regulate gene expression in plants, there are few well characterised cis-regulatory motifs. In Arabidopsis, over-expression of the MYB transcription factor PAP1 (PRODUCTION OF ANTHOCYANIN PIGMENT 1 leads to transgenic plants with elevated anthocyanin levels due to the co-ordinated up-regulation of genes in the anthocyanin biosynthetic pathway. In addition to the anthocyanin biosynthetic genes, there are a number of un-associated genes that also change in expression level. This may be a direct or indirect consequence of the over-expression of PAP1. Results Oligo array analysis of PAP1 over-expression Arabidopsis plants identified genes co-ordinately up-regulated in response to the elevated expression of this transcription factor. Transient assays on the promoter regions of 33 of these up-regulated genes identified eight promoter fragments that were transactivated by PAP1. Bioinformatic analysis on these promoters revealed a common cis-regulatory motif that we showed is required for PAP1 dependent transactivation. Conclusion Co-ordinated gene regulation by individual transcription factors is a complex collection of both direct and indirect effects. Transient transactivation assays provide a rapid method to identify direct target genes from indirect target genes. Bioinformatic analysis of the promoters of these direct target genes is able to locate motifs that are common to this sub-set of promoters, which is impossible to identify with the larger set of direct and indirect target genes. While this type of analysis does not prove a direct interaction between protein and DNA

  4. Plasticity of the cis-regulatory input function of a gene.

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    Avraham E Mayo

    2006-04-01

    Full Text Available The transcription rate of a gene is often controlled by several regulators that bind specific sites in the gene's cis-regulatory region. The combined effect of these regulators is described by a cis-regulatory input function. What determines the form of an input function, and how variable is it with respect to mutations? To address this, we employ the well-characterized lac operon of Escherichia coli, which has an elaborate input function, intermediate between Boolean AND-gate and OR-gate logic. We mapped in detail the input function of 12 variants of the lac promoter, each with different point mutations in the regulator binding sites, by means of accurate expression measurements from living cells. We find that even a few mutations can significantly change the input function, resulting in functions that resemble Pure AND gates, OR gates, or single-input switches. Other types of gates were not found. The variant input functions can be described in a unified manner by a mathematical model. The model also lets us predict which functions cannot be reached by point mutations. The input function that we studied thus appears to be plastic, in the sense that many of the mutations do not ruin the regulation completely but rather result in new ways to integrate the inputs.

  5. Transcription of Mammalian cis-Regulatory Elements Is Restrained by Actively Enforced Early Termination.

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    Austenaa, Liv M I; Barozzi, Iros; Simonatto, Marta; Masella, Silvia; Della Chiara, Giulia; Ghisletti, Serena; Curina, Alessia; de Wit, Elzo; Bouwman, Britta A M; de Pretis, Stefano; Piccolo, Viviana; Termanini, Alberto; Prosperini, Elena; Pelizzola, Mattia; de Laat, Wouter; Natoli, Gioacchino

    2015-11-01

    Upon recruitment to active enhancers and promoters, RNA polymerase II (Pol II) generates short non-coding transcripts of unclear function. The mechanisms that control the length and the amount of ncRNAs generated by cis-regulatory elements are largely unknown. Here, we show that the adaptor protein WDR82 and its associated complexes actively limit such non-coding transcription. WDR82 targets the SET1 H3K4 methyltransferases and the nuclear protein phosphatase 1 (PP1) complexes to the initiating Pol II. WDR82 and PP1 also interact with components of the transcriptional termination and RNA processing machineries. Depletion of WDR82, SET1, or the PP1 subunit required for its nuclear import caused distinct but overlapping transcription termination defects at highly expressed genes and active enhancers and promoters, thus enabling the increased synthesis of unusually long ncRNAs. These data indicate that transcription initiated from cis-regulatory elements is tightly coordinated with termination mechanisms that impose the synthesis of short RNAs. PMID:26593720

  6. Genome-wide de novo prediction of cis-regulatory binding sites in prokaryotes

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    Zhang, Shaoqiang; Xu, Minli; Su, Zhengchang

    2009-01-01

    Although cis-regulatory binding sites (CRBSs) are at least as important as the coding sequences in a genome, our general understanding of them in most sequenced genomes is very limited due to the lack of efficient and accurate experimental and computational methods for their characterization, which has largely hindered our understanding of many important biological processes. In this article, we describe a novel algorithm for genome-wide de novo prediction of CRBSs with high accuracy. We designed our algorithm to circumvent three identified difficulties for CRBS prediction using comparative genomics principles based on a new method for the selection of reference genomes, a new metric for measuring the similarity of CRBSs, and a new graph clustering procedure. When operon structures are correctly predicted, our algorithm can predict 81% of known individual binding sites belonging to 94% of known cis-regulatory motifs in the Escherichia coli K12 genome, while achieving high prediction specificity. Our algorithm has also achieved similar prediction accuracy in the Bacillus subtilis genome, suggesting that it is very robust, and thus can be applied to any other sequenced prokaryotic genome. When compared with the prior state-of-the-art algorithms, our algorithm outperforms them in both prediction sensitivity and specificity. PMID:19383880

  7. A primer on regression methods for decoding cis-regulatory logic

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    Das, Debopriya; Pellegrini, Matteo; Gray, Joe W.

    2009-03-03

    The rapidly emerging field of systems biology is helping us to understand the molecular determinants of phenotype on a genomic scale [1]. Cis-regulatory elements are major sequence-based determinants of biological processes in cells and tissues [2]. For instance, during transcriptional regulation, transcription factors (TFs) bind to very specific regions on the promoter DNA [2,3] and recruit the basal transcriptional machinery, which ultimately initiates mRNA transcription (Figure 1A). Learning cis-Regulatory Elements from Omics Data A vast amount of work over the past decade has shown that omics data can be used to learn cis-regulatory logic on a genome-wide scale [4-6]--in particular, by integrating sequence data with mRNA expression profiles. The most popular approach has been to identify over-represented motifs in promoters of genes that are coexpressed [4,7,8]. Though widely used, such an approach can be limiting for a variety of reasons. First, the combinatorial nature of gene regulation is difficult to explicitly model in this framework. Moreover, in many applications of this approach, expression data from multiple conditions are necessary to obtain reliable predictions. This can potentially limit the use of this method to only large data sets [9]. Although these methods can be adapted to analyze mRNA expression data from a pair of biological conditions, such comparisons are often confounded by the fact that primary and secondary response genes are clustered together--whereas only the primary response genes are expected to contain the functional motifs [10]. A set of approaches based on regression has been developed to overcome the above limitations [11-32]. These approaches have their foundations in certain biophysical aspects of gene regulation [26,33-35]. That is, the models are motivated by the expected transcriptional response of genes due to the binding of TFs to their promoters. While such methods have gathered popularity in the computational domain

  8. Discovering cis-regulatory RNAs in Shewanella genomes by Support Vector Machines.

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    Xu, Xing; Ji, Yongmei; Stormo, Gary D

    2009-04-01

    An increasing number of cis-regulatory RNA elements have been found to regulate gene expression post-transcriptionally in various biological processes in bacterial systems. Effective computational tools for large-scale identification of novel regulatory RNAs are strongly desired to facilitate our exploration of gene regulation mechanisms and regulatory networks. We present a new computational program named RSSVM (RNA Sampler+Support Vector Machine), which employs Support Vector Machines (SVMs) for efficient identification of functional RNA motifs from random RNA secondary structures. RSSVM uses a set of distinctive features to represent the common RNA secondary structure and structural alignment predicted by RNA Sampler, a tool for accurate common RNA secondary structure prediction, and is trained with functional RNAs from a variety of bacterial RNA motif/gene families covering a wide range of sequence identities. When tested on a large number of known and random RNA motifs, RSSVM shows a significantly higher sensitivity than other leading RNA identification programs while maintaining the same false positive rate. RSSVM performs particularly well on sets with low sequence identities. The combination of RNA Sampler and RSSVM provides a new, fast, and efficient pipeline for large-scale discovery of regulatory RNA motifs. We applied RSSVM to multiple Shewanella genomes and identified putative regulatory RNA motifs in the 5' untranslated regions (UTRs) in S. oneidensis, an important bacterial organism with extraordinary respiratory and metal reducing abilities and great potential for bioremediation and alternative energy generation. From 1002 sets of 5'-UTRs of orthologous operons, we identified 166 putative regulatory RNA motifs, including 17 of the 19 known RNA motifs from Rfam, an additional 21 RNA motifs that are supported by literature evidence, 72 RNA motifs overlapping predicted transcription terminators or attenuators, and other candidate regulatory RNA motifs

  9. [Identification and mapping of cis-regulatory elements within long genomic sequences].

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    Akopov, S B; Chernov, I P; Vetchinova, A S; Bulanenkova, S S; Nikolaev, L G

    2007-01-01

    The publication of the human and other metazoan genome sequences opened up the possibility for mapping and analysis of genomic regulatory elements. Unfortunately, experimental data on genomic positions of such sequences as enhancers, silencers, insulators, transcription terminators, and replication origins are very limited, especially at the whole genome level. As most genomic regulatory elements (e.g., enhancers) are generally gene-, tissue-, or cell-specific, the prediction of these elements in silico is often ambiguous. Therefore, the development of high-throughput experimental approaches for identification and mapping of genomic functional elements is highly desirable. In this review we discuss novel approaches to high-throughput experimental identification of mammalian genomes cis-regulatory elements which is a necessary step toward the complete genome annotation. PMID:18240562

  10. Cis-regulatory architecture of a brain signaling center predates the origin of chordates.

    Science.gov (United States)

    Yao, Yao; Minor, Paul J; Zhao, Ying-Tao; Jeong, Yongsu; Pani, Ariel M; King, Anna N; Symmons, Orsolya; Gan, Lin; Cardoso, Wellington V; Spitz, François; Lowe, Christopher J; Epstein, Douglas J

    2016-05-01

    Genomic approaches have predicted hundreds of thousands of tissue-specific cis-regulatory sequences, but the determinants critical to their function and evolutionary history are mostly unknown. Here we systematically decode a set of brain enhancers active in the zona limitans intrathalamica (zli), a signaling center essential for vertebrate forebrain development via the secreted morphogen Sonic hedgehog (Shh). We apply a de novo motif analysis tool to identify six position-independent sequence motifs together with their cognate transcription factors that are essential for zli enhancer activity and Shh expression in the mouse embryo. Using knowledge of this regulatory lexicon, we discover new Shh zli enhancers in mice and a functionally equivalent element in hemichordates, indicating an ancient origin of the Shh zli regulatory network that predates the chordate phylum. These findings support a strategy for delineating functionally conserved enhancers in the absence of overt sequence homologies and over extensive evolutionary distances. PMID:27064252

  11. Lessons from Domestication: Targeting Cis-Regulatory Elements for Crop Improvement.

    Science.gov (United States)

    Swinnen, Gwen; Goossens, Alain; Pauwels, Laurens

    2016-06-01

    Domestication of wild plant species has provided us with crops that serve our human nutritional needs. Advanced DNA sequencing has propelled the unveiling of underlying genetic changes associated with domestication. Interestingly, many changes reside in cis-regulatory elements (CREs) that control the expression of an unmodified coding sequence. Sequence variation in CREs can impact gene expression levels, but also developmental timing and tissue specificity of expression. When genes are involved in multiple pathways or active in several organs and developmental stages CRE modifications are favored in contrast to mutations in coding regions, due to the lack of detrimental pleiotropic effects. Therefore, learning from domestication, we propose that CREs are interesting targets for genome editing to create new alleles for plant breeding. PMID:26876195

  12. Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus

    Science.gov (United States)

    Lee, Jeong Ho; Silhavy, Jennifer L.; Lee, Ji Eun; Al-Gazali, Lihadh; Thomas, Sophie; Davis, Erica E.; Bielas, Stephanie L.; Hill, Kiley J.; Iannicelli, Miriam; Brancati, Francesco; Gabriel, Stacey B.; Russ, Carsten; Logan, Clare V.; Sharif, Saghira Malik; Bennett, Christopher P.; Abe, Masumi; Hildebrandt, Friedhelm; Diplas, Bill H.; Attié-Bitach, Tania; Katsanis, Nicholas; Rajab, Anna; Koul, Roshan; Sztriha, Laszlo; Waters, Elizabeth R.; Ferro-Novick, Susan; Woods, C. Geoffrey; Johnson, Colin A.; Valente, Enza Maria; Zaki, Maha S.; Gleeson, Joseph G.

    2013-01-01

    Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements. PMID:22282472

  13. Brachyury, Foxa2 and the cis-Regulatory Origins of the Notochord.

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    Diana S José-Edwards

    2015-12-01

    Full Text Available A main challenge of modern biology is to understand how specific constellations of genes are activated to differentiate cells and give rise to distinct tissues. This study focuses on elucidating how gene expression is initiated in the notochord, an axial structure that provides support and patterning signals to embryos of humans and all other chordates. Although numerous notochord genes have been identified, the regulatory DNAs that orchestrate development and propel evolution of this structure by eliciting notochord gene expression remain mostly uncharted, and the information on their configuration and recurrence is still quite fragmentary. Here we used the simple chordate Ciona for a systematic analysis of notochord cis-regulatory modules (CRMs, and investigated their composition, architectural constraints, predictive ability and evolutionary conservation. We found that most Ciona notochord CRMs relied upon variable combinations of binding sites for the transcription factors Brachyury and/or Foxa2, which can act either synergistically or independently from one another. Notably, one of these CRMs contains a Brachyury binding site juxtaposed to an (AC microsatellite, an unusual arrangement also found in Brachyury-bound regulatory regions in mouse. In contrast, different subsets of CRMs relied upon binding sites for transcription factors of widely diverse families. Surprisingly, we found that neither intra-genomic nor interspecific conservation of binding sites were reliably predictive hallmarks of notochord CRMs. We propose that rather than obeying a rigid sequence-based cis-regulatory code, most notochord CRMs are rather unique. Yet, this study uncovered essential elements recurrently used by divergent chordates as basic building blocks for notochord CRMs.

  14. Brachyury, Foxa2 and the cis-Regulatory Origins of the Notochord.

    Science.gov (United States)

    José-Edwards, Diana S; Oda-Ishii, Izumi; Kugler, Jamie E; Passamaneck, Yale J; Katikala, Lavanya; Nibu, Yutaka; Di Gregorio, Anna

    2015-12-01

    A main challenge of modern biology is to understand how specific constellations of genes are activated to differentiate cells and give rise to distinct tissues. This study focuses on elucidating how gene expression is initiated in the notochord, an axial structure that provides support and patterning signals to embryos of humans and all other chordates. Although numerous notochord genes have been identified, the regulatory DNAs that orchestrate development and propel evolution of this structure by eliciting notochord gene expression remain mostly uncharted, and the information on their configuration and recurrence is still quite fragmentary. Here we used the simple chordate Ciona for a systematic analysis of notochord cis-regulatory modules (CRMs), and investigated their composition, architectural constraints, predictive ability and evolutionary conservation. We found that most Ciona notochord CRMs relied upon variable combinations of binding sites for the transcription factors Brachyury and/or Foxa2, which can act either synergistically or independently from one another. Notably, one of these CRMs contains a Brachyury binding site juxtaposed to an (AC) microsatellite, an unusual arrangement also found in Brachyury-bound regulatory regions in mouse. In contrast, different subsets of CRMs relied upon binding sites for transcription factors of widely diverse families. Surprisingly, we found that neither intra-genomic nor interspecific conservation of binding sites were reliably predictive hallmarks of notochord CRMs. We propose that rather than obeying a rigid sequence-based cis-regulatory code, most notochord CRMs are rather unique. Yet, this study uncovered essential elements recurrently used by divergent chordates as basic building blocks for notochord CRMs. PMID:26684323

  15. Combinatorial regulation modules on GmSBP2 promoter: a distal cis-regulatory domain confines the SBP2 promoter activity to the vascular tissue in vegetative organs.

    Science.gov (United States)

    Waclawovsky, Alessandro J; Freitas, Rejane L; Rocha, Carolina S; Contim, Luis Antônio S; Fontes, Elizabeth P B

    2006-01-01

    The Glycine max sucrose binding protein (GmSBP2) promoter directs phloem-specific expression of reporter genes in transgenic tobacco. Here, we identified cis-regulatory domains (CRD) that contribute with positive and negative regulation for the tissue-specific pattern of the GmSPB2 promoter. Negative regulatory elements in the distal CRD-A (-2000 to -700) sequences suppressed expression from the GmSBP2 promoter in tissues other than seed tissues and vascular tissues of vegetative organs. Deletion of this region relieved repression resulting in a constitutive promoter highly active in all tissues analyzed. Further deletions from the strong constitutive -700GmSBP2 promoter delimited several intercalating enhancer-like and repressing domains that function in a context-dependent manner. Histochemical examination revealed that the CRD-C (-445 to -367) harbors both negative and positive elements. This region abolished promoter expression in roots and in all tissues of stems except for the inner phloem. In contrast, it restores root meristem expression when fused to the -132pSBP2-GUS construct, which contains root meristem expression-repressing determinants mapped to the 44-bp CRD-G (-136 to -92). Thus, the GmSBP2 promoter is functionally organized into a proximal region with the combinatorial modular configuration of plant promoters and a distal domain, which restricts gene expression to the vascular tissues in vegetative organs. PMID:16574256

  16. Deletion of an X-inactivation boundary disrupts adjacent gene silencing.

    Directory of Open Access Journals (Sweden)

    Lindsay M Horvath

    2013-11-01

    Full Text Available In mammalian females, genes on one X are largely silenced by X-chromosome inactivation (XCI, although some "escape" XCI and are expressed from both Xs. Escapees can closely juxtapose X-inactivated genes and provide a tractable model for assessing boundary function at epigenetically regulated loci. To delimit sequences at an XCI boundary, we examined female mouse embryonic stem cells carrying X-linked BAC transgenes derived from an endogenous escape locus. Previously we determined that large BACs carrying escapee Kdm5c and flanking X-inactivated transcripts are properly regulated. Here we identify two lines with truncated BACs that partially and completely delete the distal Kdm5c XCI boundary. This boundary is not required for escape, since despite integrating into regions that are normally X inactivated, transgenic Kdm5c escapes XCI, as determined by RNA FISH and by structurally adopting an active conformation that facilitates long-range preferential association with other escapees. Yet, XCI regulation is disrupted in the transgene fully lacking the distal boundary; integration site genes up to 350 kb downstream of the transgene now inappropriately escape XCI. Altogether, these results reveal two genetically separable XCI regulatory activities at Kdm5c. XCI escape is driven by a dominant element(s retained in the shortest transgene that therefore lies within or upstream of the Kdm5c locus. Additionally, the distal XCI boundary normally plays an essential role in preventing nearby genes from escaping XCI.

  17. Bacterial regulon modeling and prediction based on systematic cis regulatory motif analyses

    Science.gov (United States)

    Liu, Bingqiang; Zhou, Chuan; Li, Guojun; Zhang, Hanyuan; Zeng, Erliang; Liu, Qi; Ma, Qin

    2016-03-01

    Regulons are the basic units of the response system in a bacterial cell, and each consists of a set of transcriptionally co-regulated operons. Regulon elucidation is the basis for studying the bacterial global transcriptional regulation network. In this study, we designed a novel co-regulation score between a pair of operons based on accurate operon identification and cis regulatory motif analyses, which can capture their co-regulation relationship much better than other scores. Taking full advantage of this discovery, we developed a new computational framework and built a novel graph model for regulon prediction. This model integrates the motif comparison and clustering and makes the regulon prediction problem substantially more solvable and accurate. To evaluate our prediction, a regulon coverage score was designed based on the documented regulons and their overlap with our prediction; and a modified Fisher Exact test was implemented to measure how well our predictions match the co-expressed modules derived from E. coli microarray gene-expression datasets collected under 466 conditions. The results indicate that our program consistently performed better than others in terms of the prediction accuracy. This suggests that our algorithms substantially improve the state-of-the-art, leading to a computational capability to reliably predict regulons for any bacteria.

  18. Characterization of Putative cis-Regulatory Elements in Genes Preferentially Expressed in Arabidopsis Male Meiocytes

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    Junhua Li

    2014-01-01

    Full Text Available Meiosis is essential for plant reproduction because it is the process during which homologous chromosome pairing, synapsis, and meiotic recombination occur. The meiotic transcriptome is difficult to investigate because of the size of meiocytes and the confines of anther lobes. The recent development of isolation techniques has enabled the characterization of transcriptional profiles in male meiocytes of Arabidopsis. Gene expression in male meiocytes shows unique features. The direct interaction of transcription factors (TFs with DNA regulatory sequences forms the basis for the specificity of transcriptional regulation. Here, we identified putative cis-regulatory elements (CREs associated with male meiocyte-expressed genes using in silico tools. The upstream regions (1 kb of the top 50 genes preferentially expressed in Arabidopsis meiocytes possessed conserved motifs. These motifs are putative binding sites of TFs, some of which share common functions, such as roles in cell division. In combination with cell-type-specific analysis, our findings could be a substantial aid for the identification and experimental verification of the protein-DNA interactions for the specific TFs that drive gene expression in meiocytes.

  19. The Hematopoietic Stem and Progenitor Cell Cistrome: GATA Factor-Dependent cis-Regulatory Mechanisms.

    Science.gov (United States)

    Hewitt, K J; Johnson, K D; Gao, X; Keles, S; Bresnick, E H

    2016-01-01

    Transcriptional regulators mediate the genesis and function of the hematopoietic system by binding complex ensembles of cis-regulatory elements to establish genetic networks. While thousands to millions of any given cis-element resides in a genome, how transcriptional regulators select these sites and how site attributes dictate functional output is not well understood. An instructive system to address this problem involves the GATA family of transcription factors that control vital developmental and physiological processes and are linked to multiple human pathologies. Although GATA factors bind DNA motifs harboring the sequence GATA, only a very small subset of these abundant motifs are occupied in genomes. Mechanistic studies revealed a unique configuration of a GATA factor-regulated cis-element consisting of an E-box and a downstream GATA motif separated by a short DNA spacer. GATA-1- or GATA-2-containing multiprotein complexes at these composite elements control transcription of genes critical for hematopoietic stem cell emergence in the mammalian embryo, hematopoietic progenitor cell regulation, and erythroid cell maturation. Other constituents of the complex include the basic helix-loop-loop transcription factor Scl/TAL1, its heterodimeric partner E2A, and the Lim domain proteins LMO2 and LDB1. This chapter reviews the structure/function of E-box-GATA composite cis-elements, which collectively constitute an important sector of the hematopoietic stem and progenitor cell cistrome. PMID:27137654

  20. Validation of skeletal muscle cis-regulatory module predictions reveals nucleotide composition bias in functional enhancers.

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    Andrew T Kwon

    2011-12-01

    Full Text Available We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions.

  1. Changes in cis-regulatory elements of a key floral regulator are associated with divergence of inflorescence architectures.

    Science.gov (United States)

    Kusters, Elske; Della Pina, Serena; Castel, Rob; Souer, Erik; Koes, Ronald

    2015-08-15

    Higher plant species diverged extensively with regard to the moment (flowering time) and position (inflorescence architecture) at which flowers are formed. This seems largely caused by variation in the expression patterns of conserved genes that specify floral meristem identity (FMI), rather than changes in the encoded proteins. Here, we report a functional comparison of the promoters of homologous FMI genes from Arabidopsis, petunia, tomato and Antirrhinum. Analysis of promoter-reporter constructs in petunia and Arabidopsis, as well as complementation experiments, showed that the divergent expression of leafy (LFY) and the petunia homolog aberrant leaf and flower (ALF) results from alterations in the upstream regulatory network rather than cis-regulatory changes. The divergent expression of unusual floral organs (UFO) from Arabidopsis, and the petunia homolog double top (DOT), however, is caused by the loss or gain of cis-regulatory promoter elements, which respond to trans-acting factors that are expressed in similar patterns in both species. Introduction of pUFO:UFO causes no obvious defects in Arabidopsis, but in petunia it causes the precocious and ectopic formation of flowers. This provides an example of how a change in a cis-regulatory region can account for a change in the plant body plan. PMID:26220938

  2. Deciphering Cis-Regulatory Element Mediated Combinatorial Regulation in Rice under Blast Infected Condition.

    Science.gov (United States)

    Deb, Arindam; Kundu, Sudip

    2015-01-01

    Combinations of cis-regulatory elements (CREs) present at the promoters facilitate the binding of several transcription factors (TFs), thereby altering the consequent gene expressions. Due to the eminent complexity of the regulatory mechanism, the combinatorics of CRE-mediated transcriptional regulation has been elusive. In this work, we have developed a new methodology that quantifies the co-occurrence tendencies of CREs present in a set of promoter sequences; these co-occurrence scores are filtered in three consecutive steps to test their statistical significance; and the significantly co-occurring CRE pairs are presented as networks. These networks of co-occurring CREs are further transformed to derive higher order of regulatory combinatorics. We have further applied this methodology on the differentially up-regulated gene-sets of rice tissues under fungal (Magnaporthe) infected conditions to demonstrate how it helps to understand the CRE-mediated combinatorial gene regulation. Our analysis includes a wide spectrum of biologically important results. The CRE pairs having a strong tendency to co-occur often exhibit very similar joint distribution patterns at the promoters of rice. We couple the network approach with experimental results of plant gene regulation and defense mechanisms and find evidences of auto and cross regulation among TF families, cross-talk among multiple hormone signaling pathways, similarities and dissimilarities in regulatory combinatorics between different tissues, etc. Our analyses have pointed a highly distributed nature of the combinatorial gene regulation facilitating an efficient alteration in response to fungal attack. All together, our proposed methodology could be an important approach in understanding the combinatorial gene regulation. It can be further applied to unravel the tissue and/or condition specific combinatorial gene regulation in other eukaryotic systems with the availability of annotated genomic sequences and suitable

  3. Identification of High-Impact cis-Regulatory Mutations Using Transcription Factor Specific Random Forest Models.

    Science.gov (United States)

    Svetlichnyy, Dmitry; Imrichova, Hana; Fiers, Mark; Kalender Atak, Zeynep; Aerts, Stein

    2015-11-01

    Cancer genomes contain vast amounts of somatic mutations, many of which are passenger mutations not involved in oncogenesis. Whereas driver mutations in protein-coding genes can be distinguished from passenger mutations based on their recurrence, non-coding mutations are usually not recurrent at the same position. Therefore, it is still unclear how to identify cis-regulatory driver mutations, particularly when chromatin data from the same patient is not available, thus relying only on sequence and expression information. Here we use machine-learning methods to predict functional regulatory regions using sequence information alone, and compare the predicted activity of the mutated region with the reference sequence. This way we define the Predicted Regulatory Impact of a Mutation in an Enhancer (PRIME). We find that the recently identified driver mutation in the TAL1 enhancer has a high PRIME score, representing a "gain-of-target" for MYB, whereas the highly recurrent TERT promoter mutation has a surprisingly low PRIME score. We trained Random Forest models for 45 cancer-related transcription factors, and used these to score variations in the HeLa genome and somatic mutations across more than five hundred cancer genomes. Each model predicts only a small fraction of non-coding mutations with a potential impact on the function of the encompassing regulatory region. Nevertheless, as these few candidate driver mutations are often linked to gains in chromatin activity and gene expression, they may contribute to the oncogenic program by altering the expression levels of specific oncogenes and tumor suppressor genes. PMID:26562774

  4. Recurrent modification of a conserved cis-regulatory element underlies fruit fly pigmentation diversity.

    Directory of Open Access Journals (Sweden)

    William A Rogers

    2013-08-01

    Full Text Available The development of morphological traits occurs through the collective action of networks of genes connected at the level of gene expression. As any node in a network may be a target of evolutionary change, the recurrent targeting of the same node would indicate that the path of evolution is biased for the relevant trait and network. Although examples of parallel evolution have implicated recurrent modification of the same gene and cis-regulatory element (CRE, little is known about the mutational and molecular paths of parallel CRE evolution. In Drosophila melanogaster fruit flies, the Bric-à-brac (Bab transcription factors control the development of a suite of sexually dimorphic traits on the posterior abdomen. Female-specific Bab expression is regulated by the dimorphic element, a CRE that possesses direct inputs from body plan (ABD-B and sex-determination (DSX transcription factors. Here, we find that the recurrent evolutionary modification of this CRE underlies both intraspecific and interspecific variation in female pigmentation in the melanogaster species group. By reconstructing the sequence and regulatory activity of the ancestral Drosophila melanogaster dimorphic element, we demonstrate that a handful of mutations were sufficient to create independent CRE alleles with differing activities. Moreover, intraspecific and interspecific dimorphic element evolution proceeded with little to no alterations to the known body plan and sex-determination regulatory linkages. Collectively, our findings represent an example where the paths of evolution appear biased to a specific CRE, and drastic changes in function were accompanied by deep conservation of key regulatory linkages.

  5. Recurrent Modification of a Conserved Cis-Regulatory Element Underlies Fruit Fly Pigmentation Diversity

    Science.gov (United States)

    Rogers, William A.; Salomone, Joseph R.; Tacy, David J.; Camino, Eric M.; Davis, Kristen A.; Rebeiz, Mark; Williams, Thomas M.

    2013-01-01

    The development of morphological traits occurs through the collective action of networks of genes connected at the level of gene expression. As any node in a network may be a target of evolutionary change, the recurrent targeting of the same node would indicate that the path of evolution is biased for the relevant trait and network. Although examples of parallel evolution have implicated recurrent modification of the same gene and cis-regulatory element (CRE), little is known about the mutational and molecular paths of parallel CRE evolution. In Drosophila melanogaster fruit flies, the Bric-à-brac (Bab) transcription factors control the development of a suite of sexually dimorphic traits on the posterior abdomen. Female-specific Bab expression is regulated by the dimorphic element, a CRE that possesses direct inputs from body plan (ABD-B) and sex-determination (DSX) transcription factors. Here, we find that the recurrent evolutionary modification of this CRE underlies both intraspecific and interspecific variation in female pigmentation in the melanogaster species group. By reconstructing the sequence and regulatory activity of the ancestral Drosophila melanogaster dimorphic element, we demonstrate that a handful of mutations were sufficient to create independent CRE alleles with differing activities. Moreover, intraspecific and interspecific dimorphic element evolution proceeded with little to no alterations to the known body plan and sex-determination regulatory linkages. Collectively, our findings represent an example where the paths of evolution appear biased to a specific CRE, and drastic changes in function were accompanied by deep conservation of key regulatory linkages. PMID:24009528

  6. Bioinformatic analysis of cis-regulatory interactions between progesterone and estrogen receptors in breast cancer

    Directory of Open Access Journals (Sweden)

    Matloob Khushi

    2014-11-01

    Full Text Available Chromatin factors interact with each other in a cell and sequence-specific manner in order to regulate transcription and a wealth of publically available datasets exists describing the genomic locations of these interactions. Our recently published BiSA (Binding Sites Analyser database contains transcription factor binding locations and epigenetic modifications collected from published studies and provides tools to analyse stored and imported data. Using BiSA we investigated the overlapping cis-regulatory role of estrogen receptor alpha (ERα and progesterone receptor (PR in the T-47D breast cancer cell line. We found that ERα binding sites overlap with a subset of PR binding sites. To investigate further, we re-analysed raw data to remove any biases introduced by the use of distinct tools in the original publications. We identified 22,152 PR and 18,560 ERα binding sites (<5% false discovery rate with 4,358 overlapping regions among the two datasets. BiSA statistical analysis revealed a non-significant overall overlap correlation between the two factors, suggesting that ERα and PR are not partner factors and do not require each other for binding to occur. However, Monte Carlo simulation by Binary Interval Search (BITS, Relevant Distance, Absolute Distance, Jaccard and Projection tests by Genometricorr revealed a statistically significant spatial correlation of binding regions on chromosome between the two factors. Motif analysis revealed that the shared binding regions were enriched with binding motifs for ERα, PR and a number of other transcription and pioneer factors. Some of these factors are known to co-locate with ERα and PR binding. Therefore spatially close proximity of ERα binding sites with PR binding sites suggests that ERα and PR, in general function independently at the molecular level, but that their activities converge on a specific subset of transcriptional targets.

  7. Studying the functional conservation of cis-regulatory modules and their transcriptional output

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    Bailey Timothy L

    2008-04-01

    Full Text Available Abstract Background Cis-regulatory modules (CRMs are distinct, genomic regions surrounding the target gene that can independently activate the promoter to drive transcription. The activation of a CRM is controlled by the binding of a certain combination of transcription factors (TFs. It would be of great benefit if the transcriptional output mediated by a specific CRM could be predicted. Of equal benefit would be identifying in silico a specific CRM as the driver of the expression in a specific tissue or situation. We extend a recently developed biochemical modeling approach to manage both prediction tasks. Given a set of TFs, their protein concentrations, and the positions and binding strengths of each of the TFs in a putative CRM, the model predicts the transcriptional output of the gene. Our approach predicts the location of the regulating CRM by using predicted TF binding sites in regions near the gene as input to the model and searching for the region that yields a predicted transcription rate most closely matching the known rate. Results Here we show the ability of the model on the example of one of the CRMs regulating the eve gene, MSE2. A model trained on the MSE2 in D. melanogaster was applied to the surrounding sequence of the eve gene in seven other Drosophila species. The model successfully predicts the correct MSE2 location and output in six out of eight Drosophila species we examine. Conclusion The model is able to generalize from D. melanogaster to other Drosophila species and accurately predicts the location and transcriptional output of MSE2 in those species. However, we also show that the current model is not specific enough to function as a genome-wide CRM scanner, because it incorrectly predicts other genomic regions to be MSE2s.

  8. Promoter analysis reveals cis-regulatory motifs associated with the expression of the WRKY transcription factor CrWRKY1 in Catharanthus roseus.

    Science.gov (United States)

    Yang, Zhirong; Patra, Barunava; Li, Runzhi; Pattanaik, Sitakanta; Yuan, Ling

    2013-12-01

    WRKY transcription factors (TFs) are emerging as an important group of regulators of plant secondary metabolism. However, the cis-regulatory elements associated with their regulation have not been well characterized. We have previously demonstrated that CrWRKY1, a member of subgroup III of the WRKY TF family, regulates biosynthesis of terpenoid indole alkaloids in the ornamental and medicinal plant, Catharanthus roseus. Here, we report the isolation and functional characterization of the CrWRKY1 promoter. In silico analysis of the promoter sequence reveals the presence of several potential TF binding motifs, indicating the involvement of additional TFs in the regulation of the TIA pathway. The CrWRKY1 promoter can drive the expression of a β-glucuronidase (GUS) reporter gene in native (C. roseus protoplasts and transgenic hairy roots) and heterologous (transgenic tobacco seedlings) systems. Analysis of 5'- or 3'-end deletions indicates that the sequence located between positions -140 to -93 bp and -3 to +113 bp, relative to the transcription start site, is critical for promoter activity. Mutation analysis shows that two overlapping as-1 elements and a CT-rich motif contribute significantly to promoter activity. The CrWRKY1 promoter is induced in response to methyl jasmonate (MJ) treatment and the promoter region between -230 and -93 bp contains a putative MJ-responsive element. The CrWRKY1 promoter can potentially be used as a tool to isolate novel TFs involved in the regulation of the TIA pathway. PMID:23979312

  9. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

    DEFF Research Database (Denmark)

    Møller, Rikke S; Weber, Yvonne G; Klitten, Laura L;

    2013-01-01

    Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been ...... associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs)....

  10. ChIP-Seq-Annotated Heliconius erato Genome Highlights Patterns of cis-Regulatory Evolution in Lepidoptera.

    Science.gov (United States)

    Lewis, James J; van der Burg, Karin R L; Mazo-Vargas, Anyi; Reed, Robert D

    2016-09-13

    Uncovering phylogenetic patterns of cis-regulatory evolution remains a fundamental goal for evolutionary and developmental biology. Here, we characterize the evolution of regulatory loci in butterflies and moths using chromatin immunoprecipitation sequencing (ChIP-seq) annotation of regulatory elements across three stages of head development. In the process we provide a high-quality, functionally annotated genome assembly for the butterfly, Heliconius erato. Comparing cis-regulatory element conservation across six lepidopteran genomes, we find that regulatory sequences evolve at a pace similar to that of protein-coding regions. We also observe that elements active at multiple developmental stages are markedly more conserved than elements with stage-specific activity. Surprisingly, we also find that stage-specific proximal and distal regulatory elements evolve at nearly identical rates. Our study provides a benchmark for genome-wide patterns of regulatory element evolution in insects, and it shows that developmental timing of activity strongly predicts patterns of regulatory sequence evolution. PMID:27626657

  11. Mutagenesis of GATA motifs controlling the endoderm regulator elt-2 reveals distinct dominant and secondary cis-regulatory elements.

    Science.gov (United States)

    Du, Lawrence; Tracy, Sharon; Rifkin, Scott A

    2016-04-01

    Cis-regulatory elements (CREs) are crucial links in developmental gene regulatory networks, but in many cases, it can be difficult to discern whether similar CREs are functionally equivalent. We found that despite similar conservation and binding capability to upstream activators, different GATA cis-regulatory motifs within the promoter of the C. elegans endoderm regulator elt-2 play distinctive roles in activating and modulating gene expression throughout development. We fused wild-type and mutant versions of the elt-2 promoter to a gfp reporter and inserted these constructs as single copies into the C. elegans genome. We then counted early embryonic gfp transcripts using single-molecule RNA FISH (smFISH) and quantified gut GFP fluorescence. We determined that a single primary dominant GATA motif located 527bp upstream of the elt-2 start codon was necessary for both embryonic activation and later maintenance of transcription, while nearby secondary GATA motifs played largely subtle roles in modulating postembryonic levels of elt-2. Mutation of the primary activating site increased low-level spatiotemporally ectopic stochastic transcription, indicating that this site acts repressively in non-endoderm cells. Our results reveal that CREs with similar GATA factor binding affinities in close proximity can play very divergent context-dependent roles in regulating the expression of a developmentally critical gene in vivo. PMID:26896592

  12. Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge (22q11 deletion syndrome

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    Beverly A. Karpinski

    2014-02-01

    Full Text Available We assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS, a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V, glossopharyngeal (IX or vagus (X cranial nerves (CNs that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.

  13. CisMiner: genome-wide in-silico cis-regulatory module prediction by fuzzy itemset mining.

    Directory of Open Access Journals (Sweden)

    Carmen Navarro

    Full Text Available Eukaryotic gene control regions are known to be spread throughout non-coding DNA sequences which may appear distant from the gene promoter. Transcription factors are proteins that coordinately bind to these regions at transcription factor binding sites to regulate gene expression. Several tools allow to detect significant co-occurrences of closely located binding sites (cis-regulatory modules, CRMs. However, these tools present at least one of the following limitations: 1 scope limited to promoter or conserved regions of the genome; 2 do not allow to identify combinations involving more than two motifs; 3 require prior information about target motifs. In this work we present CisMiner, a novel methodology to detect putative CRMs by means of a fuzzy itemset mining approach able to operate at genome-wide scale. CisMiner allows to perform a blind search of CRMs without any prior information about target CRMs nor limitation in the number of motifs. CisMiner tackles the combinatorial complexity of genome-wide cis-regulatory module extraction using a natural representation of motif combinations as itemsets and applying the Top-Down Fuzzy Frequent- Pattern Tree algorithm to identify significant itemsets. Fuzzy technology allows CisMiner to better handle the imprecision and noise inherent to regulatory processes. Results obtained for a set of well-known binding sites in the S. cerevisiae genome show that our method yields highly reliable predictions. Furthermore, CisMiner was also applied to putative in-silico predicted transcription factor binding sites to identify significant combinations in S. cerevisiae and D. melanogaster, proving that our approach can be further applied genome-wide to more complex genomes. CisMiner is freely accesible at: http://genome2.ugr.es/cisminer. CisMiner can be queried for the results presented in this work and can also perform a customized cis-regulatory module prediction on a query set of transcription factor binding

  14. LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome.

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    Ayumi Matsumoto

    Full Text Available Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID, low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574-91 264 613 bp, which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.

  15. Disrupted anatomic networks in the 22q11.2 deletion syndrome.

    Science.gov (United States)

    Schmitt, J Eric; Yi, James; Calkins, Monica E; Ruparel, Kosha; Roalf, David R; Cassidy, Amy; Souders, Margaret C; Satterthwaite, Theodore D; McDonald-McGinn, Donna M; Zackai, Elaine H; Gur, Ruben C; Emanuel, Beverly S; Gur, Raquel E

    2016-01-01

    The 22q11.2 deletion syndrome (22q11DS) is an uncommon genetic disorder with an increased risk of psychosis. Although the neural substrates of psychosis and schizophrenia are not well understood, aberrations in cortical networks represent intriguing potential mechanisms. Investigations of anatomic networks within 22q11DS are sparse. We investigated group differences in anatomic network structure in 48 individuals with 22q11DS and 370 typically developing controls by analyzing covariance patterns in cortical thickness among 68 regions of interest using graph theoretical models. Subjects with 22q11DS had less robust geographic organization relative to the control group, particularly in the occipital and parietal lobes. Multiple global graph theoretical statistics were decreased in 22q11DS. These results are consistent with prior studies demonstrating decreased connectivity in 22q11DS using other neuroimaging methodologies. PMID:27622139

  16. EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia in Female Mice

    Directory of Open Access Journals (Sweden)

    Bo Young Choi

    2014-10-01

    Full Text Available EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.

  17. Conserved cis-regulatory modules in promoters of genes encoding wheat high-molecular-weight glutenin subunits

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    Catherine eRAVEL

    2014-11-01

    Full Text Available The concentration and composition of the gliadin and glutenin seed storage proteins (SSPs in wheat flour are the most important determinants of its end-use value. In cereals, the synthesis of SSPs is predominantly regulated at the transcriptional level by a complex network involving at least five cis-elements in gene promoters. The high-molecular-weight glutenin subunits (HMW-GS are encoded by two tightly linked genes located on the long arms of group 1 chromosomes. Here, we sequenced and annotated the HMW-GS gene promoters of 22 electrophoretic wheat alleles to identify putative cis-regulatory motifs. We focused on 24 motifs known to be involved in SSP gene regulation. Most of them were identified in at least one HMW-GS gene promoter sequence. A common regulatory framework was observed in all the HMW-GS gene promoters, as they shared conserved cis-regulatory modules including all the five motifs known to regulate the transcription of SSP genes. This common regulatory framework comprises a composite box made of the GATA motifs and GCN4-like Motifs (GLMs and was shown to be functional as the GLMs are able to bind a bZIP transcriptional factor SPA (Storage Protein Activator. In addition to this regulatory framework, each HMW-GS gene promoter had additional motifs organized differently. The promoters of most highly expressed x-type HMW-GS genes contain an additional box predicted to bind R2R3-MYB transcriptional factors. However, the differences in annotation between promoter alleles could not be related to their level of expression. In summary, we identified a common modular organization of HMW-GS gene promoters but the lack of correlation between the cis-motifs of each HMW-GS gene promoter and their level of expression suggests that other cis-elements or other mechanisms regulate HMW-GS gene expression.

  18. MotifCombinator: a web-based tool to search for combinations of cis-regulatory motifs

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    Tsunoda Tatsuhiko

    2007-03-01

    Full Text Available Abstract Background A combination of multiple types of transcription factors and cis-regulatory elements is often required for gene expression in eukaryotes, and the combinatorial regulation confers specific gene expression to tissues or environments. To reveal the combinatorial regulation, computational methods are developed that efficiently infer combinations of cis-regulatory motifs that are important for gene expression as measured by DNA microarrays. One promising type of computational method is to utilize regression analysis between expression levels and scores of motifs in input sequences. This type takes full advantage of information on expression levels because it does not require that the expression level of each gene be dichotomized according to whether or not it reaches a certain threshold level. However, there is no web-based tool that employs regression methods to systematically search for motif combinations and that practically handles combinations of more than two or three motifs. Results We here introduced MotifCombinator, an online tool with a user-friendly interface, to systematically search for combinations composed of any number of motifs based on regression methods. The tool utilizes well-known regression methods (the multivariate linear regression, the multivariate adaptive regression spline or MARS, and the multivariate logistic regression method for this purpose, and uses the genetic algorithm to search for combinations composed of any desired number of motifs. The visualization systems in this tool help users to intuitively grasp the process of the combination search, and the backup system allows users to easily stop and restart calculations that are expected to require large computational time. This tool also provides preparatory steps needed for systematic combination search – i.e., selecting single motifs to constitute combinations and cutting out redundant similar motifs based on clustering analysis. Conclusion

  19. Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11

    DEFF Research Database (Denmark)

    Tzschach, Andreas; Bisgaard, Anne-Marie; Kirchhoff, Maria;

    2010-01-01

    and hypotonia. We also report on the results of breakpoint analysis by array painting in a mentally retarded patient with a balanced chromosome translocation 46,XY,t(10;13)(q22;p13)dn. The breakpoint in 10q22 was found to disrupt C10orf11, a brain-expressed gene in the common deleted interval of......Interstitial deletions of chromosome band 10q22 are rare. We report on the characterization of three overlapping de novo 10q22 deletions by high-resolution array comparative genomic hybridization in three unrelated patients. Patient 1 had a 7.9 Mb deletion in 10q21.3-q22.2 and suffered from severe...

  20. Mapping cis-Regulatory Domains in the Human Genome UsingMulti-Species Conservation of Synteny

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Prabhakar, Shyam; Poulin, Francis; Rubin, EdwardM.; Couronne, Olivier

    2005-06-13

    Our inability to associate distant regulatory elements with the genes that they regulate has largely precluded their examination for sequence alterations contributing to human disease. One major obstacle is the large genomic space surrounding targeted genes in which such elements could potentially reside. In order to delineate gene regulatory boundaries we used whole-genome human-mouse-chicken (HMC) and human-mouse-frog (HMF) multiple alignments to compile conserved blocks of synteny (CBS), under the hypothesis that these blocks have been kept intact throughout evolution at least in part by the requirement of regulatory elements to stay linked to the genes that they regulate. A total of 2,116 and 1,942 CBS>200 kb were assembled for HMC and HMF respectively, encompassing 1.53 and 0.86 Gb of human sequence. To support the existence of complex long-range regulatory domains within these CBS we analyzed the prevalence and distribution of chromosomal aberrations leading to position effects (disruption of a genes regulatory environment), observing a clear bias not only for mapping onto CBS but also for longer CBS size. Our results provide a genome wide data set characterizing the regulatory domains of genes and the conserved regulatory elements within them.

  1. Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules.

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    Bin Z He

    2011-04-01

    Full Text Available Transcription factor binding site(s (TFBS gain and loss (i.e., turnover is a well-documented feature of cis-regulatory module (CRM evolution, yet little attention has been paid to the evolutionary force(s driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time.

  2. Characterization and identification of cis-regulatory elements in Arabidopsis based on single-nucleotide polymorphism information.

    Science.gov (United States)

    Korkuc, Paula; Schippers, Jos H M; Walther, Dirk

    2014-01-01

    Identifying regulatory elements and revealing their role in gene expression regulation remains a central goal of plant genome research. We exploited the detailed genomic sequencing information of a large number of Arabidopsis (Arabidopsis thaliana) accessions to characterize known and to identify novel cis-regulatory elements in gene promoter regions of Arabidopsis by relying on conservation as the hallmark signal of functional relevance. Based on the genomic layout and the obtained density profiles of single-nucleotide polymorphisms (SNPs) in sequence regions upstream of transcription start sites, the average length of promoter regions in Arabidopsis could be established at 500 bp. Genes associated with high degrees of variability of their respective upstream regions are preferentially involved in environmental response and signaling processes, while low levels of promoter SNP density are common among housekeeping genes. Known cis-elements were found to exhibit a decreased SNP density than sequence regions not associated with known motifs. For 15 known cis-element motifs, strong positional preferences relative to the transcription start site were detected based on their promoter SNP density profiles. Five novel candidate cis-element motifs were identified as consensus motifs of 17 sequence hexamers exhibiting increased sequence conservation combined with evidence of positional preferences, annotation information, and functional relevance for inducing correlated gene expression. Our study demonstrates that the currently available resolution of SNP data offers novel ways for the identification of functional genomic elements and the characterization of gene promoter sequences. PMID:24204023

  3. Conservation of shh cis-regulatory architecture of the coelacanth is consistent with its ancestral phylogenetic position

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    Lang Michael

    2010-11-01

    Full Text Available Abstract Background The modern coelacanth (Latimeria is the extant taxon of a basal sarcopterygian lineage and sister group to tetrapods. Apart from certain apomorphic traits, its morphology is characterized by a high degree of retention of ancestral vertebrate structures and little morphological change. An insight into the molecular evolution that may explain the unchanged character of Latimeria morphology requires the analysis of the expression patterns of developmental regulator genes and their cis-regulatory modules (CRMs. Results We describe the comparative and functional analysis of the sonic hedgehog (shh genomic region of Latimeria menadoensis. Several putative enhancers in the Latimeria shh locus have been identified by comparisons to sarcopterygian and actinopterygian extant species. Specific sequence conservation with all known actinopterygian enhancer elements has been detected. However, these elements are selectively missing in more recently diverged actinopterygian and sarcopterygian species. The functionality of the putative Latimeria enhancers was confirmed by reporter gene expression analysis in transient transgenic zebrafish and chick embryos. Conclusions Latimeria shh CRMs represent the ancestral set of enhancers that have emerged before the split of lobe-finned and ray-finned fishes. In contrast to lineage-specific losses and differentiations in more derived lineages, Latimeria shh enhancers reveal low levels of sequence diversification. High overall sequence conservation of shh conserved noncoding elements (CNE is consistent with the general trend of high levels of conservation of noncoding DNA in the slowly evolving Latimeria genome.

  4. ModuleMiner - improved computational detection of cis-regulatory modules: are there different modes of gene regulation in embryonic development and adult tissues?

    OpenAIRE

    Van Loo, Peter; Aerts, Stein; Thienpont, Bernard; De Moor, Bart; Moreau, Yves; Marynen, Peter

    2008-01-01

    We present ModuleMiner, a novel algorithm for computationally detecting cis-regulatory modules (CRMs) in a set of co-expressed genes. ModuleMiner outperforms other methods for CRM detection on benchmark data, and successfully detects CRMs in tissue-specific microarray clusters and in embryonic development gene sets. Interestingly, CRM predictions for differentiated tissues exhibit strong enrichment close to the transcription start site, whereas CRM predictions for embryonic development gene s...

  5. Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11

    DEFF Research Database (Denmark)

    Tzschach, Andreas; Bisgaard, Anne-Marie; Kirchhoff, Maria; Graul-Neumann, Luitgard M; Neitzel, Heidemarie; Page, Stephanie; Ahmed, Alischo; Müller, Ines; Erdogan, Fikret; Ropers, Hans-Hilger; Kalscheuer, Vera M; Ullmann, Reinhard

    2010-01-01

    Interstitial deletions of chromosome band 10q22 are rare. We report on the characterization of three overlapping de novo 10q22 deletions by high-resolution array comparative genomic hybridization in three unrelated patients. Patient 1 had a 7.9 Mb deletion in 10q21.3-q22.2 and suffered from severe...... feeding problems, facial dysmorphisms and profound mental retardation. Patients 2 and 3 had nearly identical deletions of 3.2 and 3.6 Mb, the proximal breakpoints of which were located at an identical low-copy repeat. Both patients were mentally retarded; patient 3 also suffered from growth retardation...... and hypotonia. We also report on the results of breakpoint analysis by array painting in a mentally retarded patient with a balanced chromosome translocation 46,XY,t(10;13)(q22;p13)dn. The breakpoint in 10q22 was found to disrupt C10orf11, a brain-expressed gene in the common deleted interval of...

  6. Nutritional control of gene expression in Drosophila larvae via TOR, Myc and a novel cis-regulatory element

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    Grewal Savraj S

    2010-01-01

    Full Text Available Abstract Background Nutrient availability is a key determinant of eukaryotic cell growth. In unicellular organisms many signaling and transcriptional networks link nutrient availability to the expression of metabolic genes required for growth. However, less is known about the corresponding mechanisms that operate in metazoans. We used gene expression profiling to explore this issue in developing Drosophila larvae. Results We found that starvation for dietary amino acids (AA's leads to dynamic changes in transcript levels of many metabolic genes. The conserved insulin/PI3K and TOR signaling pathways mediate nutrition-dependent growth in Drosophila and other animals. We found that many AA starvation-responsive transcripts were also altered in TOR mutants. In contrast, although PI3K overexpression induced robust changes in the expression of many metabolic genes, these changes showed limited overlap with the AA starvation expression profile. We did however identify a strong overlap between genes regulated by the transcription factor, Myc, and AA starvation-responsive genes, particularly those involved in ribosome biogenesis, protein synthesis and mitochondrial function. The consensus Myc DNA binding site is enriched in promoters of these AA starvation genes, and we found that Myc overexpression could bypass dietary AA to induce expression of these genes. We also identified another sequence motif (Motif 1 enriched in the promoters of AA starvation-responsive genes. We showed that Motif 1 was both necessary and sufficient to mediate transcriptional responses to dietary AA in larvae. Conclusions Our data suggest that many of the transcriptional effects of amino acids are mediated via signaling through the TOR pathway in Drosophila larvae. We also find that these transcriptional effects are mediated through at least two mechanisms: via the transcription factor Myc, and via the Motif 1 cis-regulatory element. These studies begin to elucidate a nutrient

  7. Decoding a signature-based model of transcription cofactor recruitment dictated by cardinal cis-regulatory elements in proximal promoter regions.

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    Christopher Benner

    2013-11-01

    Full Text Available Genome-wide maps of DNase I hypersensitive sites (DHSs reveal that most human promoters contain perpetually active cis-regulatory elements between -150 bp and +50 bp (-150/+50 bp relative to the transcription start site (TSS. Transcription factors (TFs recruit cofactors (chromatin remodelers, histone/protein-modifying enzymes, and scaffold proteins to these elements in order to organize the local chromatin structure and coordinate the balance of post-translational modifications nearby, contributing to the overall regulation of transcription. However, the rules of TF-mediated cofactor recruitment to the -150/+50 bp promoter regions remain poorly understood. Here, we provide evidence for a general model in which a series of cis-regulatory elements (here termed 'cardinal' motifs prefer acting individually, rather than in fixed combinations, within the -150/+50 bp regions to recruit TFs that dictate cofactor signatures distinctive of specific promoter subsets. Subsequently, human promoters can be subclassified based on the presence of cardinal elements and their associated cofactor signatures. In this study, furthermore, we have focused on promoters containing the nuclear respiratory factor 1 (NRF1 motif as the cardinal cis-regulatory element and have identified the pervasive association of NRF1 with the cofactor lysine-specific demethylase 1 (LSD1/KDM1A. This signature might be distinctive of promoters regulating nuclear-encoded mitochondrial and other particular genes in at least some cells. Together, we propose that decoding a signature-based, expanded model of control at proximal promoter regions should lead to a better understanding of coordinated regulation of gene transcription.

  8. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f

    OpenAIRE

    Roepke, Torsten K.; Kontogeorgis, Andrianos; Ovanez, Christopher; Xu, Xianghua; Young, Jeffrey B.; Purtell, Kerry; Goldstein, Peter A.; Christini, David J; Peters, Nicholas S.; Akar, Fadi G.; Gutstein, David E; Lerner, Daniel J.; Abbott, Geoffrey W.

    2008-01-01

    Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity....

  9. ‘In silico expression analysis’, a novel PathoPlant web tool to identify abiotic and biotic stress conditions associated with specific cis-regulatory sequences

    Science.gov (United States)

    Machens, Fabian; Brill, Yuri; Romanov, Artyom; Bülow, Lorenz; Hehl, Reinhard

    2014-01-01

    Using bioinformatics, putative cis-regulatory sequences can be easily identified using pattern recognition programs on promoters of specific gene sets. The abundance of predicted cis-sequences is a major challenge to associate these sequences with a possible function in gene expression regulation. To identify a possible function of the predicted cis-sequences, a novel web tool designated ‘in silico expression analysis’ was developed that correlates submitted cis-sequences with gene expression data from Arabidopsis thaliana. The web tool identifies the A. thaliana genes harbouring the sequence in a defined promoter region and compares the expression of these genes with microarray data. The result is a hierarchy of abiotic and biotic stress conditions to which these genes are most likely responsive. When testing the performance of the web tool, known cis-regulatory sequences were submitted to the ‘in silico expression analysis’ resulting in the correct identification of the associated stress conditions. When using a recently identified novel elicitor-responsive sequence, a WT-box (CGACTTTT), the ‘in silico expression analysis’ predicts that genes harbouring this sequence in their promoter are most likely Botrytis cinerea induced. Consistent with this prediction, the strongest induction of a reporter gene harbouring this sequence in the promoter is observed with B. cinerea in transgenic A. thaliana. Database URL: http://www.pathoplant.de/expression_analysis.php. PMID:24727366

  10. A cis-regulatory sequence from a short intergenic region gives rise to a strong microbe-associated molecular pattern-responsive synthetic promoter.

    Science.gov (United States)

    Lehmeyer, Mona; Hanko, Erik K R; Roling, Lena; Gonzalez, Lilian; Wehrs, Maren; Hehl, Reinhard

    2016-06-01

    The high gene density in Arabidopsis thaliana leaves only relatively short intergenic regions for potential cis-regulatory sequences. To learn more about the regulation of genes harbouring only very short upstream intergenic regions, this study investigates a recently identified novel microbe-associated molecular pattern (MAMP)-responsive cis-sequence located within the 101 bp long intergenic region upstream of the At1g13990 gene. It is shown that the cis-regulatory sequence is sufficient for MAMP-responsive reporter gene activity in the context of its native promoter. The 3' UTR of the upstream gene has a quantitative effect on gene expression. In context of a synthetic promoter, the cis-sequence is shown to achieve a strong increase in reporter gene activity as a monomer, dimer and tetramer. Mutation analysis of the cis-sequence determined the specific nucleotides required for gene expression activation. In transgenic A. thaliana the synthetic promoter harbouring a tetramer of the cis-sequence not only drives strong pathogen-responsive reporter gene expression but also shows a high background activity. The results of this study contribute to our understanding how genes with very short upstream intergenic regions are regulated and how these regions can serve as a source for MAMP-responsive cis-sequences for synthetic promoter design. PMID:26833485

  11. 'In silico expression analysis', a novel PathoPlant web tool to identify abiotic and biotic stress conditions associated with specific cis-regulatory sequences.

    Science.gov (United States)

    Bolívar, Julio C; Machens, Fabian; Brill, Yuri; Romanov, Artyom; Bülow, Lorenz; Hehl, Reinhard

    2014-01-01

    Using bioinformatics, putative cis-regulatory sequences can be easily identified using pattern recognition programs on promoters of specific gene sets. The abundance of predicted cis-sequences is a major challenge to associate these sequences with a possible function in gene expression regulation. To identify a possible function of the predicted cis-sequences, a novel web tool designated 'in silico expression analysis' was developed that correlates submitted cis-sequences with gene expression data from Arabidopsis thaliana. The web tool identifies the A. thaliana genes harbouring the sequence in a defined promoter region and compares the expression of these genes with microarray data. The result is a hierarchy of abiotic and biotic stress conditions to which these genes are most likely responsive. When testing the performance of the web tool, known cis-regulatory sequences were submitted to the 'in silico expression analysis' resulting in the correct identification of the associated stress conditions. When using a recently identified novel elicitor-responsive sequence, a WT-box (CGACTTTT), the 'in silico expression analysis' predicts that genes harbouring this sequence in their promoter are most likely Botrytis cinerea induced. Consistent with this prediction, the strongest induction of a reporter gene harbouring this sequence in the promoter is observed with B. cinerea in transgenic A. thaliana. DATABASE URL: http://www.pathoplant.de/expression_analysis.php. PMID:24727366

  12. Deletion of the transcriptional regulator opi1p decreases cardiolipin content and disrupts mitochondrial metabolism in Saccharomyces cerevisiae.

    Science.gov (United States)

    Luévano-Martínez, Luis Alberto; Appolinario, Patricia; Miyamoto, Sayuri; Uribe-Carvajal, Salvador; Kowaltowski, Alicia J

    2013-11-01

    Cardiolipin, the main anionic phospholipid in the inner mitochondrial membrane, provides shape, charge and osmotic support to this membrane due to its biophysical properties. In addition, it helps form respiratory supercomplexes and provides functionality to mitochondrial proteins. Defects in the biosynthesis or remodeling of cardiolipin have been related to severe diseases, such as Barth syndrome. Opi1p, a transcriptional repressor for most enzymes in phospholipid biosynthesis found in Saccharomyces cerevisiae, has been demonstrated not to affect the biosynthesis of this mitochondrial phospholipid. However, we found that opi1 deletion compromises mitochondrial metabolism producing severe respiratory defects. The mechanism producing this phenotype was explored and found to be a mitochondrial cardiolipin depletion of almost 50%, resulting in low cytochrome content and high mitochondrial DNA instability. The origin of this low cardiolipin content strongly correlated with the overproduction of inositol, an intrinsic phenotype of this mutation. Overall, our results show that adequate regulation of phospholipid synthesis is essential for the maintenance of mitochondrial function. PMID:23578934

  13. Cis-regulatory control of the nuclear receptor Coup-TF gene in the sea urchin Paracentrotus lividus embryo.

    Directory of Open Access Journals (Sweden)

    Lamprini G Kalampoki

    Full Text Available Coup-TF, an orphan member of the nuclear receptor super family, has a fundamental role in the development of metazoan embryos. The study of the gene's regulatory circuit in the sea urchin embryo will facilitate the placement of this transcription factor in the well-studied embryonic Gene Regulatory Network (GRN. The Paracentrotus lividus Coup-TF gene (PlCoup-TF is expressed throughout embryonic development preferentially in the oral ectoderm of the gastrula and the ciliary band of the pluteus stage. Two overlapping λ genomic clones, containing three exons and upstream sequences of PlCoup-TF, were isolated from a genomic library. The transcription initiation site was determined and 5' deletions and individual segments of a 1930 bp upstream region were placed ahead of a GFP reporter cassette and injected into fertilized P.lividus eggs. Module a (-532 to -232, was necessary and sufficient to confer ciliary band expression to the reporter. Comparison of P.lividus and Strongylocentrotus purpuratus upstream Coup-TF sequences, revealed considerable conservation, but none within module a. 5' and internal deletions into module a, defined a smaller region that confers ciliary band specific expression. Putative regulatory cis-acting elements (RE1, RE2 and RE3 within module a, were specifically bound by proteins in sea urchin embryonic nuclear extracts. Site-specific mutagenesis of these elements resulted in loss of reporter activity (RE1 or ectopic expression (RE2, RE3. It is proposed that sea urchin transcription factors, which bind these three regulatory sites, are necessary for spatial and quantitative regulation of the PlCoup-TF gene at pluteus stage sea urchin embryos. These findings lead to the future identification of these factors and to the hierarchical positioning of PlCoup-TF within the embryonic GRN.

  14. Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS

    DEFF Research Database (Denmark)

    Farooq, Muhammad; Troelsen, Jesper T; Boyd, Mette;

    2010-01-01

    A cis-regulatory sequence also known as zone of polarizing activity (ZPA) regulatory sequence (ZRS) located in intron 5 of LMBR1 is essential for expression of sonic hedgehog (SHH) in the developing posterior limb bud mesenchyme. Even though many point mutations causing preaxial duplication defects...

  15. In planta analysis of a cis-regulatory cytokinin response motif in Arabidopsis and identification of a novel enhancer sequence.

    Science.gov (United States)

    Ramireddy, Eswarayya; Brenner, Wolfram G; Pfeifer, Andreas; Heyl, Alexander; Schmülling, Thomas

    2013-07-01

    The phytohormone cytokinin plays a key role in regulating plant growth and development, and is involved in numerous physiological responses to environmental changes. The type-B response regulators, which regulate the transcription of cytokinin response genes, are a part of the cytokinin signaling system. Arabidopsis thaliana encodes 11 type-B response regulators (type-B ARRs), and some of them were shown to bind in vitro to the core cytokinin response motif (CRM) 5'-(A/G)GAT(T/C)-3' or, in the case of ARR1, to an extended motif (ECRM), 5'-AAGAT(T/C)TT-3'. Here we obtained in planta proof for the functionality of the latter motif. Promoter deletion analysis of the primary cytokinin response gene ARR6 showed that a combination of two extended motifs within the promoter is required to mediate the full transcriptional activation by ARR1 and other type-B ARRs. CRMs were found to be over-represented in the vicinity of ECRMs in the promoters of cytokinin-regulated genes, suggesting their functional relevance. Moreover, an evolutionarily conserved 27 bp long T-rich region between -220 and -193 bp was identified and shown to be required for the full activation by type-B ARRs and the response to cytokinin. This novel enhancer is not bound by the DNA-binding domain of ARR1, indicating that additional proteins might be involved in mediating the transcriptional cytokinin response. Furthermore, genome-wide expression profiling identified genes, among them ARR16, whose induction by cytokinin depends on both ARR1 and other specific type-B ARRs. This together with the ECRM/CRM sequence clustering indicates cooperative action of different type-B ARRs for the activation of particular target genes. PMID:23620480

  16. Distinct cis regulatory elements govern the expression of TAG1 in embryonic sensory ganglia and spinal cord.

    Directory of Open Access Journals (Sweden)

    Yoav Hadas

    Full Text Available Cell fate commitment of spinal progenitor neurons is initiated by long-range, midline-derived, morphogens that regulate an array of transcription factors that, in turn, act sequentially or in parallel to control neuronal differentiation. Included among these are transcription factors that regulate the expression of receptors for guidance cues, thereby determining axonal trajectories. The Ig/FNIII superfamily molecules TAG1/Axonin1/CNTN2 (TAG1 and Neurofascin (Nfasc are co-expressed in numerous neuronal cell types in the CNS and PNS - for example motor, DRG and interneurons - both promote neurite outgrowth and both are required for the architecture and function of nodes of Ranvier. The genes encoding TAG1 and Nfasc are adjacent in the genome, an arrangement which is evolutionarily conserved. To study the transcriptional network that governs TAG1 and Nfasc expression in spinal motor and commissural neurons, we set out to identify cis elements that regulate their expression. Two evolutionarily conserved DNA modules, one located between the Nfasc and TAG1 genes and the second directly 5' to the first exon and encompassing the first intron of TAG1, were identified that direct complementary expression to the CNS and PNS, respectively, of the embryonic hindbrain and spinal cord. Sequential deletions and point mutations of the CNS enhancer element revealed a 130bp element containing three conserved E-boxes required for motor neuron expression. In combination, these two elements appear to recapitulate a major part of the pattern of TAG1 expression in the embryonic nervous system.

  17. PP2C-like Promoter and Its Deletion Variants Are Induced by ABA but Not by MeJA and SA in Arabidopsis thaliana

    Science.gov (United States)

    Bhalothia, Purva; Sangwan, Chetna; Alok, Anshu; Mehrotra, Sandhya; Mehrotra, Rajesh

    2016-01-01

    Gene expression is mediated through interaction between cis regulatory elements and its cognate transcription factors. Cis regulatory elements are defined as non-coding DNA sequences that provide the binding sites for transcription factors and are clustered in the upstream region of genes. ACGT cis regulatory element is one of the important cis regulatory elements found to be involved in diverse biological processes like auxin response, salicylic acid (SA) response, UV light response, ABA response and jasmonic acid (JA) response. We identified through in silico analysis that the upstream region of protein phosphatase 2C (PP2C) gene has a distinct genetic architecture of ACGT elements. In the present study, the activation of the full length promoter and its deletion constructs like 900 base pair, 500 base pair, 400 base pair and NRM (Nathji Rajesh Mehrotra) were examined by stable transformation in Arabidopsis thaliana using β-glucuronidase as the reporter gene. Evaluation of deletion constructs of PP2C-like promoter was carried out in the presence of phytohormones like abscisic acid (ABA), SA and JA. Our result indicated that the full length and 900 base pair promoter-reporter constructs of PP2C-like promoter was induced in response to ABA but not to methyl jasmonate and SA. PMID:27200023

  18. Cis-Regulatory Elements Determine Germline Specificity and Expression Level of an Isopentenyltransferase Gene in Sperm Cells of Arabidopsis.

    Science.gov (United States)

    Zhang, Jinghua; Yuan, Tong; Duan, Xiaomeng; Wei, Xiaoping; Shi, Tao; Li, Jia; Russell, Scott D; Gou, Xiaoping

    2016-03-01

    Flowering plant sperm cells transcribe a divergent and complex complement of genes. To examine promoter function, we chose an isopentenyltransferase gene known as PzIPT1. This gene is highly selectively transcribed in one sperm cell morphotype of Plumbago zeylanica, which preferentially fuses with the central cell during fertilization and is thus a founding cell of the primary endosperm. In transgenic Arabidopsis (Arabidopsis thaliana), PzIPT1 promoter displays activity in both sperm cells and upon progressive promoter truncation from the 5'-end results in a progressive decrease in reporter production, consistent with occurrence of multiple enhancer sites. Cytokinin-dependent protein binding motifs are identified in the promoter sequence, which respond with stimulation by cytokinin. Expression of PzIPT1 promoter in sperm cells confers specificity independently of previously reported Germline Restrictive Silencer Factor binding sequence. Instead, a cis-acting regulatory region consisting of two duplicated 6-bp Male Gamete Selective Activation (MGSA) motifs occurs near the site of transcription initiation. Disruption of this sequence-specific site inactivates expression of a GFP reporter gene in sperm cells. Multiple copies of the MGSA motif fused with the minimal CaMV35S promoter elements confer reporter gene expression in sperm cells. Similar duplicated MGSA motifs are also identified from promoter sequences of sperm cell-expressed genes in Arabidopsis, suggesting selective activation is possibly a common mechanism for regulation of gene expression in sperm cells of flowering plants. PMID:26739233

  19. Maps of cis-Regulatory Nodes in Megabase Long Genome Segments are an Inevitable Intermediate Step Toward Whole Genome Functional Mapping.

    Science.gov (United States)

    Nikolaev, Lev G; Akopov, Sergey B; Chernov, Igor P; Sverdlov, Eugene D

    2007-04-01

    The availability of complete human and other metazoan genome sequences has greatly facilitated positioning and analysis of various genomic functional elements, with initial emphasis on coding sequences. However, complete functional maps of sequenced eukaryotic genomes should include also positions of all non-coding regulatory elements. Unfortunately, experimental data on genomic positions of a multitude of regulatory sequences, such as enhancers, silencers, insulators, transcription terminators, and replication origins are very limited, especially at the whole genome level. Since most genomic regulatory elements (e.g. enhancers) are generally gene-, tissue-, or cell-specific, the prediction of these elements by computational methods is difficult and often ambiguous. Therefore, the development of high-throughput experimental approaches for identifying and mapping genomic functional elements is highly desirable. At the same time, the creation of whole-genome map of hundreds of thousands of regulatory elements in several hundreds of tissue/cell types is presently far beyond our capabilities. A possible alternative for the whole genome approach is to concentrate efforts on individual genomic segments and then to integrate the data obtained into a whole genome functional map. Moreover, the maps of polygenic fragments with functional cis-regulatory elements would provide valuable data on complex regulatory systems, including their variability and evolution. Here, we reviewed experimental approaches to the realization of these ideas, including our own developments of experimental techniques for selection of cis-acting functionally active DNA fragments from large (megabase-sized) segments of mammalian genomes. PMID:18660850

  20. Maps of cis-Regulatory Nodes in Megabase Long Genome Segments are an Inevitable Intermediate Step Toward Whole Genome Functional Mapping

    Science.gov (United States)

    Nikolaev, Lev G; Akopov, Sergey B; Chernov, Igor P; Sverdlov, Eugene D

    2007-01-01

    The availability of complete human and other metazoan genome sequences has greatly facilitated positioning and analysis of various genomic functional elements, with initial emphasis on coding sequences. However, complete functional maps of sequenced eukaryotic genomes should include also positions of all non-coding regulatory elements. Unfortunately, experimental data on genomic positions of a multitude of regulatory sequences, such as enhancers, silencers, insulators, transcription terminators, and replication origins are very limited, especially at the whole genome level. Since most genomic regulatory elements (e.g. enhancers) are generally gene-, tissue-, or cell-specific, the prediction of these elements by computational methods is difficult and often ambiguous. Therefore, the development of high-throughput experimental approaches for identifying and mapping genomic functional elements is highly desirable. At the same time, the creation of whole-genome map of hundreds of thousands of regulatory elements in several hundreds of tissue/cell types is presently far beyond our capabilities. A possible alternative for the whole genome approach is to concentrate efforts on individual genomic segments and then to integrate the data obtained into a whole genome functional map. Moreover, the maps of polygenic fragments with functional cis-regulatory elements would provide valuable data on complex regulatory systems, including their variability and evolution. Here, we reviewed experimental approaches to the realization of these ideas, including our own developments of experimental techniques for selection of cis-acting functionally active DNA fragments from large (megabase-sized) segments of mammalian genomes. PMID:18660850

  1. A Hox Transcription Factor Collective Binds a Highly Conserved Distal-less cis-Regulatory Module to Generate Robust Transcriptional Outcomes.

    Science.gov (United States)

    Uhl, Juli D; Zandvakili, Arya; Gebelein, Brian

    2016-04-01

    cis-regulatory modules (CRMs) generate precise expression patterns by integrating numerous transcription factors (TFs). Surprisingly, CRMs that control essential gene patterns can differ greatly in conservation, suggesting distinct constraints on TF binding sites. Here, we show that a highly conserved Distal-less regulatory element (DCRE) that controls gene expression in leg precursor cells recruits multiple Hox, Extradenticle (Exd) and Homothorax (Hth) complexes to mediate dual outputs: thoracic activation and abdominal repression. Using reporter assays, we found that abdominal repression is particularly robust, as neither individual binding site mutations nor a DNA binding deficient Hth protein abolished cooperative DNA binding and in vivo repression. Moreover, a re-engineered DCRE containing a distinct configuration of Hox, Exd, and Hth sites also mediated abdominal Hox repression. However, the re-engineered DCRE failed to perform additional segment-specific functions such as thoracic activation. These findings are consistent with two emerging concepts in gene regulation: First, the abdominal Hox/Exd/Hth factors utilize protein-protein and protein-DNA interactions to form repression complexes on flexible combinations of sites, consistent with the TF collective model of CRM organization. Second, the conserved DCRE mediates multiple cell-type specific outputs, consistent with recent findings that pleiotropic CRMs are associated with conserved TF binding and added evolutionary constraints. PMID:27058369

  2. Combining computational prediction of cis-regulatory elements with a new enhancer assay to efficiently label neuronal structures in the medaka fish.

    Directory of Open Access Journals (Sweden)

    Emmanuel Mongin

    Full Text Available The developing vertebrate nervous system contains a remarkable array of neural cells organized into complex, evolutionarily conserved structures. The labeling of living cells in these structures is key for the understanding of brain development and function, yet the generation of stable lines expressing reporter genes in specific spatio-temporal patterns remains a limiting step. In this study we present a fast and reliable pipeline to efficiently generate a set of stable lines expressing a reporter gene in multiple neuronal structures in the developing nervous system in medaka. The pipeline combines both the accurate computational genome-wide prediction of neuronal specific cis-regulatory modules (CRMs and a newly developed experimental setup to rapidly obtain transgenic lines in a cost-effective and highly reproducible manner. 95% of the CRMs tested in our experimental setup show enhancer activity in various and numerous neuronal structures belonging to all major brain subdivisions. This pipeline represents a significant step towards the dissection of embryonic neuronal development in vertebrates.

  3. PlantPAN: Plant promoter analysis navigator, for identifying combinatorial cis-regulatory elements with distance constraint in plant gene groups

    Directory of Open Access Journals (Sweden)

    Huang Hsien-Da

    2008-11-01

    Full Text Available Abstract Background The elucidation of transcriptional regulation in plant genes is important area of research for plant scientists, following the mapping of various plant genomes, such as A. thaliana, O. sativa and Z. mays. A variety of bioinformatic servers or databases of plant promoters have been established, although most have been focused only on annotating transcription factor binding sites in a single gene and have neglected some important regulatory elements (tandem repeats and CpG/CpNpG islands in promoter regions. Additionally, the combinatorial interaction of transcription factors (TFs is important in regulating the gene group that is associated with the same expression pattern. Therefore, a tool for detecting the co-regulation of transcription factors in a group of gene promoters is required. Results This study develops a database-assisted system, PlantPAN (Plant Promoter Analysis Navigator, for recognizing combinatorial cis-regulatory elements with a distance constraint in sets of plant genes. The system collects the plant transcription factor binding profiles from PLACE, TRANSFAC (public release 7.0, AGRIS, and JASPER databases and allows users to input a group of gene IDs or promoter sequences, enabling the co-occurrence of combinatorial transcription factor binding sites (TFBSs within a defined distance (20 bp to 200 bp to be identified. Furthermore, the new resource enables other regulatory features in a plant promoter, such as CpG/CpNpG islands and tandem repeats, to be displayed. The regulatory elements in the conserved regions of the promoters across homologous genes are detected and presented. Conclusion In addition to providing a user-friendly input/output interface, PlantPAN has numerous advantages in the analysis of a plant promoter. Several case studies have established the effectiveness of PlantPAN. This novel analytical resource is now freely available at http://PlantPAN.mbc.nctu.edu.tw.

  4. Specific deletion of Cdc42 does not affect meiotic spindle organization/migration and homologous chromosome segregation but disrupts polarity establishment and cytokinesis in mouse oocytes

    DEFF Research Database (Denmark)

    Wang, Zhen-Bo; Jiang, Zong-Zhe; Zhang, Qing-Hua;

    2013-01-01

    female infertility in mice. Cdc42 deletion has little effect on meiotic spindle organization and migration to the cortex but inhibits polar body emission, although homologous chromosome segregation occurs. The failure of cytokinesis is due to the loss of polarized Arp2/3 accumulation and actin cap...... polarized actin cap and oocyte polarity, and it determines asymmetric divisions resulting in two polar bodies. Here we investigate the functions of Cdc42 in oocyte meiotic maturation by oocyte-specific deletion of Cdc42 through Cre-loxP conditional knockout technology. We find that Cdc42 deletion causes...

  5. Treatment with Sodium Orthovanadate Reduces Blood-Brain Barrier Disruption via Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Phosphorylation in Experimental Subarachnoid Hemorrhage

    OpenAIRE

    Hasegawa, Yu; Suzuki, Hidenori; Altay, Orhan; Chen, Hank; Zhang, John H.

    2011-01-01

    Attenuation of blood-brain barrier (BBB) disruption is one of the therapeutic candidates for treatment of subarachnoid hemorrhage (SAH). In this study, the protective effect of sodium orthovanadate (SOV) on BBB disruption was investigated in SAH using the endovascular perforation model. Fifty-five rats were randomly assigned to sham-operated, SAH treated with saline (as a vehicle) or 10mg/kg SOV groups, and evaluated for neurofunction and Evans blue dye extravasation. The phosphorylation of p...

  6. Disruption of O-GlcNAc cycling by deletion of O-GlcNAcase (Oga/Mgea5 changed gene expression pattern in mouse embryonic fibroblast (MEF cells

    Directory of Open Access Journals (Sweden)

    Chithra Keembiyehetty

    2015-09-01

    Full Text Available Adding a single O-GlcNAc moiety to a Ser/Thr molecule of a protein by O-GlcNAc transferase and transiently removing it by O-GlcNAcase is referred to as O-GlcNAc cycling (or O-GlcNAcylation. This O-GlcNAc modification is sensitive to nutrient availability and also shows cross talk with phosphorylation signaling, affecting downstream targets. A mouse model system was developed and evaluated to show genome wide transcriptional changes associated with disruption of O-GlcNAc cycling. Mouse embryonic fibroblast cells derived from O-GlcNAcase (Oga knock out (KO, heterozygous (Het and wild type (WT embryos were used for an Affymetrix based microarray. Results are deposited in GEO dataset GSE52721. Data reveals that Oga KO MEFs had 2534 transcripts differentially expressed at 1.5 fold level while Oga heterozygous MEFs had 959 transcripts changed compared to WT MEFs. There were 1835 transcripts differentially expressed at 1.5 fold Het versus WT comparison group. Gene ontology analysis indicated differentially expressed genes enriched in metabolic, growth, and cell proliferation categories.

  7. Disruption of the ProSAP2 Gene in a t(12;22)(q24.1;q13.3) Is Associated with the 22q13.3 Deletion Syndrome

    OpenAIRE

    Bonaglia, Maria Clara; Giorda, Roberto; Borgatti, Renato; Felisari, Giorgio; Gagliardi, Chiara; Selicorni, Angelo; Zuffardi, Orsetta

    2001-01-01

    The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigation...

  8. PP2C-like Promoter and Its Deletion Variants Are Induced by ABA but Not by MeJA and SA in Arabidopsis thaliana

    OpenAIRE

    Bhalothia, Purva; Sangwan, Chetna; Alok, Anshu; Mehrotra, Sandhya; Mehrotra, Rajesh

    2016-01-01

    Gene expression is mediated through interaction between cis regulatory elements and its cognate transcription factors. Cis regulatory elements are defined as non-coding DNA sequences that provide the binding sites for transcription factors and are clustered in the upstream region of genes. ACGT cis regulatory element is one of the important cis regulatory elements found to be involved in diverse biological processes like auxin response, salicylic acid (SA) response, UV light response, ABA res...

  9. Partial deletion 11q

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Tommerup, N; Sørensen, F B;

    1995-01-01

    We describe the cytogenetic findings and the dysmorphic features in a stillborn girl with a large de novo terminal deletion of the long arm of chromosome 11. The karyotype was 46,XX,del(11)(q21qter). By reviewing previous reports of deletion 11q, we found that cleft lip and palate are most...... frequently seen in proximal 11q deletions involving 11q21. Telomeric staining using the PRINS technique demonstrated normal telomeric sequences in the deleted chromosome 11....

  10. Identification of an Alu-repeat-mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype.

    Science.gov (United States)

    Schilter, Kala F; Reis, Linda M; Sorokina, Elena A; Semina, Elena V

    2015-11-01

    Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole-exome sequencing (WES) and whole-genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37-bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled-coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult-onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis-regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss-of-function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu-mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu-mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role

  11. Family Disruptions

    Science.gov (United States)

    ... Spread the Word Shop AAP Find a Pediatrician Family Life Medical Home Family Dynamics Adoption & Foster Care ... Life Listen Español Text Size Email Print Share Family Disruptions Page Content Article Body No matter how ...

  12. 3p deletion syndrome.

    Science.gov (United States)

    Kaur, Anupam; Khetarpal, S

    2013-08-01

    3p deletion is a rare cytogenetic finding. Here we describe a 3 months old male with congenital malformations. His karyotype revealed 3p deletion 46,XY,del(3)(p25-pter). The child had flexion deformity of wrist and elbow which has never been reported before. PMID:24036645

  13. Deletion mutations of bacteriophage

    International Nuclear Information System (INIS)

    Resolution of mutation mechanism with structural changes of DNA was discussed through the studies using bacteriophage lambda. One of deletion mutations inductions of phage lambda is the irradiation of ultraviolet ray. It is not clear if the inductions are caused by errors in reparation of ultraviolet-induced damage or by the activation of int gene. Because the effective site of int gene lies within the regions unnecessary for existing, it is considered that int gene is connected to deletion mutations induction. A certain system using prophage complementarity enables to detect deletion mutations at essential hereditary sites and to solve the relations of deletion mutations with other recombination system, DNA reproduction and repairment system. Duplication and multiplication of hereditary elements were discussed. If lambda deletion mutations of the system, which can control recombination, reproduction and repairment of added DNA, are constructed, mutations mechanism with great changes of DNA structure can be solved by phage lambda. (Ichikawa, K.)

  14. Improved gene disruption method for Torulaspora delbrueckii.

    Science.gov (United States)

    Pacheco, Andreia; Almeida, Maria Judite; Sousa, Maria João

    2009-02-01

    PCR-based disruption cassettes are one of the most commonly used strategies for gene targeting in Saccharomyces cerevisiae. The efficiencies of gene disruption using this conventional method are highly variable among species, and often quite low with nonconventional yeasts. Here we describe an improved strategy to obtain deletion mutants in baker's yeast Torulaspora delbrueckii, one of the most abundant non-Saccharomyces species, present in home-made corn and rye bread dough. PMID:19016885

  15. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  16. Quantum deletion: Beyond the no-deletion principle

    International Nuclear Information System (INIS)

    Suppose we are given two identical copies of an unknown quantum state and we wish to delete one copy from among the given two copies. The quantum no-deletion principle restricts us from perfectly deleting a copy but it does not prohibit us from deleting a copy approximately. Here we construct two types of a 'universal quantum deletion machine' which approximately deletes a copy such that the fidelity of deletion does not depend on the input state. The two types of universal quantum deletion machines are (1) a conventional deletion machine described by one unitary operator and (2) a modified deletion machine described by two unitary operators. Here it is shown that the modified deletion machine deletes a qubit with fidelity 3/4, which is the maximum limit for deleting an unknown quantum state. In addition to this we also show that the modified deletion machine retains the qubit in the first mode with average fidelity 0.77 (approx.) which is slightly greater than the fidelity of measurement for two given identical states, showing how precisely one can determine its state [S. Massar and S. Popescu, Phys. Rev. Lett. 74, 1259 (1995)]. We also show that the deletion machine itself is input state independent, i.e., the information is not hidden in the deleting machine, and hence we can delete the information completely from the deletion machine

  17. Disrupted Disclosure

    DEFF Research Database (Denmark)

    Krause Hansen, Hans; Uldam, Julie

    While projects of governance by transparency have become widespread over the past decades, theyare usually investigated and theorized in isolation from the wider field of visibility and surveillancein which they are embedded. Building on theories of governance, visibility and surveillance...... appearances become challenged through disruptive disclosures in mediaenvironments characterized by multiple levels of visibility, with companies both observing andbeing observed by civil society groups that criticize them; (c) why and how the mobilization aroundtransparency and ensuing practices...

  18. Patterns of cis regulatory variation in diverse human populations.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    Full Text Available The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.

  19. Deciphering cis-regulatory control in inflammatory cells

    OpenAIRE

    Ghisletti, Serena; Natoli, Gioacchino

    2013-01-01

    In innate immune system cells, such as macrophages and dendritic cells, deployment of inducible gene expression programmes in response to microbes and danger signals requires highly precise regulatory mechanisms. The inflammatory response has to be tailored based on both the triggering stimulus and its dose, and it has to be unfolded in a kinetically complex manner that suits the different phases of the inflammatory process. Genomic characterization of regulatory elements in this context indi...

  20. Computational methods to dissect cis-regulatory transcriptional networks

    Indian Academy of Sciences (India)

    Vibha Rani

    2007-12-01

    The formation of diverse cell types from an invariant set of genes is governed by biochemical and molecular processes that regulate gene activity. A complete understanding of the regulatory mechanisms of gene expression is the major function of genomics. Computational genomics is a rapidly emerging area for deciphering the regulation of metazoan genes as well as interpreting the results of high-throughput screening. The integration of computer science with biology has expedited molecular modelling and processing of large-scale data inputs such as microarrays, analysis of genomes, transcriptomes and proteomes. Many bioinformaticians have developed various algorithms for predicting transcriptional regulatory mechanisms from the sequence, gene expression and interaction data. This review contains compiled information of various computational methods adopted to dissect gene expression pathways.

  1. Hunting for Cis-Regulatory Elements in Proteins.

    Science.gov (United States)

    Gibson, Toby J; Kumar, Manjeet

    2016-02-24

    A new bioinformatics tool predicts natively disordered protein control elements that function in cis, opening the door to more systematic studies of this biomedically important class of protein modules. PMID:27135160

  2. Edit Distance with Block Deletions

    OpenAIRE

    Dana Shapira; Storer, James A.

    2011-01-01

    Several variants of the edit distance problem with block deletions are considered. Polynomial time optimal algorithms are presented for the edit distance with block deletions allowing character insertions and character moves, but without block moves. We show that the edit distance with block moves and block deletions is NP-complete (Nondeterministic Polynomial time problems in which any given solution to such problem can be verified in polynomial time, and any NP problem can be converted into...

  3. Deletion analysis of spinal muscular atrophy in southern Indian population

    Directory of Open Access Journals (Sweden)

    Swaminathan Bhairavi

    2008-01-01

    Full Text Available Background: Proximal spinal muscular atrophy (SMA is a genetically heterogeneous disease with paresis and muscle atrophy due to loss of anterior horn cell function. The survival of motor neuron gene (SMN and neuronal apoptosis inhibitory protein (NAIP play a primary role. Both the gene homologues exist as inverted duplications on Chromosome 5q. The telomeric/functional (SMN1 and the centromeric (SMN2 copies differ from each other in eight nucleotides. The C→T transition (at Codon 280 within Exon 7 of SMN2 causes disruption of an exonic splicing enhancer (ESE and/or creates an exonic splicing silencer (ESS leading to abnormal splicing and a truncated protein. Objective: To determine the molecular genetics of SMN1 and NAIP genes in SMA from southern India. Materials and Methods: In the present study, 37 patients from the neuromuscular disorders clinic of National Institute of Mental Health and Neurosciences were assayed for the deletions in the SMN1 and NAIP genes using PCR-RFLP methods. Results: Among the SMA Type I patients, 43% showed deletions of SMN1 and NAIP. In patients Type II SMA, 57% showed deletions of the SMN1 exons. Conclusion: Thus, deletions were found to occur in 47.8% of the Type I and II patients. Lower sensitivity of gene deletion study in clinically suspected SMA needs further study as clinical diagnosis of SMA is not gold standard. However, the results do correlate with other studies conducted in India.

  4. ATLAS DQ2 DELETION SERVICE

    CERN Document Server

    Oleynik, D; The ATLAS collaboration; Garonne, V; Campana, S

    2012-01-01

    ATLAS DQ2 Deletion service is a sub system of the ATLAS Distributed Data Management (DDM) project DQ2. DDM DQ2 responsible for the replication, access and bookkeeping of ATLAS data across more than 130 distributed grid sites. It also enforces data management policies decided on by the collaboration and defined in the ATLAS computing model. Responsibility of ATLAS DQ2 Deletion service is serving deletion requests on the grid by interacting with grid middleware and the DQ2 catalogues. Furthermore, it also takes care of retry strategies, check-pointing transactions, load management and fault tolerance. In this talk special attention is paid to the technical details, which are used to achieve the high performance of service, accomplished without overloading either site storage, catalogues or other DQ2 components. Also specialty of database backend implementation will be described. Special section will be devote to the deletion monitoring service that allows operators a detailed view of the working system.

  5. ATLAS DQ2 Deletion Service

    CERN Document Server

    OLEYNIK, D; The ATLAS collaboration; GARONNE, V; CAMPANA, S

    2012-01-01

    The ATLAS Distributed Data Management project DQ2 is responsible for the replication, access and bookkeeping of ATLAS data across more than 100 distributed grid sites. It also enforces data management policies decided on by the collaboration and defined in the ATLAS computing model. The DQ2 deletion service is one of the most important DDM services. This distributed service interacts with 3rd party grid middleware and the DQ2 catalogs to serve data deletion requests on the grid. Furthermore, it also takes care of retry strategies, check-pointing transactions, load management and fault tolerance. In this paper special attention is paid to the technical details which are used to achieve the high performance of service (peaking at more than 4 millions files deleted per day), accomplished without overloading either site storage, catalogs or other DQ2 components. Special attention is also paid to the deletion monitoring service that allows operators a detailed view of the working system.

  6. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities

    OpenAIRE

    Hodge, Jennelle C.; Mitchell, Elyse; Pillalamarri, Vamsee; Toler, Tomi L.; Bartel, Frank; Hutton M Kearney; Zou, Ying S; Tan, Wen-Hann; Hanscom, Carrie; Kirmani, Salman; Hanson, Rae R.; Skinner, Steven A.; Rogers, Curtis; Everman, David B.; Boyd, Ellen

    2013-01-01

    Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 contribute to a spectrum of neurodevelopmental phenotypes, however the impact of this locus in human psychopathology has not been described. To characterize the structural variation landscape of MBD5 disruptions and the associated psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation, and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diag...

  7. Effects of crp deletion in Salmonella enterica serotype Gallinarum

    Directory of Open Access Journals (Sweden)

    Rubino Salvatore

    2007-05-01

    Full Text Available Abstract Background Salmonella enterica serotype Gallinarum (S. Gallinarum remains an important pathogen of poultry, especially in developing countries. There is a need to develop effective and safe vaccines. In the current study, the effect of crp deletion was investigated with respect to virulence and biochemical properties and the possible use of a deletion mutant as vaccine candidate was preliminarily tested. Methods Mutants were constructed in S. Gallinarum by P22 transduction from Salmonella Typhimurium (S. Typhimurium with deletion of the crp gene. The effect was characterized by measuring biochemical properties and by testing of invasion in a chicken loop model and by challenge of six-day-old chickens. Further, birds were immunized with the deleted strain and challenged with the wild type isolate. Results The crp deletions caused complete attenuation of S. Gallinarum. This was shown by ileal loop experiments not to be due to significantly reduced invasion. Strains with such deletions may have vaccine potential, since oral inoculatoin with S. Gallinarum Δcrp completely protected against challenge with the same dose of wild type S. Gallinarum ten days post immunization. Interestingly, the mutations did not cause the same biochemical and growth changes to the two biotypes of S. Gallinarum. All biochemical effects but not virulence could be complemented by providing an intact crp-gene from S. Typhimurium on the plasmid pSD110. Conclusion Transduction of a Tn10 disrupted crp gene from S. Typhimurium caused attenuation in S. Gallinarum and mutated strains are possible candidates for live vaccines against fowl typhoid.

  8. Oncolytic Replication of E1b-Deleted Adenoviruses

    Directory of Open Access Journals (Sweden)

    Pei-Hsin Cheng

    2015-11-01

    Full Text Available Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viralmRNAexport, and cell cycle disruption.

  9. ATLAS DQ2 Deletion Service

    CERN Document Server

    OLEYNIK, D; The ATLAS collaboration; GARONNE, V; CAMPANA, S

    2012-01-01

    The ATLAS Distributed Data Management project DQ2 is responsible for the replication, access and bookkeeping of ATLAS data across more than 100 distributed grid sites. It also enforces data management policies decided on by the collaboration and defined in the ATLAS computing model. The DQ2 Deletion Service is one of the most important DDM services. This distributed service interacts with 3rd party grid middleware and the DQ2 catalogues to serve data deletion requests on the grid. Furthermore, it also takes care of retry strategies, check-pointing transactions, load management and fault tolerance. In this paper special attention is paid to the technical details which are used to achieve the high performance of service, accomplished without overloading either site storage, catalogues or other DQ2 components. Special attention is also paid to the deletion monitoring service that allows operators a detailed view of the working system.

  10. Understanding disruptions in tokamaks

    International Nuclear Information System (INIS)

    This paper describes progress achieved since 2007 in understanding disruptions in tokamaks, when the effect of plasma current sharing with the wall was introduced into theory. As a result, the toroidal asymmetry of the plasma current measurements during vertical disruption event (VDE) on the Joint European Torus was explained. A new kind of plasma equilibria and mode coupling was introduced into theory, which can explain the duration of the external kink 1/1 mode during VDE. The paper presents first results of numerical simulations using a free boundary plasma model, relevant to disruptions.

  11. Disrupting Vestibular Activity Disrupts Body Ownership.

    Science.gov (United States)

    Hoover, Adria E N; Harris, Laurence R

    2015-01-01

    People are more sensitive at detecting asynchrony between a self-generated movement and visual feedback concerning that movement when the movement is viewed from a first-person perspective. We call this the 'self-advantage' and interpret it as an objective measure of self. Here we ask if disruption of the vestibular system in healthy individuals affects the self-advantage. Participants performed finger movements while viewing their hand in a first-person ('self') or third-person ('other') perspective and indicated which of two periods (one with minimum delay and the other with an added delay of 33-264 ms) was delayed. Their sensitivity to the delay was calculated from the psychometric functions obtained. During the testing, disruptive galvanic vestibular stimulation (GVS) was applied in five-minute blocks interleaved with five minutes of no stimulation for a total of 40 min. We confirmed the self-advantage under no stimulation (31 ms). In the presence of disruptive GVS this advantage disappeared and there was no longer a difference in performance between perspectives. The threshold delay for the 'other' perspective was not affected by the GVS. These results suggest that an intact vestibular signal is required to distinguish 'self' from 'other' and to maintain a sense of body ownership. PMID:26595957

  12. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts....... The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improves search in complementary technologies, while demoting it when strategic interests are misaligned in disruptive...... technologies. However, incumbent sources engaged in capability reconfiguration to accommodate disruption improve search efforts in disruptive technologies. The paper concludes that the value of external sources is contingent on more than their knowledge. Specifically, interdependence of sources in search gives...

  13. Seven gene deletions in seven days

    DEFF Research Database (Denmark)

    Ingemann Jensen, Sheila; Lennen, Rebecca; Herrgard, Markus;

    2015-01-01

    enables growth at 37 °C, thereby facilitating removal of integrated antibiotic cassettes and deletion of additional genes in the same day. Phosphorothioated primers were demonstrated to enable simultaneous deletions during one round of electroporation. Utilizing these methods, we constructed strains in...... deletion of multiple genes in several E. coli variants. The method enables deletion of up to seven genes in as little as seven days....

  14. 76 FR 22680 - Procurement List; Deletions

    Science.gov (United States)

    2011-04-22

    ... INFORMATION: Deletions On 2/25/2011 (76 FR 10571), the Committee for Purchase From People Who Are Blind or... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Deletions from the Procurement List. SUMMARY:...

  15. Disruption prediction at JET

    International Nuclear Information System (INIS)

    The sudden loss of the plasma magnetic confinement, known as disruption, is one of the major issue in a nuclear fusion machine as JET (Joint European Torus). Disruptions pose very serious problems to the safety of the machine. The energy stored in the plasma is released to the machine structure in few milliseconds resulting in forces that at JET reach several Mega Newtons. The problem is even more severe in the nuclear fusion power station where the forces are in the order of one hundred Mega Newtons. The events that occur during a disruption are still not well understood even if some mechanisms that can lead to a disruption have been identified and can be used to predict them. Unfortunately it is always a combination of these events that generates a disruption and therefore it is not possible to use simple algorithms to predict it. This thesis analyses the possibility of using neural network algorithms to predict plasma disruptions in real time. This involves the determination of plasma parameters every few milliseconds. A plasma boundary reconstruction algorithm, XLOC, has been developed in collaboration with Dr. D. O'Brien and Dr. J. Ellis capable of determining the plasma wall/distance every 2 milliseconds. The XLOC output has been used to develop a multilayer perceptron network to determine plasma parameters as li and qψ with which a machine operational space has been experimentally defined. If the limits of this operational space are breached the disruption probability increases considerably. Another approach for prediction disruptions is to use neural network classification methods to define the JET operational space. Two methods have been studied. The first method uses a multilayer perceptron network with softmax activation function for the output layer. This method can be used for classifying the input patterns in various classes. In this case the plasma input patterns have been divided between disrupting and safe patterns, giving the possibility of

  16. Abnormal auditory and language pathways in children with 16p11.2 deletion

    OpenAIRE

    Berman, Jeffrey I.; Darina Chudnovskaya; Lisa Blaskey; Emily Kuschner; Pratik Mukherjee; Randall Buckner; Srikantan Nagarajan; Chung, Wendy K.; Spiro, John E; Sherr, Elliott H; Roberts, Timothy P. L.

    2015-01-01

    Copy number variations at chromosome 16p11.2 contribute to neurodevelopmental disorders, including autism spectrum disorder (ASD). This study seeks to improve our understanding of the biological basis of behavioral phenotypes common in ASD, in particular the prominent and prevalent disruption of spoken language seen in children with the 16p11.2 BP4–BP5 deletion. We examined the auditory and language white matter pathways with diffusion MRI in a cohort of 36 pediatric deletion carriers and 45 ...

  17. A persistent mitochondrial deletion reduces fitness and sperm performance in heteroplasmic populations of C. elegans

    Directory of Open Access Journals (Sweden)

    Chin Kara

    2007-03-01

    Full Text Available Abstract Background Mitochondrial DNA (mtDNA mutations are of increasing interest due to their involvement in aging, disease, fertility, and their role in the evolution of the mitochondrial genome. The presence of reactive oxygen species and the near lack of repair mechanisms cause mtDNA to mutate at a faster rate than nuclear DNA, and mtDNA deletions are not uncommon in the tissues of individuals, although germ-line mtDNA is largely lesion-free. Large-scale deletions in mtDNA may disrupt multiple genes, and curiously, some large-scale deletions persist over many generations in a heteroplasmic state. Here we examine the phenotypic effects of one such deletion, uaDf5, in Caenorhabditis elegans (C. elegans. Our study investigates the phenotypic effects of this 3 kbp deletion. Results The proportion of uaDf5 chromosomes in worms was highly heritable, although uaDf5 content varied from worm to worm and within tissues of individual worms. We also found an impact of the uaDf5 deletion on metabolism. The deletion significantly reduced egg laying rate, defecation rate, and lifespan. Examination of sperm bearing the uaDf5 deletion revealed that sperm crawled more slowly, both in vitro and in vivo. Conclusion Worms harboring uaDf5 are at a selective disadvantage compared to worms with wild-type mtDNA. These effects should lead to the rapid extinction of the deleted chromosome, but it persists indefinitely. We discuss both the implications of this phenomenon and the possible causes of a shortened lifespan for uaDf5 mutant worms.

  18. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    Extant research on external knowledge search and open innovation assumes that collaborators are aligned in their strategic interests towards solving innovation problems. However, disruptive innovation is known to threaten the competitive advantage of incumbent firms, thereby creating a potential...... conflict of interest between these firms and their collaborators. This paper explores the extent to which strategic interests influence joint problem solving in both complementary and disruptive technologies by analyzing the effects of incumbent collaboration. The analysis disentangles inability and...... strategic intent to find that non-incumbents experience suppression of problem solving likelihood within disruptive technologies when incumbent collaborators are not strategically committed. The paper contributes to extant theory by showing the influence of firms’ underlying strategic interests on their...

  19. Interruptions disrupt reading comprehension.

    Science.gov (United States)

    Foroughi, Cyrus K; Werner, Nicole E; Barragán, Daniela; Boehm-Davis, Deborah A

    2015-06-01

    Previous research suggests that being interrupted while reading a text does not disrupt the later recognition or recall of information from that text. This research is used as support for Ericsson and Kintsch's (1995) long-term working memory (LT-WM) theory, which posits that disruptions while reading (e.g., interruptions) do not impair subsequent text comprehension. However, to fully comprehend a text, individuals may need to do more than recognize or recall information that has been presented in the text at a later time. Reading comprehension often requires individuals to connect and synthesize information across a text (e.g., successfully identifying complex topics such as themes and tones) and not just make a familiarity-based decision (i.e., recognition). The goal for this study was to determine whether interruptions while reading disrupt reading comprehension when the questions assessing comprehension require participants to connect and synthesize information across the passage. In Experiment 1, interruptions disrupted reading comprehension. In Experiment 2, interruptions disrupted reading comprehension but not recognition of information from the text. In Experiment 3, the addition of a 15-s time-out prior to the interruption successfully removed these negative effects. These data suggest that the time it takes to process the information needed to successfully comprehend text when reading is greater than that required for recognition. Any interference (e.g., an interruption) that occurs during the comprehension process may disrupt reading comprehension. This evidence supports the need for transient activation of information in working memory for successful text comprehension and does not support LT-WM theory. PMID:25867225

  20. Heme oxygenase-1 deletion affects stress erythropoiesis.

    Directory of Open Access Journals (Sweden)

    Yu-An Cao

    Full Text Available BACKGROUND: Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1 deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis. METHODOLOGY/PRINCIPAL FINDINGS: We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/- or hmox(+/+ bone marrow cells, we evaluated (i the erythrocyte parameters in the peripheral blood; (ii the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii the patterns of histological iron staining; and (iv the number of Mac-1(+-cells expressing TNF-α. In the spleens of mice that received hmox(+/- cells, we show (i decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii increases in the insoluble iron levels and decreases in the soluble iron levels; (iii increased numbers of Mac-1(+-cells expressing TNF-α; and (iv decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations. CONCLUSIONS/SIGNIFICANCE: As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

  1. Potential Novel Mechanism for Axenfeld-Rieger Syndrome: Deletion of a Distant Region Containing Regulatory Elements of PITX2

    OpenAIRE

    Volkmann, Bethany A.; Zinkevich, Natalya S.; Mustonen, Aki; Schilter, Kala F.; Bosenko, Dmitry V.; Reis, Linda M.; Broeckel, Ulrich; Link, Brian A.; Semina, Elena V.

    2011-01-01

    The authors describe an identification of conserved PITX2 enhancers located within a gene desert upstream of the gene and a deletion of this upstream region in a patient with Axenfeld-Rieger syndrome with no disruption of the PTIX2 coding region. The data suggest a new mechanism of Axenfeld-Rieger syndrome.

  2. Deletion 22q13.3 syndrome

    OpenAIRE

    Phelan Mary C

    2008-01-01

    Abstract The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndr...

  3. 1p36 deletion syndrome: an update

    Directory of Open Access Journals (Sweden)

    Jordan VK

    2015-08-01

    Full Text Available Valerie K Jordan,1 Hitisha P Zaveri,2 Daryl A Scott1,2 1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Abstract: Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes. Keywords: chromosome 1p36, chromosome deletion, 1p36 deletion syndrome, monosomy 1p36

  4. Endocrine disrupting compounds

    DEFF Research Database (Denmark)

    Bøgh, I B; Christensen, P; Dantzer, V;

    2001-01-01

    With the growing concern that environmental chemicals might impair human and animal fertility, it is important to investigate the possible influence of these substances on sexual differentiation and genital development of mammals. Many of these substances are suspected to interfere with endocrine...... of alkylphenols, these are disseminated in the environment with sewage sludge, and domestic animals and humans are likely to be exposed via the food chain. Using the pig as an in vivo model, we studied the effect of intrauterine exposure to tertiary octylphenol (OP) on essential reproductive...... usefulness of in vivo animal or embryo models for the evaluation of possible consequences of human exposure to endocrine disrupting compounds is discussed. Furthermore, possible consequences of exposure to endocrine disrupting compounds for the embryo transfer industry are addressed....

  5. Coincident disruptive coloration

    OpenAIRE

    Cuthill, Innes C.; Székely, Aron

    2008-01-01

    Even if an animal matches its surroundings perfectly in colour and texture, any mismatch between the spatial phase of its pattern and that of the background, or shadow created by its three-dimensional relief, is potentially revealing. Nevertheless, for camouflage to be fully broken, the shape must be recognizable. Disruptive coloration acts against object recognition by the use of high-contrast internal colour boundaries to break up shape and form. As well as the general outline, characterist...

  6. Schematically disruptive game design

    OpenAIRE

    Howell, Peter

    2011-01-01

    Many games focus their resources at satiating player ‘needs’, and meeting perceived expectations that players have of how games should behave and of what constitutes enjoyable, gratifying gameplay. This paper outlines an alternate position on game design – one which focuses on disrupting these expectations, on designing games that players cannot succeed in simply by relying on their pre-acquired gameplay experiences. A critique of current game design trends is offered, and possible future out...

  7. Search and Disrupt

    OpenAIRE

    Ørding Olsen, Anders

    2015-01-01

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts. The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improv...

  8. Celibacy and Family Disruption

    OpenAIRE

    Emaletdinov B. M.

    2013-01-01

    Causes for celibacy, divorces and successful marriage are discussed in the article. Absence of true love and inability to build and keep it are the main reasons for family disruption. Amorousness, immature love and various forms of false or flawed love substitute the true feeling. It is caused by increased women’s independence, loss of mutual understanding and trust (due to infidelity or jealousy), incompatibility of characters or values. Celibacy is often conditioned by physical disability, ...

  9. 78 FR 56679 - Procurement List; Deletions

    Science.gov (United States)

    2013-09-13

    ... 8/2/2013 (78 FR 46927-46928), the Committee for Purchase From People Who Are Blind or Severely... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Deletions AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Deletions from the Procurement List. SUMMARY:...

  10. The chromosome 9q subtelomere deletion syndrome

    NARCIS (Netherlands)

    Stewart, D.R.; Kleefstra, T.

    2007-01-01

    The chromosome 9q subtelomere deletion syndrome (9qSTDS) is among the first and most common clinically recognizable syndromes to arise from widespread testing by fluorescent in situ hybridization (FISH) of subtelomere deletions. There are about 50 reported cases worldwide. Affected individuals invar

  11. 13Q DELETIONS IN LYMPHOID MALIGNANCIES

    NARCIS (Netherlands)

    HERMANSON, M; GRANDER, D; MERUP, M; WU, XS; HEYMAN, M; RASOOL, O; JULIUSSON, G; GAHRTON, G; DETLOFSSON, R; NIKIFOROVA, N; BUYS, C; SODERHALL, S; YANKOVSKY, N; ZABAROVSKY, E; EINHORN, S

    1995-01-01

    Previous studies have indicated that a candidate tumor suppressor gene resides telomeric of the RB1 gene at 13q14, a region that is commonly deleted in B-cell chronic lymphocytic leukemia (B-CLL). In this study, we have evaluated the frequency and minimal region of overlap for 13q deletions in malig

  12. Deletions in the fifth alpha helix of HIV-1 matrix block virus release

    International Nuclear Information System (INIS)

    The matrix (MA) protein of HIV-1 is the N-terminal component of the Gag structural protein and is critical for the early and late stages of viral replication. MA contains five α-helices (α1–α5). Deletions in the N-terminus of α5 as small as three amino acids impaired virus release. Electron microscopy of one deletion mutant (MA∆96-120) showed that its particles were tethered to the surface of cells by membranous stalks. Immunoblots indicated all mutants were processed completely, but mutants with large deletions had alternative processing intermediates. Consistent with the EM data, MA∆96-120 retained membrane association and multimerization capability. Co-expression of this mutant inhibited wild type particle release. Alanine scanning mutation in this region did not affect virus release, although the progeny virions were poorly infectious. Combined, these data demonstrate that structural ablation of the α5 of MA inhibits virus release. - Highlights: • Deletions were identified in the C-terminus of matrix that block virus release. • These deletion mutants still multimerized and associated with membranes. • TEM showed the mutant particles were tethered to the cell surface. • Amino acid mutagenesis of the region did not affect release. • The data suggests that disruption of matrix structure blocks virus release

  13. Abnormal auditory and language pathways in children with 16p11.2 deletion

    Directory of Open Access Journals (Sweden)

    Jeffrey I. Berman

    2015-01-01

    Full Text Available Copy number variations at chromosome 16p11.2 contribute to neurodevelopmental disorders, including autism spectrum disorder (ASD. This study seeks to improve our understanding of the biological basis of behavioral phenotypes common in ASD, in particular the prominent and prevalent disruption of spoken language seen in children with the 16p11.2 BP4–BP5 deletion. We examined the auditory and language white matter pathways with diffusion MRI in a cohort of 36 pediatric deletion carriers and 45 age-matched controls. Diffusion MR tractography of the auditory radiations and the arcuate fasciculus was performed to generate tract specific measures of white matter microstructure. In both tracts, deletion carriers exhibited significantly higher diffusivity than that of controls. Cross-sectional diffusion parameters in these tracts changed with age with no group difference in the rate of maturation. Within deletion carriers, the left-hemisphere arcuate fasciculus mean and radial diffusivities were significantly negatively correlated with clinical language ability, but not non-verbal cognitive ability. Diffusion metrics in the right-hemisphere arcuate fasciculus were not predictive of language ability. These results provide insight into the link between the 16p11.2 deletion, abnormal auditory and language pathway structures, and the specific behavioral deficits that may contribute to neurodevelopmental disorders such as ASD.

  14. Deletions in the fifth alpha helix of HIV-1 matrix block virus release

    Energy Technology Data Exchange (ETDEWEB)

    Sanford, Bridget; Li, Yan; Maly, Connor J.; Madson, Christian J. [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); Chen, Han [Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE (United States); Zhou, You [Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE (United States); Nebraska Center for Virology, Lincoln, NE (United States); Belshan, Michael, E-mail: michaelbelshan@creighton.edu [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); Nebraska Center for Virology, Lincoln, NE (United States)

    2014-11-15

    The matrix (MA) protein of HIV-1 is the N-terminal component of the Gag structural protein and is critical for the early and late stages of viral replication. MA contains five α-helices (α1–α5). Deletions in the N-terminus of α5 as small as three amino acids impaired virus release. Electron microscopy of one deletion mutant (MA∆96-120) showed that its particles were tethered to the surface of cells by membranous stalks. Immunoblots indicated all mutants were processed completely, but mutants with large deletions had alternative processing intermediates. Consistent with the EM data, MA∆96-120 retained membrane association and multimerization capability. Co-expression of this mutant inhibited wild type particle release. Alanine scanning mutation in this region did not affect virus release, although the progeny virions were poorly infectious. Combined, these data demonstrate that structural ablation of the α5 of MA inhibits virus release. - Highlights: • Deletions were identified in the C-terminus of matrix that block virus release. • These deletion mutants still multimerized and associated with membranes. • TEM showed the mutant particles were tethered to the cell surface. • Amino acid mutagenesis of the region did not affect release. • The data suggests that disruption of matrix structure blocks virus release.

  15. Disruption - Access cards service

    CERN Document Server

    2014-01-01

    We would like to inform you that between 10 November and 15 December 2014, the access cards service in Building 55 will be disrupted, as the GS Department has decided to improve the facilities for users of this building. During the work, you will find the registration, biometric registration and dosimeter exchange services on the second floor of Building 55 and the vehicle sticker service on the ground floor along with the access cards service. We thank you for your understanding and apologise for any inconvenience caused.

  16. Sustainable Disruption Management

    DEFF Research Database (Denmark)

    Vaaben, Bo Valdemar

    The world we live in is globalized. Goods are seldom made in the place where they are used or consumed, and we do increasingly travel to other countries for either business or pleasure. In our everyday lives we rely on well-functioning global transportations systems to continue the standard of li...... disruption management. The real-world results show considerable yearly savings of above 5.1 million USD for a medium size airline operating in European airspace, which is significantly affected by airspace congestions....

  17. Celibacy and Family Disruption

    Directory of Open Access Journals (Sweden)

    Emaletdinov B. M.

    2013-01-01

    Full Text Available Causes for celibacy, divorces and successful marriage are discussed in the article. Absence of true love and inability to build and keep it are the main reasons for family disruption. Amorousness, immature love and various forms of false or flawed love substitute the true feeling. It is caused by increased women’s independence, loss of mutual understanding and trust (due to infidelity or jealousy, incompatibility of characters or values. Celibacy is often conditioned by physical disability, revaluation of freedom and independence, huge requirements to partners, consumer attitude to life, infertility, alcohol and drug abuse, abnormalities in personality and sexuality.

  18. Relativistic tidal disruption events

    Directory of Open Access Journals (Sweden)

    Levan A.

    2012-12-01

    Full Text Available In March 2011 Swift detected an extremely luminous and long-lived outburst from the nucleus of an otherwise quiescent, low luminosity (LMC-like galaxy. Named Swift J1644+57, its combination of high-energy luminosity (1048 ergs s−1 at peak, rapid X-ray variability (factors of >100 on timescales of 100 seconds and luminous, rising radio emission suggested that we were witnessing the birth of a moderately relativistic jet (Γ ∼ 2 − 5, created when a star is tidally disrupted by the supermassive black hole in the centre of the galaxy. A second event, Swift J2058+0516, detected two months later, with broadly similar properties lends further weight to this interpretation. Taken together this suggests that a fraction of tidal disruption events do indeed create relativistic outflows, demonstrates their detectability, and also implies that low mass galaxies can host massive black holes. Here, I briefly outline the observational properties of these relativistic tidal flares observed last year, and their evolution over the first year since their discovery.

  19. Disruptions in the TFTR tokamak

    International Nuclear Information System (INIS)

    For a successful reactor, it will be useful to predict the occurrence of disruptions and to understand disruption effects including how a plasma disrupts onto the wall and how reproducibly it does so. Studies of disruptions on TFTR at both high-βpol and high-density have shown that, in both types, a fast growing m/n=1/1 mode plays an important role. In highdensity disruptions, a newly observed fast m/n = 1/1 mode occurs early in the thermal decay phase. For the first time in TFTR q-profile measurements just prior to disruptions have been made. Experimental studies of heat deposition patterns on the first wall of TFTR due to disruptions have provided information on MHD phenomena prior to or during the disruption, how the energy is released to the wall, and the reproducibility of the heat loads from disruptions. This information is important in the design of future devices such as ITER. Several new processes of runaway electron generation are theoretically suggested and their application to TFTR and ITER is considered, together with a preliminary assessment of x-ray data from runaways generated during disruptions

  20. Dystrophin gene deletions in South Indian Duchenne muscular dystrophy patients.

    OpenAIRE

    Mallikarjuna Rao G; Hussain T.; Geetha Devi N; Jain S; Chandak G; Ananda Raj M

    2003-01-01

    66 unrelated patients from Southern India with Duchenne Muscular Dystrophy (DMD) were studied for intragenic deletion in 18 exons and Pm region of the DMD gene using multiplex PCR. Of these 41 (62.1%) showed intragenic deletions. 78% of the deletions were located at the distal hotspot region (44-55 exons) and 22% of the deletions were located at the proximal region (exon 2-19). Exon 50 is most frequently deleted. Deletions in isolated cases were significantly more compare...

  1. Directed mutagenesis in Candida albicans: one-step gene disruption to isolate ura3 mutants

    International Nuclear Information System (INIS)

    A method for introducing specific mutations into the diploid Candida albicans by one-step gene disruption and subsequent UV-induced recombination was developed. The cloned C. albicans URA3 gene was disrupted with the C. albicans ADE2 gene, and the linearized DNA was used for transformation of two ade2 mutants, SGY-129 and A81-Pu. Both an insertional inactivation of the URA3 gene and a disruption which results in a 4.0-kilobase deletion were made. Southern hybridization analyses demonstrated that the URA3 gene was disrupted on one of the chromosomal homologs in 15 of the 18 transformants analyzed. These analyses also revealed restriction site dimorphism of EcoRI at the URA3 locus which provides a unique marker to distinguish between chromosomal homologs. This enabled us to show that either homolog could be disrupted and that disrupted transformants of SGY-129 contained more than two copies of the URA3 locus. The A81-Pu transformants heterozygous for the ura3 mutations were rendered homozygous and Ura- by UV-induced recombination. The homozygosity of a deletion mutant and an insertion mutant was confirmed by Southern hybridization. Both mutants were transformed to Ura+ with plasmids containing the URA3 gene and in addition, were resistant to 5-fluoro-orotic acid, a characteristic of Saccharomyces cerevisiae ura3 mutants as well as of orotidine-5'-phosphate decarboxylase mutants of other organisms

  2. Cell disruption for microalgae biorefineries.

    Science.gov (United States)

    Günerken, E; D'Hondt, E; Eppink, M H M; Garcia-Gonzalez, L; Elst, K; Wijffels, R H

    2015-01-01

    Microalgae are a potential source for various valuable chemicals for commercial applications ranging from nutraceuticals to fuels. Objective in a biorefinery is to utilize biomass ingredients efficiently similarly to petroleum refineries in which oil is fractionated in fuels and a variety of products with higher value. Downstream processes in microalgae biorefineries consist of different steps whereof cell disruption is the most crucial part. To maintain the functionality of algae biochemicals during cell disruption while obtaining high disruption yields is an important challenge. Despite this need, studies on mild disruption of microalgae cells are limited. This review article focuses on the evaluation of conventional and emerging cell disruption technologies, and a comparison thereof with respect to their potential for the future microalgae biorefineries. The discussed techniques are bead milling, high pressure homogenization, high speed homogenization, ultrasonication, microwave treatment, pulsed electric field treatment, non-mechanical cell disruption and some emerging technologies. PMID:25656098

  3. Genetics Home Reference: 18q deletion syndrome

    Science.gov (United States)

    ... to severe, but some affected individuals have normal intelligence and development. Seizures, hyperactivity, aggression, and autistic behaviors ... into two types : individuals with deletions near the end of the long arm of chromosome 18 are ...

  4. Disruptive camouflage impairs object recognition

    OpenAIRE

    Richard J. Webster; Hassall, Christopher; Herdman, Chris M.; Godin, Jean-Guy J.; Sherratt, Thomas N.

    2013-01-01

    Whether hiding from predators, or avoiding battlefield casualties, camouflage is widely employed to prevent detection. Disruptive coloration is a seemingly well-known camouflage mechanism proposed to function by breaking up an object's salient features (for example their characteristic outline), rendering objects more difficult to recognize. However, while a wide range of animals are thought to evade detection using disruptive patterns, there is no direct experimental evidence that disruptive...

  5. Endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Mandrup, Karen

    BACKGROUND: Endocrine disrupting chemicals (EDCs) may contribute to reproductive changes in boys in the Western world, however, less is known about influence of EDCs in women. The incidence of precocious breast development is increasing in USA and Europe and mammary gland development has been...... examination showed changes in epithelial morphology in male (hypertrophic epithelium) and female (lobuloalveolar morphology) mammary glands in adult rats exposed to phytoestrogens. Anti-androgenic chemicals showed signs of feminisation of adult male mammary glands. No effects of anti-androgens were observed...... in female mammary glands. The histological changes observed in adult female and male mammary glands were not present consistently in the groups of estrogenic or anti-androgenic chemicals and may be due to other modes of action of thechemicals. Female genital malformations were affected by the potent...

  6. Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma

    OpenAIRE

    Flora, Adriano; Klisch, Tiemo J.; Schuster, Gabriele; Zoghbi, Huda Y.

    2009-01-01

    Granule neuron precursors (GNPs) are the most actively proliferating cells in the post-natal nervous system and mutations in pathways controlling their cell cycle can result in medulloblastoma. The transcription factor Atoh1 has been suspected to contribute to GNP proliferation, but its role in normal and neoplastic post-natal cerebellar development remains unexplored. We show that Atoh1 regulates the signal transduction pathway of Sonic Hedgehog, an extracellular factor that is essential for...

  7. Repartnering after First Union Disruption

    Science.gov (United States)

    Wu, Zheng; Schimmele, Christoph M.

    2005-01-01

    Using data from the 1995 General Social Survey (N= 2,639), this study examines two competing repartnering choices made by Canadians after first union disruption: marriage or cohabitation. About 42% of women and 54% of men form a second union 5 years after union disruption, with cohabitation being the most prevalent choice. The timing of second…

  8. Incomplete spontaneous ureteral disruption

    International Nuclear Information System (INIS)

    Background. The aim of the authors was to present the case of spontaneous partial ureteral rupture during a renal colic, caused by an anorganic concrement in the proximal part of the left ureter, at the level of the transverse processus of L3. Case report. On the excretory urography imaging, the dilatation of the canal system, cups, necks and pyelon, was observed. At the level of the pyeloureteric passage, the contrast medium was leaking. The leakage was found to be extending along the psoas muscle to the pelvis. On the transversal CT imaging scans, the contrast medium was seen along the medial and dorsal part of the perirenal space, and in the distal part, along the psoas muscle to the pelvis. The ureter was imaged from the pyeloureterical rupture to the site of the concrement. No signs of the damage of the renal parenchyma or perirenal bleeding were detected. During surgery, the site of the rupture was found and also a lot of the perirenal and periureteral liquid. After the extraction of the concrement, the suture of the rupture was made. Postoperative urography and CT showed a normal ureteral image. Conclusions. At the spontaneous partial disruption of the ureter, the contrast medium is still seen in the ureter, distally from the site of the rupture and as extravasation along the psoas muscle. (author)

  9. Disrupting Ethnography through Rhizoanalysis

    Directory of Open Access Journals (Sweden)

    Diana Masny

    2014-10-01

    Full Text Available This article interrogates principles of ethnography in education proposed by Mills and Morton: raw tellings, analytic pattern, vignette and empathy. This article adopts a position that is uncomfortable, unconventional and interesting. It involves a deterritorialization/ rupture of ethnography in education in order to reterritorialize a different concept: rhizoanalysis, a way to position theory and data that is multilayered, complex and messy. Rhizoanalysis, the main focus of this article is not a method. It is an approach to research conditioned by a reality in which Deleuze and Guattari disrupt representation, interpretation and subjectivity. In this article, Multiple Literacies Theory, a theoretical and practical framework, becomes a lens to examine a rhizomatic study of a Korean family recently arrived to Australia and attending English as a second language classes. Observations and interviews recorded the daily lives of the family. The vignettes were selected by reading data intensively and immanently through a process of palpation, an innovative approach to educational research. Rhizoanalysis proposes to abandon the given and invent different ways of thinking about and doing research and what might happen when reading data differently, intensively and immanently, through Multiple Literacies Theory. Rhizoanalysis, a game-changer in the way research can be conducted, affords a different lens to tackle issues in education through research.

  10. Finding cis-regulatory modules in Drosophila using phylogenetic hidden Markov models

    DEFF Research Database (Denmark)

    Wong, Wendy S W; Nielsen, Rasmus

    2007-01-01

    MOTIVATION: Finding the regulatory modules for transcription factors binding is an important step in elucidating the complex molecular mechanisms underlying regulation of gene expression. There are numerous methods available for solving this problem, however, very few of them take advantage of th...

  11. Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer.

    Science.gov (United States)

    Diaferia, Giuseppe R; Balestrieri, Chiara; Prosperini, Elena; Nicoli, Paola; Spaggiari, Paola; Zerbi, Alessandro; Natoli, Gioacchino

    2016-03-15

    The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high- and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low-grade primary PDACs and cell lines, where it maintained the acetylation of grade-specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression. PMID:26769127

  12. Identification and Characterization of a cis-Regulatory Element for Zygotic Gene Expression in Chlamydomonas reinhardtii.

    Science.gov (United States)

    Hamaji, Takashi; Lopez, David; Pellegrini, Matteo; Umen, James

    2016-01-01

    Upon fertilization Chlamydomonas reinhardtii zygotes undergo a program of differentiation into a diploid zygospore that is accompanied by transcription of hundreds of zygote-specific genes. We identified a distinct sequence motif we term a zygotic response element (ZYRE) that is highly enriched in promoter regions of C reinhardtii early zygotic genes. A luciferase reporter assay was used to show that native ZYRE motifs within the promoter of zygotic gene ZYS3 or intron of zygotic gene DMT4 are necessary for zygotic induction. A synthetic luciferase reporter with a minimal promoter was used to show that ZYRE motifs introduced upstream are sufficient to confer zygotic upregulation, and that ZYRE-controlled zygotic transcription is dependent on the homeodomain transcription factor GSP1. We predict that ZYRE motifs will correspond to binding sites for the homeodomain proteins GSP1-GSM1 that heterodimerize and activate zygotic gene expression in early zygotes. PMID:27172209

  13. Cis-regulatory programs in the development and evolution of vertebrate paired appendages.

    Science.gov (United States)

    Gehrke, Andrew R; Shubin, Neil H

    2016-09-01

    Differential gene expression is the core of development, mediating the genetic changes necessary for determining cell identity. The regulation of gene activity by cis-acting elements (e.g., enhancers) is a crucial mechanism for determining differential gene activity by precise control of gene expression in embryonic space and time. Modifications to regulatory regions can have profound impacts on phenotype, and therefore developmental and evolutionary biologists have increasingly focused on elucidating the transcriptional control of genes that build and pattern body plans. Here, we trace the evolutionary history of transcriptional control of three loci key to vertebrate appendage development (Fgf8, Shh, and HoxD/A). Within and across these regulatory modules, we find both complex and flexible regulation in contrast with more fixed enhancers that appear unchanged over vast timescales of vertebrate evolution. The transcriptional control of vertebrate appendage development was likely already incredibly complex in the common ancestor of fish, implying that subtle changes to regulatory networks were more likely responsible for alterations in phenotype rather than the de novo addition of whole regulatory domains. Finally, we discuss the dangers of relying on inter-species transgenesis when testing enhancer function, and call for more controlled regulatory swap experiments when inferring the evolutionary history of enhancer elements. PMID:26783722

  14. Network discovery pipeline elucidates conserved time-of-day-specific cis-regulatory modules.

    Directory of Open Access Journals (Sweden)

    Todd P Michael

    2008-02-01

    Full Text Available Correct daily phasing of transcription confers an adaptive advantage to almost all organisms, including higher plants. In this study, we describe a hypothesis-driven network discovery pipeline that identifies biologically relevant patterns in genome-scale data. To demonstrate its utility, we analyzed a comprehensive matrix of time courses interrogating the nuclear transcriptome of Arabidopsis thaliana plants grown under different thermocycles, photocycles, and circadian conditions. We show that 89% of Arabidopsis transcripts cycle in at least one condition and that most genes have peak expression at a particular time of day, which shifts depending on the environment. Thermocycles alone can drive at least half of all transcripts critical for synchronizing internal processes such as cell cycle and protein synthesis. We identified at least three distinct transcription modules controlling phase-specific expression, including a new midnight specific module, PBX/TBX/SBX. We validated the network discovery pipeline, as well as the midnight specific module, by demonstrating that the PBX element was sufficient to drive diurnal and circadian condition-dependent expression. Moreover, we show that the three transcription modules are conserved across Arabidopsis, poplar, and rice. These results confirm the complex interplay between thermocycles, photocycles, and the circadian clock on the daily transcription program, and provide a comprehensive view of the conserved genomic targets for a transcriptional network key to successful adaptation.

  15. RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements

    OpenAIRE

    Chatagnon, Amandine; Veber, Philippe; Morin, Valérie; Bedo, Justin; Triqueneaux, Gérard; Sémon, Marie; Laudet, Vincent; D'Alché-Buc, Florence; Benoit, Gérard

    2015-01-01

    In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play a key role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated w...

  16. RAR/RXR binding dynamics distinguish pluripotency from differentiation associated cis-regulatory elements.

    Science.gov (United States)

    Chatagnon, Amandine; Veber, Philippe; Morin, Valérie; Bedo, Justin; Triqueneaux, Gérard; Sémon, Marie; Laudet, Vincent; d'Alché-Buc, Florence; Benoit, Gérard

    2015-05-26

    In mouse embryonic cells, ligand-activated retinoic acid receptors (RARs) play a key role in inhibiting pluripotency-maintaining genes and activating some major actors of cell differentiation. To investigate the mechanism underlying this dual regulation, we performed joint RAR/RXR ChIP-seq and mRNA-seq time series during the first 48 h of the RA-induced Primitive Endoderm (PrE) differentiation process in F9 embryonal carcinoma (EC) cells. We show here that this dual regulation is associated with RAR/RXR genomic redistribution during the differentiation process. In-depth analysis of RAR/RXR binding sites occupancy dynamics and composition show that in undifferentiated cells, RAR/RXR interact with genomic regions characterized by binding of pluripotency-associated factors and high prevalence of the non-canonical DR0-containing RA response element. By contrast, in differentiated cells, RAR/RXR bound regions are enriched in functional Sox17 binding sites and are characterized with a higher frequency of the canonical DR5 motif. Our data offer an unprecedentedly detailed view on the action of RA in triggering pluripotent cell differentiation and demonstrate that RAR/RXR action is mediated via two different sets of regulatory regions tightly associated with cell differentiation status. PMID:25897113

  17. Extensive conservation of ancient microsynteny across metazoans due to cis-regulatory constraints

    OpenAIRE

    Irimia, Manuel; Tena, Juan J.; Alexis, Maria S.; Fernandez-Miñan, Ana; Maeso, Ignacio; Bogdanović, Ozren; de la Calle-Mustienes, Elisa; Roy, Scott W; Gómez-Skarmeta, José L.; Fraser, Hunter B.

    2012-01-01

    The order of genes in eukaryotic genomes has generally been assumed to be neutral, since gene order is largely scrambled over evolutionary time. Only a handful of exceptional examples are known, typically involving deeply conserved clusters of tandemly duplicated genes (e.g., Hox genes and histones). Here we report the first systematic survey of microsynteny conservation across metazoans, utilizing 17 genome sequences. We identified nearly 600 pairs of unrelated genes that have remained tight...

  18. Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins.

    Science.gov (United States)

    Indjeian, Vahan B; Kingman, Garrett A; Jones, Felicity C; Guenther, Catherine A; Grimwood, Jane; Schmutz, Jeremy; Myers, Richard M; Kingsley, David M

    2016-01-14

    Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal evolution. Armor bone-size differences in sticklebacks map to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor-plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form. PMID:26774823

  19. A cis-Regulatory Mutation of PDSS2 Causes Silky-Feather in Chickens

    OpenAIRE

    Feng, Chungang; Gao, Yu; Dorshorst, Ben; Song, Chi; Gu, Xiaorong; Li, Qingyuan; Li, Jinxiu; Liu, Tongxin; Rubin, Carl-Johan; Zhao, Yiqiang; Wang, Yanqiang; Fei, Jing; Li, Huifang; Chen, Kuanwei; Qu, Hao

    2014-01-01

    Author Summary The feather is an excellent model for evolution and development due to its complex structure and vast diversity. Some chickens have silky-feather because of a loss of hooklets in pennaceous feathers, while most chickens have the wild-type normal feather. Hooklets are formed in the last differentiation stage of the life cycle of a pennaceous feather. Chickens with silky-feather are homozygous for a recessive allele (hookless, h). Silkie chicken from China is one of the breeds sh...

  20. Cis-regulatory mechanisms of left/right asymmetric neuron-subtype specification in C. elegans

    OpenAIRE

    Etchberger, John F.; Eileen B Flowers; Poole, Richard J.; Bashllari, Enkelejda; Hobert, Oliver

    2008-01-01

    Anatomically and functionally defined neuron types are sometimes further classified into individual subtypes based on unique functional or molecular properties. To better understand how developmental programs controlling neuron type specification are mechanistically linked to programs controlling neuronal subtype specification, we have analyzed a neuronal subtype specification program that occurs across the left/right axis in the nervous system of the nematode C. elegans. A terminal selector ...

  1. Gene deletion analysis of a Chinese boy with Xp21 contiguous gene deletion syndrome

    Institute of Scientific and Technical Information of China (English)

    麻宏伟; 姜俊; 王岳平; 王志超; 陈丽英; 松尾雅文

    2004-01-01

    @@ Xp21 contiguous gene deletion syndrome, sometimes called complex glycerol kinase deficiency, is associated with variable size Xp21 deletions that usually include the glycerol kinase gene and span multiple Xp21 disease gene loci in the region. The order of the potentially affected loci are as follows:

  2. When Disruptive Approaches Meet Disruptive Technologies: Learning at a Distance.

    Science.gov (United States)

    Gibson, Chere Campbell

    2000-01-01

    Reviews research on constructivism in learning and selection of learning strategies. Suggests linking constructivism with instructional technologies for continuing medical education in order to "disrupt" reactive, habitual ways of learning and encourage active engagement. (SK)

  3. 9q22 Deletion - First Familial Case

    Directory of Open Access Journals (Sweden)

    Yamamoto Toshiyuki

    2011-06-01

    Full Text Available Abstract Background Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400 due to haploinsufficiency of the PTCH1 gene (MIM *601309. Methods and Results We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K. The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337 which causing both brachydactyly type 1 (MIM #113000 and Robinow syndrome (MIM #268310, and the immunologically active SYK gene (MIM *600085. The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations. Conclusions This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.

  4. Endocrine Effects of Circadian Disruption.

    Science.gov (United States)

    Bedrosian, Tracy A; Fonken, Laura K; Nelson, Randy J

    2016-01-01

    Disruption of circadian rhythms, provoked by artificial lighting at night, inconsistent sleep-wake schedules, and transmeridian air travel, is increasingly prevalent in modern society. Desynchrony of biological rhythms from environmental light cycles has dramatic consequences for human health. In particular, disrupting homeostatic oscillations in endocrine tissues and the hormones that these tissues regulate can have cascading effects on physiology and behavior. Accumulating evidence suggests that chronic disruption of circadian organization of endocrine function may lead to metabolic, reproductive, sleep, and mood disorders. This review discusses circadian control of endocrine systems and the consequences of distorting rhythmicity of these systems. PMID:26208951

  5. Intersections of certain deleted digits sets

    CERN Document Server

    Pedersen, Steen

    2011-01-01

    We consider some properties of the intersection of deleted digits Cantor sets with their translates. We investigate conditions on the set of digits such that, for any t between zero and the dimension of the deleted digits Cantor set itself, the set of translations such that the intersection has Hausdorff dimension equal to t is dense in the set F of translations such that the intersection is non-empty. We make some simple observations regarding properties of the set F, in particular, we characterize when F is an interval, in terms of conditions on the digit set.

  6. Deletion 22q13.3 syndrome

    Directory of Open Access Journals (Sweden)

    Phelan Mary C

    2008-05-01

    Full Text Available Abstract The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH or array comparative genomic hybridization (CGH is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy. Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements

  7. Some analogies between quantum cloning and quantum deleting

    International Nuclear Information System (INIS)

    We further verify the impossibility of deleting an arbitrary unknown quantum state, and also show it is impossible to delete two nonorthogonal quantum states as a consequence of unitarity of quantum mechanics. A quantum approximate (deterministic) deleting machine and a probabilistic (exact) deleting machine are constructed. The estimation for the global fidelity characterizing the efficiency of the quantum approximate deleting is given. We then demonstrate that unknown nonorthogonal states chosen from a set with their multiple copies can evolve into a linear superposition of multiple deletions and failure branches by a unitary process if and only if the states are linearly independent. It is notable that the proof for necessity is somewhat different from Pati's [Phys. Rev. Lett. 83, 2849 (1999)]. Another deleting machine for the input states that are unnecessarily linearly independent is also presented. The bounds on the success probabilities of these deleting machines are derived. So we expound some preliminary analogies between quantum cloning and deleting

  8. Vortex disruption by magnetohydrodynamic feedback

    CERN Document Server

    Mak, Julian; Hughes, D W

    2016-01-01

    In an electrically conducting fluid, vortices stretch out a weak, large-scale magnetic field to form strong current sheets on their edges. Associated with these current sheets are magnetic stresses, which are subsequently released through reconnection, leading to vortex disruption, and possibly even destruction. This disruption phenomenon is investigated here in the context of two-dimensional, homogeneous, incompressible magnetohydrodynamics. We derive a simple order of magnitude estimate for the magnetic stresses --- and thus the degree of disruption --- that depends on the strength of the background magnetic field (measured by the parameter $M$, a ratio between the Alfv\\'en speed and a typical flow speed) and on the magnetic diffusivity (measured by the magnetic Reynolds number $\\mbox{Rm}$). The resulting estimate suggests that significant disruption occurs when $M^{2}\\mbox{Rm} = O(1)$. To test our prediction, we analyse direct numerical simulations of vortices generated by the breakup of unstable shear flo...

  9. Beam emittance and beam disruption

    International Nuclear Information System (INIS)

    Beam disruption during the collision of intense relativistic bunches has been studied by R. Hollebeek. In the case of oppositely charged bunches, focussing effects occur causing a decrease in the effective bunch cross section, and thereby an increase of luminosity by an enhancement factor H. The term disruption derives from the fact that the beam emittance changes markedly during the collision. 1 ref., 1 fig., 1 tab

  10. Deletion of GPIHBP1 causing severe chylomicronemia.

    Science.gov (United States)

    Rios, Jonathan J; Shastry, Savitha; Jasso, Juan; Hauser, Natalie; Garg, Abhimanyu; Bensadoun, André; Cohen, Jonathan C; Hobbs, Helen H

    2012-05-01

    Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1. PMID:22008945

  11. Sequence analysis of 17 NRXN1 deletions

    DEFF Research Database (Denmark)

    Hoeffding, Louise Kristine Enggaard; Hansen, Thomas; Ingason, Andrés;

    2014-01-01

    molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and...

  12. Familial deletion 18p syndrome: case report

    Directory of Open Access Journals (Sweden)

    Lemyre Emmanuelle

    2006-07-01

    Full Text Available Abstract Background Deletion 18p is a frequent deletion syndrome characterized by dysmorphic features, growth deficiencies, and mental retardation with a poorer verbal performance. Until now, five families have been described with limited clinical description. We report transmission of deletion 18p from a mother to her two daughters and review the previous cases. Case presentation The proband is 12 years old and has short stature, dysmorphic features and moderate mental retardation. Her sister is 9 years old and also has short stature and similar dysmorphic features. Her cognitive performance is within the borderline to mild mental retardation range. The mother also presents short stature. Psychological evaluation showed moderate mental retardation. Chromosome analysis from the sisters and their mother revealed the same chromosomal deletion: 46, XX, del(18(p11.2. Previous familial cases were consistent regarding the transmission of mental retardation. Our family differs in this regard with variable cognitive impairment and does not display poorer verbal than non-verbal abilities. An exclusive maternal transmission is observed throughout those families. Women with del(18p are fertile and seem to have a normal miscarriage rate. Conclusion Genetic counseling for these patients should take into account a greater range of cognitive outcome than previously reported.

  13. Union-Find with Constant Time Deletions

    DEFF Research Database (Denmark)

    Alstrup, Stephen; Thorup, Mikkel; Gørtz, Inge Li;

    2014-01-01

    operations performed, and α_M/N_(n) is a functional inverse of Ackermann’s function. They left open the question whether delete operations can be implemented more efficiently than find operations, for example, in o(log n) worst-case time. We resolve this open problem by presenting a relatively simple...

  14. Insertion and deletion processes in recent human history.

    Directory of Open Access Journals (Sweden)

    Per Sjödin

    Full Text Available BACKGROUND: Although insertions and deletions (indels account for a sizable portion of genetic changes within and among species, they have received little attention because they are difficult to type, are alignment dependent and their underlying mutational process is poorly understood. A fundamental question in this respect is whether insertions and deletions are governed by similar or different processes and, if so, what these differences are. METHODOLOGY/PRINCIPAL FINDINGS: We use published resequencing data from Seattle SNPs and NIEHS human polymorphism databases to construct a genomewide data set of short polymorphic insertions and deletions in the human genome (n = 6228. We contrast these patterns of polymorphism with insertions and deletions fixed in the same regions since the divergence of human and chimpanzee (n = 10,546. The macaque genome is used to resolve all indels into insertions and deletions. We find that the ratio of deletions to insertions is greater within humans than between human and chimpanzee. Deletions segregate at lower frequency in humans, providing evidence for deletions being under stronger purifying selection than insertions. The insertion and deletion rates correlate with several genomic features and we find evidence that both insertions and deletions are associated with point mutations. Finally, we find no evidence for a direct effect of the local recombination rate on the insertion and deletion rate. CONCLUSIONS/SIGNIFICANCE: Our data strongly suggest that deletions are more deleterious than insertions but that insertions and deletions are otherwise generally governed by the same genomic factors.

  15. Disruptive event analysis: volcanism and igneous intrusion

    International Nuclear Information System (INIS)

    Three basic topics are addressed for the disruptive event analysis: first, the range of disruptive consequences of a radioactive waste repository by volcanic activity; second, the possible reduction of the risk of disruption by volcanic activity through selective siting of a repository; and third, the quantification of the probability of repository disruption by volcanic activity

  16. Disruption studies on ASDEX upgrade

    International Nuclear Information System (INIS)

    Disruptions generate large thermal and mechanical stresses on the tokamak components and are occasionally responsible for damages to the machine. For a future reactor disruptions have a significant impact on the design since all loading conditions must be analyzed in accordance with stricter design criteria (due to safety or difficult maintenance). Therefore the uncertainties affecting the predicted stresses must be reduced as much as possible with a more comprehensive set of measurements and analyses in this generation of experimental machines, and avoidance/predictive methods must be developed further. Disruption studies on ASDEX Upgrade are focused on these subjects, namely on: (1) understanding the physical mechanisms leading to this phenomenon in order to learn to avoid it or to predict its occurrence and to mitigate its effects; (2) analyzing the effects of disruptions on the machine to determine the functional dependence of the thermal and mechanical loads upon the discharge parameters. This allows, firstly, to dimension or reinforce the machine components to withstand these loads and, secondly, to extrapolate them to tokamaks still in the design phase; (3) learning to mitigate the consequence of disruptions, i.e. thermal loads, mechanical forces and runaways with injection of impurity pellets or gas. This paper is focused on most recent results concerning points, i.e. on the analysis of the degree of asymmetry of the forces and on the use of impurity puff for mitigation

  17. Disruption studies in ASDEX Upgrade

    International Nuclear Information System (INIS)

    Disruption generate large thermal and mechanical stresses on the tokamak components. For a future reactor disruptions have a significant impact on the design since all loading conditions must be analyzed in accordance with stricter design criteria (due to safety or difficult maintenance). Therefore the uncertainties affecting the predicted stresses must be reduced as much as possible with a more comprehensive set of measurements and analyses in this generation of experimental machines, and avoidance/ predictive methods must be developed further. The study of disruptions on ASDEX Upgrade is focused on these subjects, namely on: (1) understanding the physical mechanisms leading to this phenomenon and learning to avoid it or to predict its occurrence (with neural networks, for example) and to mitigate its effects; (2) analyzing the effects of disruptions on the machine to determine the functional dependence of the thermal and mechanical loads upon the discharge parameters. This allows to dimension or reinforce the machine components to withstand these loads and to extrapolate them to tokamaks still in the design phase; (3) learning to mitigate the consequence of disruptions. (author)

  18. Deletions and candidate genes in Williams syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Perez Jurado, L.A.; Peoples, R.; Francke, U. [Stanford Univ. CA (United States)] [and others

    1994-09-01

    Hemizygosity at the elastin locus (ELN) on chromosome 7q11.23 has recently been reported in several familial and sporadic cases of the developmental disorder, Williams syndrome (WS). Because the deletion is greater than the span of the ELN gene, a contiguous gene deletion syndrome has been suggested as the probable molecular basis for this condition. Thus far, neither the size of the deletion(s), nor other genes within it are known. We have analyzed samples from 27 sporadic WS patients by genotyping two multiallelic ELN intragenic polymorphisms, detectable by PCR amplification, and by Southern blotting for ELN gene dosage. Twenty four patients were hemizygous at the ELN locus while 3 showed no deletion or detectable rearrangement. Genotype studies on parental DNA were informative in 12 of the deletions. All 12 were due to de novo events, 8 in the maternal and 4 in the paternal chromosome. In an attempt to identify genes involved in WS we are also using a candidate gene approach. Delayed clearance of an exogenous calcium load with normal or slightly increased calcitonin levels in serum has been documented in WS patients suggesting a defective calcitonin action or calcium sensing function. The calcitonin receptor (CTR) gene is, therefore, a good candidate since CTR has a dual role as a hormonal receptor for calcitonin and an extracellular calcium sensor. We have mapped the CTR gene to chromosome 7q21.1 by PCR-SSCA of somatic cell hybrids and FISH analysis. Using two color FISH with probes for ELN and CTR, both loci are located on 7q at a distance of {approximately}10 Mb, CTR being telomeric. Our CTR probe does not detect any genomic abnormality by FISH or Southern blot in the patients` samples analyzed. We have identified a diallelic polymorphism in the CTR cDNA and are currently testing the hypothesis of an impaired CTR expression as responsible for some of the clinical features of WS by analysing the CTR transcripts by RT-PCR.

  19. Probabilistic deletion of copies of linearly independent quantum states

    International Nuclear Information System (INIS)

    We show that each of two copies of the nonorthogonal states randomly selected from a certain set S can be probabilistically deleted by a general unitary-reduction operation if and only if the states are linearly independent. We derive a tight bound on the best possible deleting efficiencies. These results for 2→1 probabilistic deleting are also generalized into the case of N→M deleting (N,M positive integers and N>M)

  20. Comparative studies of genome-wide maps of nucleosomes between deletion mutants of elp3 and hos2 genes of Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Takashi Matsumoto

    Full Text Available In order to elucidate the influence of histone acetylation upon nucleosomal DNA length and nucleosome position, we compared nucleosome maps of the following three yeast strains; strain BY4741 (control, the elp3 (one of histone acetyltransferase genes deletion mutant, and the hos2 (one of histone deactylase genes deletion mutant of Saccharomyces cerevisiae. We sequenced mononucleosomal DNA fragments after treatment with micrococcal nuclease. After mapping the DNA fragments to the genome, we identified the nucleosome positions. We showed that the distributions of the nucleosomal DNA lengths of the control and the hos2 disruptant were similar. On the other hand, the distribution of the nucleosomal DNA lengths of the elp3 disruptant shifted toward shorter than that of the control. It strongly suggests that inhibition of Elp3-induced histone acetylation causes the nucleosomal DNA length reduction. Next, we compared the profiles of nucleosome mapping numbers in gene promoter regions between the control and the disruptant. We detected 24 genes with low conservation level of nucleosome positions in promoters between the control and the elp3 disruptant as well as between the control and the hos2 disruptant. It indicates that both Elp3-induced acetylation and Hos2-induced deacetylation influence the nucleosome positions in the promoters of those 24 genes. Interestingly, in 19 of the 24 genes, the profiles of nucleosome mapping numbers were similar between the two disruptants.

  1. 42 CFR 401.118 - Deletion of identifying details.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 2 2010-10-01 2010-10-01 false Deletion of identifying details. 401.118 Section... Deletion of identifying details. When CMS publishes or otherwise makes available an opinion or order... identifying details will be deleted....

  2. Interstitial deletion of the short arm of chromosome 4.

    OpenAIRE

    Ray, M; Evans, J.; Rockman-Greenberg, C; Wickstrom, D

    1984-01-01

    A 17 year old girl investigated for mental retardation and minor anomalies was found to have an interstitial deletion of 4p. Her clinical and cytogenetic findings are compared with previous reported case of interstitial 4p deletion and with terminal 4p--deletions (Wolf-Hirschhorn syndrome).

  3. Rac1 deletion causes thymic atrophy.

    Directory of Open Access Journals (Sweden)

    Lukas Hunziker

    Full Text Available The thymic stroma supports T lymphocyte development and consists of an epithelium maintained by thymic epithelial progenitors. The molecular pathways that govern epithelial homeostasis are poorly understood. Here we demonstrate that deletion of Rac1 in Keratin 5/Keratin 14 expressing embryonic and adult thymic epithelial cells leads to loss of the thymic epithelial compartment. Rac1 deletion led to an increase in c-Myc expression and a generalized increase in apoptosis associated with a decrease in thymic epithelial proliferation. Our results suggest Rac1 maintains the epithelial population, and equilibrium between Rac1 and c-Myc may control proliferation, apoptosis and maturation of the thymic epithelial compartment. Understanding thymic epithelial maintenance is a step toward the dual goals of in vitro thymic epithelial cell culture and T cell differentiation, and the clinical repair of thymic damage from graft-versus-host-disease, chemotherapy or irradiation.

  4. Orbital deletion procedure and its applications

    Institute of Scientific and Technical Information of China (English)

    莫亦荣; 林梦海; 吴玮; 张乾二

    1999-01-01

    The orbital deletion procedure is introduced, which is suited to quantitatively investigating the electronic delocalization effiect in earboeations and boranes. While the routine, ab initio molecular orbital methods can generate wavefunetions for real systems where all electrons are delocalized, the present orbital deletion procedure can generate wavefunctions for hypothetical reference molecules where electronic delocalization effect is deactivated. The latter wavefunetion normlly corresponds In the most stable resonance structure in terms of the resonance theory. By comparing and analyzing the delocalized and the localized wavefunetions, one can obtain a quantitative and instinct pieture to show how electronic deloealizalion inside a molecule affects the molecular structure, energy as well as other physical properties. Two examples are detailedly discussed. The first is related to the hypercoujugation of alkyl groups in carbocations and a comparison of the order of stability of carbocations is made, T

  5. Deletion Diagnostics for Alternating Logistic Regressions

    OpenAIRE

    Preisser, John S; By, Kunthel; Perin, Jamie; Qaqish, Bahjat F.

    2012-01-01

    Deletion diagnostics are introduced for the regression analysis of clustered binary outcomes estimated with alternating logistic regressions, an implementation of generalized estimating equations (GEE) that estimates regression coefficients in a marginal mean model and in a model for the intracluster association given by the log odds ratio. The diagnostics are developed within an estimating equations framework that recasts the estimating functions for association parameters based upon conditi...

  6. FOXP2 gene deletion and infant feeding difficulties: a case report.

    Science.gov (United States)

    Zimmerman, Emily; Maron, Jill L

    2016-01-01

    Forkhead box protein P2 (FOXP2) is a well-studied gene known to play an essential role in normal speech development. Deletions in the gene have been shown to result in developmental speech disorders and regulatory disruption of downstream gene targets associated with common forms of language impairments. Despite similarities in motor planning and execution between speech development and oral feeding competence, there have been no reports to date linking deletions within the FOXP2 gene to oral feeding impairments in the newborn. The patient was a nondysmorphic, appropriately and symmetrically grown male infant born at 35-wk gestational age. He had a prolonged neonatal intensive care unit stay because of persistent oral feeding incoordination requiring gastrostomy tube placement. Cardiac and neurological imagings were within normal limits. A microarray analysis found an ∼9-kb loss within chromosome band 7q3.1 that contains exon 2 of FOXP2, demonstrating a single copy of this region instead of the normal two copies per diploid gene. This case study expands our current understanding of the role FOXP2 exerts on motor planning and coordination necessary for both oral feeding success and speech-language development. This case report has important consequences for future diagnosis and treatment for infants with FOXP2 deletions, mutations, and varying levels of gene expression. PMID:27148578

  7. FOXP2 gene deletion and infant feeding difficulties: a case report

    Science.gov (United States)

    Zimmerman, Emily; Maron, Jill L.

    2016-01-01

    Forkhead box protein P2 (FOXP2) is a well-studied gene known to play an essential role in normal speech development. Deletions in the gene have been shown to result in developmental speech disorders and regulatory disruption of downstream gene targets associated with common forms of language impairments. Despite similarities in motor planning and execution between speech development and oral feeding competence, there have been no reports to date linking deletions within the FOXP2 gene to oral feeding impairments in the newborn. The patient was a nondysmorphic, appropriately and symmetrically grown male infant born at 35-wk gestational age. He had a prolonged neonatal intensive care unit stay because of persistent oral feeding incoordination requiring gastrostomy tube placement. Cardiac and neurological imagings were within normal limits. A microarray analysis found an ∼9-kb loss within chromosome band 7q3.1 that contains exon 2 of FOXP2, demonstrating a single copy of this region instead of the normal two copies per diploid gene. This case study expands our current understanding of the role FOXP2 exerts on motor planning and coordination necessary for both oral feeding success and speech–language development. This case report has important consequences for future diagnosis and treatment for infants with FOXP2 deletions, mutations, and varying levels of gene expression.

  8. Deletion of Dystrophin In-Frame Exon 5 Leads to a Severe Phenotype: Guidance for Exon Skipping Strategies.

    Science.gov (United States)

    Toh, Zhi Yon Charles; Thandar Aung-Htut, May; Pinniger, Gavin; Adams, Abbie M; Krishnaswarmy, Sudarsan; Wong, Brenda L; Fletcher, Sue; Wilton, Steve D

    2016-01-01

    Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels) manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes. PMID:26745801

  9. Deletion of Dystrophin In-Frame Exon 5 Leads to a Severe Phenotype: Guidance for Exon Skipping Strategies.

    Directory of Open Access Journals (Sweden)

    Zhi Yon Charles Toh

    Full Text Available Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes.

  10. Secure Deletion of Data from SSD

    Directory of Open Access Journals (Sweden)

    Akli Fundo

    2014-08-01

    Full Text Available The deletion of data from storage is an important component on data security. The deletion of entire disc or special files is well-known on hard drives, but this is quite different on SSDs, because they have a different architecture inside, and the main problem is if they serve the same methods like hard drives for data deletion or erasing. The built-in operations are used to do this on SSDs. The purpose of this review is to analyses some methods which are proposed to erase data form SSDs and their results too, to see which of them offers the best choice. In general we will see that the techniques of erasing data from entire disc from hard drives can be used also on SSDs, but there’s a problem with bugs. On the other hand, we cannot use the same techniques of erasing a file from hard drives and SSDs. To make this possible, there are required changes in FTL layer, which is responsible for mapping between logic addresses and physical addresses.

  11. JET and COMPASS asymmetrical disruptions

    Czech Academy of Sciences Publication Activity Database

    Gerasimov, S.N.; Abreu, P.; Baruzzo, M.; Drozdov, V.; Dvornova, A.; Havlíček, Josef; Hender, T.C.; Hronová-Bilyková, Olena; Kruezi, U.; Li, X.; Markovič, Tomáš; Pánek, Radomír; Rubinacci, G.; Tsalas, M.; Ventre, S.; Villone, F.; Zakharov, L.E.

    2015-01-01

    Roč. 55, č. 11 (2015), s. 113006-113006. ISSN 0029-5515 R&D Projects: GA MŠk(CZ) LM2011021 Institutional support: RVO:61389021 Keywords : tokamak * asymmetrical disruption * JET * COMPASS Subject RIV: BL - Plasma and Gas Discharge Physics Impact factor: 3.062, year: 2014

  12. Disruptive Innovation in Healthcare & Rehabilitation

    DEFF Research Database (Denmark)

    Brooks, Anthony Lewis

    2014-01-01

    Disruption is a powerful body of theory that describes how people interact and react, how behavior is shaped, how organizational cultures form and influence decisions. Innovation is the process of translating an idea or invention into a product or service that creates value or for which customers...

  13. Supply disruption cost for power network planning

    International Nuclear Information System (INIS)

    A description is given of the method of approach to calculate the total annual socio-economic cost of power supply disruption and non-supplied energy, included the utilities' cost for planning. The total socio-economic supply disruption cost is the sum of the customers' disruption cost and the utilities' cost for failure and disruption. The mean weighted disruption cost for Norway for one hour disruption is NOK 19 per kWh. The customers' annual disruption cost is calculated with basis in the specific disruption cost referred to heavy load (January) and dimensioning maximum loads. The loads are reduced by factors taking into account the time variations of the failure frequency, duration, the loads and the disruption cost. 6 refs

  14. Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis.

    Science.gov (United States)

    Dever, Daniel P; Adham, Zachariah O; Thompson, Bryan; Genestine, Matthieu; Cherry, Jonathan; Olschowka, John A; DiCicco-Bloom, Emanuel; Opanashuk, Lisa A

    2016-05-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated member of the basic-helix-loop-helix/PER-ARNT-SIM(PAS) transcription factor superfamily that also mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence suggests that AhR influences the development of many tissues, including the central nervous system. Our previous studies suggest that sustained AhR activation by TCDD and/or AhR deletion disrupts cerebellar granule neuron precursor (GNP) development. In the current study, to determine whether endogenous AhR controls GNP development in a cell-autonomous manner, we created a GNP-specific AhR deletion mouse, AhR(fx/fx) /Math1(CRE/+) (AhR CKO). Selective AhR deletion in GNPs produced abnormalities in proliferation and differentiation. Specifically, fewer GNPs were engaged in S-phase, as demonstrated by ∼25% reductions in thymidine (in vitro) and Bromodeoxyuridine (in vivo) incorporation. Furthermore, total granule neuron numbers in the internal granule layer at PND21 and PND60 were diminished in AhR conditional knockout (CKO) mice compared with controls. Conversely, differentiation was enhanced, including ∼40% increase in neurite outgrowth and 50% increase in GABARα6 receptor expression in deletion mutants. Our results suggest that AhR activity plays a role in regulating granule neuron number and differentiation, possibly by coordinating this GNP developmental transition. These studies provide novel insights for understanding the normal roles of AhR signaling during cerebellar granule cell neurogenesis and may have important implications for the effects of environmental factors in cerebellar dysgenesis. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 533-550, 2016. PMID:26243376

  15. Obtaining a Planar Graph by Vertex Deletion

    OpenAIRE

    Marx, Dániel; Schlotter, Ildikó

    2008-01-01

    In the k-Apex problem the task is to find at most k vertices whose deletion makes the given graph planar. The graphs for which there exists a solution form a minor closed class of graphs, hence by the deep results of Robertson and Seymour, there is an O(n^3) time algorithm for every fixed value of k. However, the proof is extremely complicated and the constants hidden by the big-O notation are huge. Here we give a much simpler algorithm for this problem with quadratic running time, by iterati...

  16. A high-throughput gene disruption methodology for the entomopathogenic fungus Metarhizium robertsii.

    Directory of Open Access Journals (Sweden)

    Chuan Xu

    Full Text Available Systematic gene disruption is a direct way to interrogate a fungal genome to functionally characterize the full suite of genes involved in various biological processes. Metarhizium robertsii is extraordinarily versatile, and it is a pathogen of arthropods, a saprophyte and a beneficial colonizer of rhizospheres. Thus, M. robertsii can be used as a representative to simultaneously study several major lifestyles that are not shared by the "model" fungi Saccharomyces cerevisiae and Neurospora crassa; a systematic genetic analysis of M. robertsii will benefit studies in other fungi. In order to systematically disrupt genes in M. robertsii, we developed a high-throughput gene disruption methodology, which includes two technologies. One is the modified OSCAR-based, high-throughput construction of gene disruption plasmids. This technology involves two donor plasmids (pA-Bar-OSCAR with the herbicide resistance genes Bar and pA-Sur-OSCAR with another herbicide resistance gene Sur and a recipient binary plasmid pPK2-OSCAR-GFP that was produced by replacing the Bar cassette in pPK2-bar-GFP with a ccdB cassette and recombination recognition sites. Using this technology, a gene disruption plasmid can be constructed in one cloning step in two days. The other is a highly efficient gene disruption technology based on homologous recombination using a Ku70 deletion mutant (ΔMrKu70 as the recipient strain. The deletion of MrKu70, a gene encoding a key component involved in nonhomologous end-joining DNA repair in fungi, dramatically increases the gene disruption efficiency. The frequency of disrupting the conidiation-associated gene Cag8 in ΔMrKu70 was 93% compared to 7% in the wild-type strain. Since ΔMrKu70 is not different from the wild-type strain in development, pathogenicity and tolerance to various abiotic stresses, it can be used as a recipient strain for a systematic gene disruption project to characterize the whole suite of genes involved in the

  17. Detection of mitochondrial DNA deletion by a modified PCR method

    Institute of Scientific and Technical Information of China (English)

    汪振诚; 王学敏; 缪明永; 章卫平; 焦炳华; 倪庆桂

    2003-01-01

    Objective: To develop a simple and efficient method for detecting small populations of mitochondrial DNA deletion. Methods: Peripheral blood cell DNA was obtained from a victim who was accidently exposed to a 60Co radiation source 11 years ago. Using the DNA as template, PCR was performed to generate multiple products including true deletions and artifacts. The full length product was recovered and used as template of secondary PCR. The suspicious deletion product of mtDNA could be confirmed if it was only yielded by first PCR. Using either original primers or their nested primers, the suspicious deletion product was amplified and authenticated as true deletion product. The template was recovered and determined to be a deletion by sequencing directly. Results: A new mtDNA deletion, spanning 889 bp from nt11688 to nt12576, was detected in the peripheral blood cells of the victim. Conclusion: The new PCR-based method is more efficient in detecting small populations of mtDNA deletion than other routine methods. MtDNA deletion is found in the victim, suggesting there is relationship between the deletion and phenotypes of the disease.

  18. Secure Deletion on Log-structured File Systems

    CERN Document Server

    Reardon, Joel; Capkun, Srdjan; Basin, David

    2011-01-01

    We address the problem of secure data deletion on log-structured file systems. We focus on the YAFFS file system, widely used on Android smartphones. We show that these systems provide no temporal guarantees on data deletion and that deleted data still persists for nearly 44 hours with average phone use and indefinitely if the phone is not used after the deletion. Furthermore, we show that file overwriting and encryption, methods commonly used for secure deletion on block-structured file systems, do not ensure data deletion in log-structured file systems. We propose three mechanisms for secure deletion on log-structured file systems. Purging is a user-level mechanism that guarantees secure deletion at the cost of negligible device wear. Ballooning is a user-level mechanism that runs continuously and gives probabilistic improvements to secure deletion. Zero overwriting is a kernel-level mechanism that guarantees immediate secure deletion without device wear. We implement these mechanisms on Nexus One smartphon...

  19. Optimal Disruption of Complex Networks

    CERN Document Server

    Zhao, Jin-Hua

    2016-01-01

    The collection of all the strongly connected components in a directed graph, among each cluster of which any node has a path to another node, is a typical example of the intertwining structure and dynamics in complex networks, as its relative size indicates network cohesion and it also composes of all the feedback cycles in the network. Here we consider finding an optimal strategy with minimal effort in removal arcs (for example, deactivation of directed interactions) to fragment all the strongly connected components into tree structure with no effect from feedback mechanism. We map the optimal network disruption problem to the minimal feedback arc set problem, a non-deterministically polynomial hard combinatorial optimization problem in graph theory. We solve the problem with statistical physical methods from spin glass theory, resulting in a simple numerical method to extract sub-optimal disruption arc sets with significantly better results than a local heuristic method and a simulated annealing method both...

  20. Disrupting the habit of interviewing

    Directory of Open Access Journals (Sweden)

    Eileen Honan

    2014-06-01

    Full Text Available This paper contributes to the growing domain of ‘post-qualitative’ research and experiments with a new (representational form to move away from traditional and clichéd descriptions of research methods. In this paper, I want to interrogate the category of interview, and the habit of interviewing, to disrupt the clichés, so as to allow thinking of different ways of writing/speaking/representing the interactions between researcher and researched that will breathe new life into qualitative inquiries. I will attempt to flatten and shred, destabilise and disrupt our common-sense ideas about interview, including those held most sacred to the qualitative community, that of anonymity and confidentiality, as well as the privilege of the ‘transcript’ in re-presenting interview data.

  1. Heme Oxygenase-1 Deletion Affects Stress Erythropoiesis

    OpenAIRE

    Cao, Yu-An; Kusy, Sophie; Luong, Richard; Wong, Ronald J.; Stevenson, David K.; Contag, Christopher H.

    2011-01-01

    Background Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here,...

  2. Disruptive technologies in higher education

    Directory of Open Access Journals (Sweden)

    Michael Flavin

    2012-08-01

    Full Text Available This paper analyses the role of “disruptive” innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs being more or less universal, but these technologies have not been universally adopted and used by students and staff. Instead, other technologies not owned or controlled by HEIs are widely used to support learning and teaching. According to Christensen's theory of Disruptive Innovation, these disruptive technologies are not designed explicitly to support learning and teaching in higher education, but have educational potential. This study uses Activity Theory and Expansive Learning to analyse data regarding the impact of disruptive technologies. The data were obtained through a questionnaire survey about awareness and use of technologies, and through observation and interviews, exploring participants’ actual practice. The survey answers tended to endorse Disruptive Innovation theory, with participants establishing meanings for technologies through their use of them, rather than in keeping with a designer's intentions. Observation revealed that learners use a narrow range of technologies to support learning, but with a tendency to use resources other than those supplied by their HEIs. Interviews showed that participants use simple and convenient technologies to support their learning and teaching. This study identifies a contradiction between learning technologies made available by HEIs, and technologies used in practice. There is no evidence to suggest that a wide range of technologies is being used to support learning and teaching. Instead, a small range of technologies is being used for a wide range of tasks. Students and lecturers are not dependent on their HEIs to support learning and teaching. Instead, they self-select technologies, with use weighted towards established brands. The

  3. Thyroid effects of endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Boas, Malene; Feldt-Rasmussen, Ulla; Main, Katharina M

    2012-01-01

    In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert ...... thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties....

  4. HOW TO IDENTIFY DISRUPTIVE NEW BUSINESSES

    OpenAIRE

    Elizabeth Robles

    2015-01-01

    In almost any industry, the most dramatic stories of growth and success were launched from a platform of disruptive innovation (Christensen et al., 2002). The probability of creating a successful, new growth business is 10 times greater if the innovators pursue a disruptive strategy rather than a sustaining one. Genuinely disruptive innovations are the ones that result in the creation of entirely new markets and business models. Few companies have introduced these innovations. Disruptive inno...

  5. Turbulence and disruptions in Tokamaks

    International Nuclear Information System (INIS)

    In the first part of this thesis, the possible explanation of the electron abnormal thermal conductivity with electromagnetic drift modes rather than simply electrostatic is discussed. A variational form is established in non collisional conditions; linear modes principal possibilities are reviewed, then quasilinear theory is used to calculate the transport phenomenon associated to each mode. They are compared to experimental results. Electron abnormal thermal conductibility is not better explained by electromagnetic modes than by electrostatic modes. In the second part, disruptions are examined; experimental manifestations are briefly recalled. Existing interpretations of these phenomenons are reviewed, which are based on magnetic islands non-linear evolution. A detailed analytical study of the case l=1, m=1 is made. Other disruptions are studied; it is shown that the disruptive process is indissociable from sudden apparition of small scale magnetic turbulence. The possibility of such a turbulence is studied. Its predictable effects are compared to experiment. Such a turbulence, is assumed to exist permanently in an attenuated form, which could justify the electronic transport anomalies in quiescent state

  6. Pharmacological disruption of maladaptive memory.

    Science.gov (United States)

    Taylor, Jane R; Torregrossa, Mary M

    2015-01-01

    Many psychiatric disorders are characterized by intrusive, distracting, and disturbing memories that either perpetuate the illness or hinder successful treatment. For example, posttraumatic stress disorder (PTSD) involves such strong reemergence of memories associated with a traumatic event that the individual feels like the event is happening again. Furthermore, drug addiction is characterized by compulsive use and repeated relapse that is often driven by internal memories of drug use and/or by exposure to external stimuli that were associated with drug use. Therefore, identifying pharmacological methods to weaken the strength of maladaptive memories is a major goal of research efforts aimed at finding new treatments for these disorders. The primary mechanism by which memories could be pharmacologically disrupted or altered is through manipulation of memory reconsolidation. Reconsolidation occurs when an established memory is remembered or reactivated, reentering a labile state before again being consolidated into long-term memory storage. Memories are subject to disruption during this labile state. In this chapter we will discuss the preclinical and clinical studies identifying potential pharmacological methods for disrupting the integrity of maladaptive memory to treat mental illness. PMID:25977090

  7. Engineering analysis of TFTR disruption

    International Nuclear Information System (INIS)

    This report covers an engineering approach quantifying the currents, forces, and times, as well as plasma position, for the worst-case disruption based on engineerign circuit assumptions for the plasma. As the plasma moves toward the wall during the current-decay phase of disruption, the wall currents affect the rate of movement and, hence, the decay time. The calculated structure-induced currents differ considerably from those calculated using a presently available criterion, which specifies that the plasma remains stationary in the center of the torus while decaying in 10 ms. This report outlines the method and basis for the engineering calculation used to determine the current and forces as a function of the circuit characteristics. It provides specific calculations for the Tokamak Fusion Test Reactor (TFTR) with variations in parameters such as the thermal decay time, the torus resistance, and plasma temperature during the current decay. The study reviews possible ways to reduce the disruption damage of TFTR by reducing the magnitude of the plasma external field energy that is absorbed by the plasma during the current decay

  8. Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy

    DEFF Research Database (Denmark)

    Bisgaard, A-M; Kirchhoff, M; Nielsen, J E; Kibaek, M; Lund, A; Schwartz, M; Christensen, E

    2008-01-01

    A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA) and...

  9. Deletion of ultraconserved elements yields viable mice

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Zhu, Yiwen; Visel, Axel; Holt, Amy; Afzal, Veena; Pennacchio, Len A.; Rubin, Edward M.

    2007-07-15

    Ultraconserved elements have been suggested to retainextended perfect sequence identity between the human, mouse, and ratgenomes due to essential functional properties. To investigate thenecessities of these elements in vivo, we removed four non-codingultraconserved elements (ranging in length from 222 to 731 base pairs)from the mouse genome. To maximize the likelihood of observing aphenotype, we chose to delete elements that function as enhancers in amouse transgenic assay and that are near genes that exhibit markedphenotypes both when completely inactivated in the mouse as well as whentheir expression is altered due to other genomic modifications.Remarkably, all four resulting lines of mice lacking these ultraconservedelements were viable and fertile, and failed to reveal any criticalabnormalities when assayed for a variety of phenotypes including growth,longevity, pathology and metabolism. In addition more targeted screens,informed by the abnormalities observed in mice where genes in proximityto the investigated elements had been altered, also failed to revealnotable abnormalities. These results, while not inclusive of all thepossible phenotypic impact of the deleted sequences, indicate thatextreme sequence constraint does not necessarily reflect crucialfunctions required for viability.

  10. Rare human diseases: 9p deletion syndrome

    Directory of Open Access Journals (Sweden)

    Galagan V.O.

    2014-09-01

    Full Text Available Objective of the study was to review the anamnesis, pheno - and genotype in patients with rare chromosome disorders such as 9p deletion syndrome. Genetic methods of investigation (clinical and genealogical, cytogenetic, FISH- method, paraclinical and instrumental methods of examination were used. Karyotyping was performed by the G-method of differential staining of chromosomes. Only three cases of pathology were diagnosed in the Medical Genetics Center over the last 10 years. By anamnesis data nobody in the probands’ families had bad habits, was exposed to occupational hazards, took part in the elimination of the Chernobyl accident or lived in contaminated areas. Clinical signs of diseases have not been identified in probands’ parents. All probands had trigonocephaly, bilateral epicanthal folds, ocular hypertelorism, downslanting palpebral fissures, long philtrum, flat face and nasal bridge, low set ears with malformed auricles. Two patients of three ones had exophthalmos, contracture of the second and third fingers, abnormal external genitalia. In all three cases there was monosomy of chromosome 9 of critical segment p 24. Normal karyotypes were seen in all parents, so there were three cases of new mutations of 9p deletion syndrome. Retardation of physical, psycho-spech, mental development in proband with or without congenital anomalies requires medical genetic counseling in a specialized institution. Cases of reproductive loss in anamnesis require cytogenetic investigation of fetal membranes and amniotic fluid.

  11. The disruptive instability in Tokamak plasmas

    NARCIS (Netherlands)

    Salzedas, F.J.B.

    2001-01-01

    Studies performed in RTP (Rijnhuizen Tokamak Project) of the most violent and dangerous instability in tokamak plasmas, the major disruption, are presented. A particular class of disruptions is analyzed, namely the density limit disruption, which occur in high density plasmas. The radiative te

  12. Genetic deletion of the desmosomal component desmoplakin promotes tumor microinvasion in a mouse model of pancreatic neuroendocrine carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Matthew G H Chun

    2010-09-01

    Full Text Available We used the RIP1-Tag2 (RT2 mouse model of islet cell carcinogenesis to profile the transcriptome of pancreatic neuroendocrine tumors (PNET that were either non-invasive or highly invasive, seeking to identify pro- and anti-invasive molecules. Expression of multiple components of desmosomes, structures that help maintain cellular adhesion, was significantly reduced in invasive carcinomas. Genetic deletion of one of these desmosomal components, desmoplakin, resulted in increased local tumor invasion without affecting tumor growth parameters in RT2 PNETs. Expression of cadherin 1, a component of the adherens junction adhesion complex, was maintained in these tumors despite the genetic deletion of desmoplakin. Our results demonstrate that loss of desmoplakin expression and resultant disruption of desmosomal adhesion can promote increased local tumor invasion independent of adherens junction status.

  13. Are there ethnic differences in deletions in the dystrophin gene?

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, M.; Verma, I.C. [All India Inst. of Medical Sciences, New Delhi (India)

    1997-01-20

    We studied 160 cases of Duchenne muscular dystrophy (DMD) drawn from all parts of India, using multiplex PCR of 27 exons. Of these, 103 (64.4%) showed intragenic deletions. Most (69.7%) of the deletions involved exons 45-51. The phenotype of cases with deletion of single exons did not differ significantly from those with deletion of multiple exons. The distribution of deletions in studies from different countries was variable, but this was accounted for either by the small number of cases studied, or by fewer exons analyzed. It is concluded that there is likely to be no ethnic difference with respect to deletions in the DMD gene. 38 refs., 2 figs., 3 tabs.

  14. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders.

    Science.gov (United States)

    Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I; Sankaran, Vijay G

    2016-04-19

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptionalcis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  15. Alterations in growth and cell death by genetic deletion of the antioxidan response factor Nrf2 ist target, the quinone reductase NQ01

    OpenAIRE

    Ariza Gómez, Julia

    2015-01-01

    To neutralize oxidative stress insults, cells have acquire complex defense mechanisms which are induced in a highly coordinated way. This coordinated response is regulated through a cis-regulatory element, called the antioxidant responsive element (ARE) or electrophile-responsive element (EpRE), located within the regulatory region of target genes (Friling, Bensimon et al. 1990, Rushmore, Morton et al. 1991). Nrf2 (Nuclear factor erythroid 2 related factor, NF-E2-related factor...

  16. A deletion map of the WAGR region on chromosome 11.

    OpenAIRE

    Gessler, M; Thomas, G H; Couillin, P; Junien, C; McGillivray, B C; Hayden, M; Jaschek, G.; Bruns, G. A.

    1989-01-01

    The WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) region has been assigned to chromosome 11p13 on the basis of overlapping constitutional deletions found in affected individuals. We have utilized 31 DNA probes which map to the WAGR deletion region, together with six reference loci and 13 WAGR-related deletions, to subdivide this area into 16 intervals. Specific intervals have been correlated with phenotypic features, leading to the identification of individual ...

  17. RNA-Editing with Combined Insertion and Deletion Preserves Regularity

    OpenAIRE

    Vink, E.P.; Zantema, H.; Bosnacki, D.

    2013-01-01

    We consider two elementary forms of string rewriting called guided insertion/deletion and guided rewriting. The original strings are modified depending on the match with a given set of auxiliary strings, called guides. Guided insertion/deletion considers matching of a string and a guide with respect to a specific correspondence of strings. Guided rewriting considers matching of a string and a guide with respect to an equivalence relation on the alphabet. Guided insertion/deletion is inspired ...

  18. Analysis of partial AZFc deletions in Malaysian infertile male subjects.

    Science.gov (United States)

    Almeamar, Hussein Ali; Ramachandran, Vasudevan; Ismail, Patimah; Nadkarni, Prashan; Fawzi, Nora

    2013-04-01

    Complete deletions in the AZF (a, b, and c) sub-regions of the Y-chromosome have been shown to contribute to unexplained male infertility. However, the role of partial AZFc deletions in male infertility remains to be verified. Three types of partial AZFc deletions have been identified. They are gr/gr, b1/b3, and b2/b3 deletions. A recent meta-analysis showed that ethnic and geographical factors might contribute to the association of partial AZFc deletions with male infertility. This study analyzed the association of partial AZFc deletions in Malaysian infertile males. Fifty two oligozoospermic infertile males and 63 fertile controls were recruited to this study. Screening for partial AZFc deletions was done using the two sequence-tagged sites approach (SY1291 and SY1191) which were analyzed using both the conventional PCR gel-electrophoresis and the high resolution melt, HRM method. Gr/gr deletions were found in 11.53% of the cases and 9.52% of the controls (p = 0.725). A B2/b3 deletion was found in one of the cases (p = 0.269). No B1/b3 deletions were identified in this study. The results of HRM analysis were consistent with those obtained using the conventional PCR gel-electrophoresis method. The HRM analysis was highly repeatable (95% limit of agreement was -0.0879 to 0.0871 for SY1191 melting temperature readings). In conclusion, our study showed that partial AZFc deletions were not associated with male infertility in Malaysian subjects. HRM analysis was a reliable, repeatable, fast, cost-effective, and semi-automated method which can be used for screening of partial AZFc deletions. PMID:23231020

  19. Deletions of the elastin gene in Williams Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Greenberg, F.; Nickerson, E.; McCaskill, C. [Baylor College of Medicine, Houston, TX (United States)] [and others

    1994-09-01

    To investigate deletions in the elastin gene in patients with Williams Syndrome (WS), we screened 37 patients and their parents for deletions in the elastin gene by both fluorescence in situ hybridization (FISH) using cosmid cELN272 containing the 5{prime} end of the elastin gene and by polymerase chain reaction (PCR) using a primer pair which amplifies intron 17 in the elastin gene, producing a polymorphic amplification product. Thirty-two patients have been investigated by both the FISH and PCR techniques, one patient was studied only by PCR, and 4 patients were studied only by FISH. Overall, 34 of 37 patients (92%) were deleted for the elastin gene. Using the PCR marker, 14 patients were informative and 12 were shown to be deleted [maternal (n=5) and paternal (n=7)]. Using cosmid cELN272, 33 of 36 patients demonstrated a deletion of chromosome 7q11.23. In one family, both the mother and daughter were deleted due to an apparently de novo deletion arising in the mother. Three patients were not deleted using the elastin cosmid; 2 of these patients have classic WS. Another non-deleted patient has the typical facial features and hypercalcemia but normal intelligence. These three patients will be important in delineating the critical region(s) responsible for the facial features, hypercalcemia, mental retardation and supravalvular aortic stenosis (SVAS). There was not an absolute correlation between deletions in elastin and SVAS, although these individuals may be at risk for other cardiovascular complications such as hypertention. Since the majority of WS patients are deleted for a portion of the elastin gene, most likely this marker will be an important diagnostic tool, although more patients will need to be studied. Those patients who are not deleted but clinically have WS will be missed using only this one marker. Expansion of the critical region to other loci and identification of additional markers will be essential for identifying all patients with WS.

  20. Feasibility of establishing deletion of the late cornified envelope genes LCE3B and LCE3C as a susceptibility factor for psoriasis

    Science.gov (United States)

    Bashir, Safia; Hassan, Iffat; Majid, Sabhiya; Bhat, Yasmeen Jabeen; Farooq, Rabia

    2016-01-01

    Background: Psoriasis is a chronic hyperproliferative inflammatory disease of the skin, genetic predisposition to which is well-established. The late cornified envelope genes LCE3B and LCE3C are involved in maintaining the integrity of skin barrier especially following skin barrier disruption. The deletion of these genes would lead to an impaired epidermal response following damage to the skin barrier thus predisposing to psoriatic lesions. This study aimed to evaluate the common deletion of late cornified envelope genes (LCE 3B/3C) in psoriasis patients of Kashmiri ethnic population of North India. Materials and Methods: It was a hospital-based, case-control study which included 100 psoriasis cases and an equal number of controls. Blood samples were obtained, and DNA was extracted from all the samples by a kit-based method. To determine the LCE3C_LCE3B-del genotype, a three-primer polymerase chain reaction assay was performed. Results: The genotype for the common LCE3C_LCE3B deletion in 100 psoriasis patients and 100 controls was determined. Among the cases, 17 cases were homozygous for insertion genotype (I/I), 40 cases were heterozygous for insertion/deletion genotype (I/D) and 43 cases were homozygous for deletion genotype (D/D), compared to controls where 20 cases were homozygous for insertion genotype (I/I), 45 cases were heterozygous for insertion/deletion genotype (I/D), and 35 cases were homozygous for deletion genotype (D/D). The del/del frequency was higher among psoriatic patients compared to controls (43% vs. 35%) although the difference was not statistically significant (P = 0.507). Conclusion: We hereby infer that LCE3C_LCE3B deletion does not appear to be associated with the risk of psoriasis in our population. PMID:27376048

  1. A Domesticated piggyBac Transposase Plays Key Roles in Heterochromatin Dynamics and DNA Cleavage during Programmed DNA Deletion in Tetrahymena thermophila

    OpenAIRE

    Cheng CY; Vogt A; Mochizuki K.; Yao MC

    2010-01-01

    Transposons comprise large fractions of eukaryotic genomes and provide genetic reservoirs for the evolution of new cellular functions. We identified TPB2, a homolog of the piggyBac transposase gene that is required for programmed DNA deletion in Tetrahymena. TPB2 was expressed exclusively during the time of DNA excision, and its encoded protein Tpb2p was localized in DNA elimination heterochromatin structures. Notably, silencing of TPB2 by RNAi disrupts the final assembly of these heterochrom...

  2. On fixed-parameter algorithms for Split Vertex Deletion

    OpenAIRE

    CYGAN, Marek; Pilipczuk, Marcin

    2012-01-01

    In the Split Vertex Deletion problem, given a graph G and an integer k, we ask whether one can delete k vertices from the graph G to obtain a split graph (i.e., a graph, whose vertex set can be partitioned into two sets: one inducing a clique and the second one inducing an independent set). In this paper we study fixed-parameter algorithms for Split Vertex Deletion parameterized by k: we show that, up to a factor quasipolynomial in k and polynomial in n, the Split Vertex Deletion problem can ...

  3. Mutational Mechanisms of Williams-Beuren Syndrome Deletions

    OpenAIRE

    Bayés, Mònica; Magano, Luis F.; Rivera, Núria; Flores, Raquel; A. Pérez Jurado, Luis

    2003-01-01

    Williams-Beuren syndrome (WBS) is a segmental aneusomy syndrome that results from a heterozygous deletion of contiguous genes at 7q11.23. Three large region-specific low-copy repeat elements (LCRs), composed of different blocks (A, B, and C), flank the WBS deletion interval and are thought to predispose to misalignment and unequal crossing-over, causing the deletions. In this study, we have determined the exact deletion size and LCR copy number in 74 patients with WBS, as well as precisely de...

  4. Zinc transporter 3 (ZnT3) gene deletion reduces spinal cord white matter damage and motor deficits in a murine MOG-induced multiple sclerosis model.

    Science.gov (United States)

    Choi, Bo Young; Kim, In Yeol; Kim, Jin Hee; Kho, A Ra; Lee, Song Hee; Lee, Bo Eun; Sohn, Min; Koh, Jae-Young; Suh, Sang Won

    2016-10-01

    The present study aimed to evaluate the role of zinc transporter 3 (ZnT3) on multiple sclerosis (MS) pathogenesis. Experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis, was induced by immunization with myelin oligodendrocyte glycoprotein (MOG35-55) in female mice. Three weeks after the initial immunization, demyelination, immune cell infiltration and blood brain barrier (BBB) disruption in the spinal cord were analyzed. Clinical signs of EAE first appeared on day 11 and reached a peak level on day 19 after the initial immunization. ZnT3 gene deletion profoundly reduced the daily clinical score of EAE. The ZnT3 gene deletion-mediated inhibition of the clinical course of EAE was accompanied by suppression of inflammation and demyelination in the spinal cord. The motor deficit accompanying neuropathological changes associated with EAE were mild in ZnT3 gene deletion mice. This reduction in motor deficit was accompanied by coincident reductions in demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, CD20+ B cells and F4/80+ microglia in the spinal cord. These results demonstrate that ZnT3 gene deletion inhibits the clinical features and neuropathological changes associated with EAE. ZnT3 gene deletion also remarkably inhibited formation of EAE-associated aberrant synaptic zinc patches, matrix metalloproteinases-9 (MMP-9) activation and BBB disruption. Therefore, amelioration of EAE-induced clinical and neuropathological changes by ZnT3 gene deletion suggests that vesicular zinc may be involved in several steps of MS pathogenesis. PMID:27370228

  5. Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus

    DEFF Research Database (Denmark)

    Kalis, Martins; Bolmeson, Caroline; Esguerra, Jonathan L.S.;

    2011-01-01

    -blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses...... revealed altered islet morphology, marked decreased ß-cell mass, reduced numbers of granules within the ß-cells and reduced granule docking in adult RIP-Cre Dicer1(¿/¿) mice. ß-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal ß-cell development as 2-week old RIP-Cre Dicer1...... and diabetes development....

  6. How to write, delete, and drive skyrmions

    International Nuclear Information System (INIS)

    Skyrmions were originally proposed by British physicist Tony Skyrme in the 1960s as topological solitons to account for the stability of baryons in particle physics. Realization of skyrmions as vortex-like swirling spin textures was discovered in ferromagnets with chiral crystal symmetry, in which ferromagnetic-exchange interactions favoring parallel spin alignment and Dzyaloshinskii-Moriya interactions favoring rotational spin alignment strongly compete. Subsequent studies have revealed that skyrmions possess numerous advantageous properties for application to information carriers in high-density and low-energy-consuming magnetic memories and logic devices. These properties are: (1) topologically protected stability, (2) small nanometric size, (3) rather high transition temperatures, and (4) ultralow fields or electric currents to drive their motion. This article first introduces fundamental properties of skyrmions and skyrmionic materials and then presents recent attempts and ideas on writing, deleting, and driving skyrmions towards establishing their functions in memory devices. (author)

  7. Disruptive Innovation in Numerical Hydrodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Waltz, Jacob I. [Los Alamos National Laboratory

    2012-09-06

    We propose the research and development of a high-fidelity hydrodynamic algorithm for tetrahedral meshes that will lead to a disruptive innovation in the numerical modeling of Laboratory problems. Our proposed innovation has the potential to reduce turnaround time by orders of magnitude relative to Advanced Simulation and Computing (ASC) codes; reduce simulation setup costs by millions of dollars per year; and effectively leverage Graphics Processing Unit (GPU) and future Exascale computing hardware. If successful, this work will lead to a dramatic leap forward in the Laboratory's quest for a predictive simulation capability.

  8. Mutants defective in secretory/vacuolar pathways in the EUROFAN collection of yeast disruptants.

    Science.gov (United States)

    Avaro, Sandrine; Belgareh-Touzé, Naïma; Sibella-Argüelles, Carla; Volland, Christiane; Haguenauer-Tsapis, Rosine

    2002-03-15

    We have screened the EUROFAN (European Functional Analysis Network) deletion strain collection for yeast mutants defective in secretory/vacuolar pathways and/or associated biochemical modifications. We used systematic Western immunoblotting to analyse the electrophoretic pattern of several markers of the secretory/vacuolar pathways, the soluble alpha-factor, the periplasmic glycoprotein invertase, the plasma membrane GPI-anchored protein Gas1p, and two vacuolar proteins, the soluble carboxypeptidase Y and the membrane-bound alkaline phosphatase, which are targeted to the vacuole by different pathways. We also used colony immunoblotting to monitor the secretion of carboxypeptidase Y into the medium, to identify disruptants impaired in vacuolar targeting. We identified 25 mutants among the 631 deletion strains. Nine of these mutants were disrupted in genes identified in recent years on the basis of their involvement in trafficking (VPS53, VAC7, VAM6, APM3, SYS1), or glycosylation (ALG12, ALG9, OST4, ROT2). Three of these genes were identified on the basis of trafficking defects by ourselves and others within the EUROFAN project (TLG2, RCY1, MON2). The deletion of ERV29, which encodes a COPII vesicle protein, impaired carboxypeptidase Y trafficking from the endoplasmic reticulum to the Golgi apparatus. We also identified eight unknown ORFs, the deletion of which reduced Golgi glycosylation or impaired the Golgi to vacuole trafficking of carboxypeptidase Y. YJR044c, which we identified as a new VPS gene, encodes a protein with numerous homologues of unknown function in sequence databases. PMID:11870858

  9. Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia.

    Science.gov (United States)

    Lee, Soo Min; Nguyen, Dara; Anand, Marie; Kant, Ritu; Köhncke, Clemens; Lisewski, Ulrike; Roepke, Torsten K; Hu, Zhaoyang; Abbott, Geoffrey W

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(─/─) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis. PMID:26984260

  10. Disruption mitigation experiment on Tore Supra

    International Nuclear Information System (INIS)

    Disruptions can cause serious damages to tokamaks due to the resulting forces on the machine's structures and to the flux of accelerated runaway electrons. Mitigation techniques are thus required. A promising method is massive gas injection (MGI), the impact of this method on runaway electrons has been investigated on Tore-Supra where runaway electrons are observed in a majority of disruptions. Helium has been injected in either stable or pre-disruptive phases. A statistical comparison of several disruptions either spontaneous or triggered by MGI indicates that MGI disruptions are less violent, with a good benefit for machine's structures. Compared to a standard disruption, a MGI disruption enables an easy plasma recovery for the next pulse without noticeable helium pollution of following plasmas. The most important effect of MGI disruptions is the total disappearance of the runaway electron production. The capability of MGI to stop already accelerated electrons has also been investigated, it is shown that MGI is not able to stop already accelerated runaways. This points to the absolute necessity to develop disruption precursor techniques to identify disruptions sufficiently in advance (6-10 ms) to allow MGI to penetrate the plasma core before the current quenches. (A.C.)

  11. Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome.

    Science.gov (United States)

    Napoli, Eleonora; Tassone, Flora; Wong, Sarah; Angkustsiri, Kathleen; Simon, Tony J; Song, Gyu; Giulivi, Cecilia

    2015-09-18

    The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ∼30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of α-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1α, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype. PMID:26221035

  12. Linguistic and Psychomotor Development in Children with Chromosome 14 Deletions

    Science.gov (United States)

    Zampini, Laura; D'Odorico, Laura; Zanchi, Paola; Zollino, Marcella; Neri, Giovanni

    2012-01-01

    The present study focussed on a specific type of rare genetic condition: chromosome 14 deletions. Children with this genetic condition often show developmental delays and brain and neurological problems, although the type and severity of symptoms varies depending on the size and location of the deleted genetic material. The specific aim of the…

  13. 49 CFR 7.6 - Deletion of identifying detail.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Deletion of identifying detail. 7.6 Section 7.6... To Be Made Public by DOT § 7.6 Deletion of identifying detail. Whenever it is determined to be necessary to prevent a clearly unwarranted invasion of personal privacy, identifying details will be...

  14. 75 FR 27313 - Procurement List; Additions and Deletions

    Science.gov (United States)

    2010-05-14

    ... INFORMATION: Additions On 3/12/2010 (75 FR 11863-11864) and 3/26/2010 (75 FR 14575-14576), the Committee for..., PA. ] Deletions On 3/5/2010 (75 FR 10223-10224) and 3/12/2010 (75 FR 11863-11864), the Committee for... products are deleted from the Procurement List: Products USB Flash Drive, Flip Style NSN:...

  15. Optimality Theory and Variable Word-Final Deletion in Faetar.

    Science.gov (United States)

    Nagy, Naomi; Reynolds, Bill

    1997-01-01

    Examines a pattern of end-of-word deletion in Faetar, a Francoprovencal dialect spoken in southern Italy, and considers synchronic variants. The article uses the word "deletion" as a synchronic description of the fact that speakers do not always phonetically produce everything in the input form. Optimality Theory accounts for such variation by…

  16. Molecular mimicry and clonal deletion: A fresh look.

    Science.gov (United States)

    Rose, Noel R

    2015-06-21

    In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous "black holes", in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease. PMID:25172771

  17. Role of DNA deletion length in mutation and cell survival

    International Nuclear Information System (INIS)

    A model is presented which is based on the assumption that malignant transformation, mutation, chromosome aberration, and reproductive death of cells are all manifestations of radiation induced deletions in the DNA of the cell, and that the size of the deletion in relation to the spacing of essential genes determines the consequences of that deletion. It is assumed that two independent types of potentially lethal lesions can result in DNA deletions, and that the relative numbers of these types of damage is dependent on radiation quality. The repair of the damage reduces the length of a deletion, but does not always eliminate it. The predictions of this model are in good agreement with a wide variety of experimental evidence. (author)

  18. Deletion of the App-Runx1 region in mice models human partial monosomy 21

    Directory of Open Access Journals (Sweden)

    Thomas Arbogast

    2015-06-01

    Full Text Available Partial monosomy 21 (PM21 is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21. The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage-sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf. Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21.

  19. Ku80-deleted cells are defective at base excision repair

    Energy Technology Data Exchange (ETDEWEB)

    Li, Han [The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, The Department of Molecular Medicine, 15355 Lambda Drive, San Antonio, TX 78245-3207 (United States); Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029 (Spain); Marple, Teresa [The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, The Department of Molecular Medicine, 15355 Lambda Drive, San Antonio, TX 78245-3207 (United States); Hasty, Paul, E-mail: hastye@uthscsa.edu [The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, The Department of Molecular Medicine, 15355 Lambda Drive, San Antonio, TX 78245-3207 (United States); Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029 (Spain)

    2013-05-15

    Graphical abstract: - Highlights: • Ku80-deleted cells are hypersensitive to ROS and alkylating agents. • Cells deleted for Ku80, but not Ku70 or Lig4, have reduced BER capacity. • OGG1 rescues hypersensitivity to H{sub 2}O{sub 2} and paraquat in Ku80-mutant cells. • Cells deleted for Ku80, but not Lig4, are defective at repairing AP sites. • Cells deleted for Ku80, but not Lig4 or Brca2 exon 27, exhibit increased PAR. - Abstract: Ku80 forms a heterodimer with Ku70, called Ku, that repairs DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. As a consequence of deleting NHEJ, Ku80-mutant cells are hypersensitive to agents that cause DNA DSBs like ionizing radiation. Here we show that Ku80 deletion also decreased resistance to ROS and alkylating agents that typically cause base lesions and single-strand breaks (SSBs). This is unusual since base excision repair (BER), not NHEJ, typically repairs these types of lesions. However, we show that deletion of another NHEJ protein, DNA ligase IV (Lig4), did not cause hypersensitivity to these agents. In addition, the ROS and alkylating agents did not induce γ-H2AX foci that are diagnostic of DSBs. Furthermore, deletion of Ku80, but not Lig4 or Ku70, reduced BER capacity. Ku80 deletion also impaired BER at the initial lesion recognition/strand scission step; thus, involvement of a DSB is unlikely. Therefore, our data suggests that Ku80 deletion impairs BER via a mechanism that does not repair DSBs.

  20. Measured currents in JET limiters during disruptions

    International Nuclear Information System (INIS)

    Structures mounted inside a tokamak must be able to withstand the electromagnetic forces which arise during disruptions of the plasma. This paper reports on halo current measurements in the JET tokamak during disruptions. A toroidally distributed array of current sensing tiles reveal that in many disruptions a high degree of toroidal uniformity exists. However in exceptional disruptions the halo current measured at different toroidal positions varies by more than a factor of 2. This latter class of disruption has been observed to result in an asymmetric displacement of the vacuum vessel. The total halo current is estimated to be up to 15% of the initial plasma current. The halo current width for a particular disruption is estimated to be 8 cm

  1. Protective effect of taurine on the light-induced disruption of isolated frog rod outer segments

    International Nuclear Information System (INIS)

    Isolated frog rod outer segments (ROS) incubated in a Krebs-bicarbonate medium, and illuminated for 2 h, show a profound alteration in their structure. This is characterized by distention of discs, vesiculation, and a marked swelling. The light-induced ROS disruption requires the presence of bicarbonate and sodium chloride. Replacement of bicarbonate by TRIS or HEPES protects ROS structure. Also, substitution of sodium chloride by sucrose or choline chloride maintains unaltered the ROS structure. Deletion of calcium, magnesium, or phosphate does not modify the effect produced by illumination. An increased accumulation of labeled bicarbonate and tritiated water is observed in illuminated ROS, as compared with controls in the dark. The presence of taurine, GABA, or glycine, at concentrations of 5-25 mM, effectively counteracts the light-induced ROS disruption. Taurine (25 mM) reduces labeled bicarbonate and tritiated water levels to those observed in the dark incubated ROS

  2. Plasma characteristics during soft disruptions

    International Nuclear Information System (INIS)

    A significant class of disruptive discharges in tokamaks is characterized by an irreversible but rather slow current decay occurring while the electron temperature is still high. For definitiveness we refer to typical JET cases, where the observed rate of current decay is of the order of 2-3MA/s and the electron temperature Te measured by the ECE polychromator may decay as fast as 6keV/s in the center and 1.5 keV/s at the position of the q=2 surface. The influx of impurities is moderate and Zeff ∼6. The Ohmic resistance ROhm calculated with the proper plasma geometry and the ECE profiles is of the order of 1 μΩ plasma during the disruptive decay and these observations cannot be reconciled with the model of a choking effect of the plasma caused solely by a sudden inflow of impurities which may drive a radiative collapse of the plasma temperature to a few eV on a ms time scale. The discharge evolution is conveniently described by the trajectories on the plane of the parameters li (internal inductance) and q(a) (safety factor). Inspection of the path followed shows that the soft disruption phase often traces backwards the current ramp up phase, where an accelerated peaking up of the current profile may be associated to the effects of observed enhancement of MHD activity, as measured by the poloidal and toroidal magnetic pick-up coils. The observed irreversible process suggests that the effective resistance Reff of the plasma may be due indeed to temperature independent MHD effects. The problem is discussed comparing the difference between the effective and the Ohmic resistances with the expected value of a model based on the coupling of unstable tearing modes with resonant surfaces close together, around the q=2 surface where a saturated background mode is assumed. The time scales of the process observed require that the power input to the plasma be evaluated considering the full coupling with the external active and passive circuit elements since it is incorrect

  3. The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion

    Energy Technology Data Exchange (ETDEWEB)

    Peoples, R.; Perez-Jurado, L.; Francke, U.; Yu-Ker Wang [Stanford Univ. Medical Center, CA (United States); Kaplan, P. [Children`s Hospital of Philadelphia, PA (United States)

    1996-06-01

    Williams syndrome (WS) is a developmental disorder with multiple system manifestations, including supraval var aortic stenosis (SVAS), peripheral pulmonic stenosis, connective tissue abnormalities, short stature, characteristic personality profile and cognitive deficits, and variable hypercalcemia in infancy. It is caused by heterozygosity for a chromosomal deletion of part of band 7q11.23 including the elastin locus (ELN). Since disruption of the ELN gene causes autosomal dominant SVAS, it is assumed that ELN haploinsufficiency is responsible for the cardiovascular features of WS. The deletion that extends from the ELN locus in both directions is {ge}200 kb in size, although estimates of {ge}2 Mb are suggested by high-resolution chromosome banding and physical mapping studies. We have searched for additional dosage-sensitive genes within the deletion that may be responsible for the noncardiovascular features. We report here that the gene for replication factor C subunit 2 (RFC2) maps within the WS deletion region and was found to be deleted in all of 18 WS patients studied. The protein product of RFC2 is part of a multimeric complex involved in DNA elongation during replication. 14 refs., 3 figs.

  4. Disrupted Sleep: From Molecules to Cognition

    OpenAIRE

    Someren, E.J.W.; Cirelli, C.; Dijk, D.-J.; Van Cauter, E; Schwartz, Sophie; Chee, M. W. L.

    2015-01-01

    Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and experimental studies of these different forms of sleep disruption show deranged physiology from subcellular levels to complex affective behavior. In keeping with the multifaceted influence of sleep on health and well-bei...

  5. Disrupted Sleep: From Molecules to Cognition

    OpenAIRE

    Van Someren, Eus J. W.; Cirelli, Chiara; Dijk, Derk-Jan; Van Cauter, Eve; Schwartz, Sophie; Chee, Michael W. L.

    2015-01-01

    UNLABELLED: Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and experimental studies of these different forms of sleep disruption show deranged physiology from subcellular levels to complex affective behavior. In keeping with the multifaceted influence of sleep on health ...

  6. Multistage Logistic Network Optimization under Disruption Risk

    OpenAIRE

    Rusman, Muhammad

    2013-01-01

    Getting over disruptions risk has been a challenging issue for many companies under the globalization that will link to potential external source such as demand uncertainties, natural disasters, and terrorist attacks. The disruption is an unexpected event that disturbs normal flows of products and materials within a supply chain. The disruption at one members of supply chain will propagate the offers and finally affect significant impacts on the entire chain. If we look back...

  7. Towards a Framework of Digital Platform Disruption

    OpenAIRE

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    2014-01-01

    Digital platforms are disruptive information technology (IT) artifacts that erode conventional business logic associated with traditional market structures. This paper presents a framework for examining the disruptive potential of digital platforms whereby we postulate that the strategic interplay of governance regimes and platform layers is deterministic of whether disruptive derivatives are permitted to flourish. This framework has been employed in a comparative case study betwe...

  8. Disruption management in passenger railway transportation.

    OpenAIRE

    Jespersen-Groth, J.; Potthoff, Daniel; Clausen, J.; Huisman, Dennis; Kroon, Leo; Maróti, Gábor; Nielsen, M.N.

    2007-01-01

    textabstractThis paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss the three main subproblems in railway disruption management: timetable adjustment, and rolling stock and crew re-scheduling. Next to a general description of these problems, we give an o...

  9. Current disruption in toroidal devices

    International Nuclear Information System (INIS)

    Attempts at raising the density or the plasma current in a tokamak above certain critical values generally result in termination of the discharge by a disruption. This sudden end of the plasma current and plasma confinement is accompanied by large induced voltages and currents in the outer structures which, in large tokamaks, can only be handled with considerable effort, and which will probably only be tolerable in reactors as rare accidents. Because of its crucial importance for the construction and operation of tokamaks, this phenomenon and its theoretical interpretation were the subject of a three-day symposium organized by the International Atomic Energy Agency and Max-Planck-Institut fuer Plasmaphysik at Garching from February 14 to 16. (orig./HT)

  10. Catastrophic disruption experiments: Recent results

    Science.gov (United States)

    Martelli, G.; Ryan, E. V.; Nakamura, A. M.; Giblin, I.

    1994-01-01

    This paper presents a review of the progress in the field of catastrophic disruption experiments over the past 4 years, since the publication of the review paper by Fujiwara et al. (1989). We describe the development of new techniques to produce shattering impacts relevant to the study of the collisional evolution of the asteroids, and summarize the results from numerous experiments which have been performed to date, using a variety of materials for both the impactor and the targets. Some of these, such as ice-on-ice, loose aggregates and pressurized targets, are quite new and have provided novel and exciting results. Some of the gaps existing previously in the data on fragment ejection-angle distributions, as well as translational and rotational velocity fields (including fine fragments) have been filled, and these new results will be surveyed.

  11. Disrupting Entanglement of Black Holes

    CERN Document Server

    Leichenauer, Stefan

    2014-01-01

    We study entanglement in thermofield double states of strongly coupled CFTs by analyzing two-sided Reissner-Nordstrom solutions in AdS. The central object of study is the mutual information between a pair of regions, one on each asymptotic boundary of the black hole. For large regions the mutual information is positive and for small ones it vanishes; we compute the critical length scale, which goes to infinity for extremal black holes, of the transition. We also generalize the butterfly effect of Shenker and Stanford to a wide class of charged black holes, showing that mutual information is disrupted upon perturbing the system and waiting for a time of order $\\log E/\\delta E$ in units of the temperature. We conjecture that the parametric form of this timescale is universal.

  12. Traffic disruption and recovery in road networks

    Science.gov (United States)

    Zhang, Lele; de Gier, Jan; Garoni, Timothy M.

    2014-05-01

    We study the impact of disruptions on road networks, and the recovery process after the disruption is removed from the system. Such disruptions could be caused by vehicle breakdown or illegal parking. We analyze the transient behavior using domain wall theory, and compare these predictions with simulations of a stochastic cellular automaton model. We find that the domain wall model can reproduce the time evolution of flow and density during the disruption and the recovery processes, for both one-dimensional systems and two-dimensional networks.

  13. Fungal ABC transporter deletion and localization analysis.

    Science.gov (United States)

    Kovalchuk, Andriy; Weber, Stefan S; Nijland, Jeroen G; Bovenberg, Roel A L; Driessen, Arnold J M

    2012-01-01

    Fungal cells are highly complex as their metabolism is compartmentalized harboring various types of subcellular organelles that are bordered by one or more membranes. Knowledge about the intracellular localization of transporter proteins is often required for the understanding of their biological function. Among different approaches available, the localization analysis based on the expression of GFP fusions is commonly used as a relatively fast and cost-efficient method that allows visualization of proteins of interest in both live and fixed cells. In addition, inactivation of transporter genes is an important tool to resolve their specific function. Here we provide a detailed protocol for the deletion and localization analysis of ABC transporters in the filamentous fungus Penicillium chrysogenum. It includes construction of expression plasmids, their transformation into fungal strains, cultivation of transformants, microscopy analysis, as well as additional protocols on staining of fungal cells with organelle-specific dyes like Hoechst 33342, MitoTracker DeepRed, and FM4-64. PMID:22183644

  14. MegaTevs: single-chain dual nucleases for efficient gene disruption.

    Science.gov (United States)

    Wolfs, Jason M; DaSilva, Matthew; Meister, Sarah E; Wang, Xu; Schild-Poulter, Caroline; Edgell, David R

    2014-07-01

    Targeting gene disruptions in complex genomes relies on imprecise repair by the non-homologous end-joining DNA pathway, creating mutagenic insertions or deletions (indels) at the break point. DNA end-processing enzymes are often co-expressed with genome-editing nucleases to enhance the frequency of indels, as the compatible cohesive ends generated by the nucleases can be precisely repaired, leading to a cycle of cleavage and non-mutagenic repair. Here, we present an alternative strategy to bias repair toward gene disruption by fusing two different nuclease active sites from I-TevI (a GIY-YIG enzyme) and I-OnuI E2 (an engineered meganuclease) into a single polypeptide chain. In vitro, the MegaTev enzyme generates two double-strand breaks to excise an intervening 30-bp fragment. In HEK 293 cells, we observe a high frequency of gene disruption without co-expression of DNA end-processing enzymes. Deep sequencing of disrupted target sites revealed minimal processing, consistent with the MegaTev sequestering the double-strand breaks from the DNA repair machinery. Off-target profiling revealed no detectable cleavage at sites where the I-TevI CNNNG cleavage motif is not appropriately spaced from the I-OnuI binding site. The MegaTev enzyme represents a small, programmable nuclease platform for extremely specific genome-engineering applications. PMID:25013171

  15. High efficiency TALENs enable F0 functional analysis by targeted gene disruption in Xenopus laevis embryos

    Directory of Open Access Journals (Sweden)

    Ken-ichi T. Suzuki

    2013-03-01

    Recently, gene editing with transcription activator-like effector nucleases (TALENs has been used in the life sciences. TALENs can be easily customized to recognize a specific DNA sequence and efficiently introduce double-strand breaks at the targeted genomic locus. Subsequent non-homologous end-joining repair leads to targeted gene disruption by base insertion, deletion, or both. Here, to readily evaluate the efficacy of TALENs in Xenopus laevis embryos, we performed the targeted gene disruption of tyrosinase (tyr and pax6 genes that are involved in pigmentation and eye formation, respectively. We constructed TALENs targeting tyr and pax6 and injected their mRNAs into fertilized eggs at the one-cell stage. Expectedly, introduction of tyr TALEN mRNA resulted in drastic loss of pigmentation with high efficiency. Similarly, for pax6, TALENs led to deformed eyes in the injected embryos. We confirmed mutations of the target alleles by restriction enzyme digestion and sequence analyses of genomic PCR products. Surprisingly, not only biallelic but also paralogous, gene disruption was observed. Our results demonstrate that targeted gene disruption by TALENs provides a method comparable to antisense morpholinos in analyzing gene function in Xenopus F0 embryos, but also applies beyond embryogenesis to any life stage.

  16. Planar F-Deletion: Approximation and Optimal FPT Algorithms

    CERN Document Server

    Fomin, Fedor; Misra, Neeldhara; Saurabh, Saket

    2012-01-01

    Let F be a finite set of graphs. In the F-Deletion problem, we are given an n-vertex, m-edge graph G and an integer k as input, and asked whether at most k vertices can be deleted from G such that the resulting graph does not contain a graph from F as a minor. F-Deletion is a generic problem and by selecting different sets of forbidden minors F, one can obtain various fundamental problems such as Vertex Cover, Feedback Vertex Set or Treewidth t-Deletion. In this paper we obtain a number of generic algorithmic results about Planar F-Deletion, when F contains at least one planar graph. The highlights of our work are - A randomized O(nm) time constant factor approximation algorithm for the optimization version of Planar F-Deletion. - A randomized O(2^{O(k)} n) time parameterized algorithm for Planar F-Deletion when F is connected. Here a family F is called connected if every graph in F is connected. The algorithm can be made deterministic at the cost of making the polynomial factor in the running time n\\log^2 n ...

  17. How to Recover Deleted Text Messages from iPhone

    OpenAIRE

    Terry

    2015-01-01

    For most of us, we are using text messages to contact our friends and family everyday with our iPhone. We also send many important information and others via text messages. So if you delete or lost important text messages from iPhone, it will be really a disaster for you. But it is not the end of the world, iPhone Data Recovery software can retrieve deleted text messages from iPhone for you easily. It provides 3 ways of recovering text messages from iPhone. It can recover deleted text mes...

  18. Delineation of 14q32.3 deletion syndrome.

    OpenAIRE

    Ortigas, A P; Stein, C K; Thomson, L L; Hoo, J J

    1997-01-01

    A patient with a 14q32.3 terminal band deletion and cat cry is reported. Review of four other 14q32.3 deletion cases suggests the possible presence of a recognisable 14q32.3 terminal deletion syndrome, which is characterised by (1) apparently postnatal onset of small head size in comparison to body size, (2) high forehead with lateral hypertrichosis, (3) epicanthic folds, (4) broad nasal bridge, (5) high arched palate, (6) single palmar crease, and (7) mild to moderate developmental delay. Al...

  19. Ectrodactyly and proximal/intermediate interstitial deletion 7q

    Energy Technology Data Exchange (ETDEWEB)

    McElveen, C.; Carvajal, M.V.; Moscatello, D. [Louisiana State Univ. Medical Center, New Orleans, LA (United States)] [and others

    1995-03-13

    We report on an individual with severe mental retardation, seizures, microcephaly, unusual face, scoliosis, and cleft feet and cleft right hand. The chromosomal study showed a proximal interstitial deletion 7q (q11.23q22). From our review of the literature, 11 patients have been reported with ectrodactyly (split hand/split foot malformation) and proximal/intermediate interstitial deletions or rearrangements of 7q. The critical segment for ectrodactyly seems to be located between 7q21.2 and 7q22.1. This malformation is present in 41% of the patients whose deletion involves the critical segment. 37 refs., 3 figs., 1 tab.

  20. RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Shawana Kamran

    2015-01-01

    Full Text Available The RCSD1 gene has recently been identified as a novel gene fusion partner of the ABL1 gene in cases of B-cell Acute Lymphoblastic Leukemia (B-ALL. The RCSD1 gene is located at 1q23 and ABL1 is located at 9q34, so that the RCSD1-ABL1 fusion typically arises through a rare reciprocal translocation t(1;9(q23;q34. Only a small number of RCSD1-ABL1 positive cases of B-ALL have been described in the literature, and the full spectrum of clinical, morphological, immunophenotypic, and molecular features associated with this genetic abnormality has not been defined. We describe extensive genetic characterization of a case of B-ALL with RCSD1-ABL1 fusion, by using conventional cytogenetic analysis, Fluorescence In Situ Hybridization (FISH studies, and Chromosomal Microarray Analysis (CMA. The use of CMA resulted in detection of an approximately 70 kb deletion at 7p12.2, which caused a disruption of the IKZF1 gene. Deletions and mutations of IKZF1 are recurring abnormalities in B-ALL and are associated with a poor prognosis. Our findings highlight the association of the deletion of IKZF1 gene with the t(1;9(q24;q34 and illustrate the importance of comprehensive cytogenetic and molecular evaluation for accurate prediction of prognosis in patients with B-cell ALL.

  1. Manufacturing doubt about endocrine disrupter science

    DEFF Research Database (Denmark)

    Bergman, Åke; Becher, Georg; Blumberg, Bruce;

    2015-01-01

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is b...

  2. Rurality and Patterns of Social Disruption.

    Science.gov (United States)

    Wilkinson, Kenneth P.

    1984-01-01

    Argues that structural cleavages provoke social disruptions where opportunities are conducive. Thus, combinations of rurality with particular structural cleavages predict specific disruption patterns. Data from northeastern United States indicate that rurality, combined with other population characteristics (provocation, ascriptive inequality,…

  3. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten Visby; Skyt Nielsen, Helena;

    identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  4. Simulation of runaway electrons in Tokamak disruptions

    International Nuclear Information System (INIS)

    Self-consistent modelling of the generation of runaway electrons and the evolution of the toroidal electric field during tokamak disruptions is presented. The process of runaway generation is analysed by combining a relativistic kinetic equation for the electrons with Maxwell's equations for the electric field. Such modelling allows for a quantitative assessment of the runaway generation during disruptions in present day tokamak experiments, and to extrapolate to future tokamaks like ITER. It is found that the current profile can change dramatically during a disruption, such that the post disruption current, carried mainly by the runaway electrons, is significantly more peaked than the current profile before the disruption. In fact, it is found that the central current density can increase in spite of a reduction in the total current. (authors)

  5. Airline Disruption Management - Perspectives, Experiences and Outlook

    DEFF Research Database (Denmark)

    Kohl, Niklas; Larsen, Allan; Larsen, Jesper;

    2004-01-01

    Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused by for...... disruptions. The purpose of this paper is twofold. In the first part it o ers an introduction to airline disruption management, provides the readers with a description of the planning processes and delivers a detailed overview of the numerous aspects of airline disruption management. In the second part we...... report on experiences from a large research and development project on airline disruption management. Within the project the first prototype of a multiple resource decision support system at the operations control center in a major airline, has been implemented....

  6. On eigenvalues, case deletion and extremes in regression

    OpenAIRE

    Velilla, Santiago

    1990-01-01

    This paper presents an approximation for assessing the effect of deleting an observation in the eigenvalues of the correlation matrix of a multiple linear regression modelo Applications in connection with the detection of collinearityinfluential observations are explored.

  7. 77 FR 38775 - Procurement List; Proposed Additions and Deletions

    Science.gov (United States)

    2012-06-29

    ... they are providing additional information. End of Certification The following products and services are..., Aberdeen Proving Ground, MD, National Ground Intelligence Center (NGIC). Rivanna Station Complex, 2055... the products proposed for deletion from the Procurement List. End of Certification The...

  8. Bmal1 and Beta cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced Beta cell failure in mice

    Science.gov (United States)

    Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in Beta cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in Beta cells. To address this, we generated mice with Beta cell ...

  9. Insertion and Deletion Processes in Recent Human History

    OpenAIRE

    Per Sjödin; Thomas Bataillon; Schierup, Mikkel H.

    2010-01-01

    BACKGROUND: Although insertions and deletions (indels) account for a sizable portion of genetic changes within and among species, they have received little attention because they are difficult to type, are alignment dependent and their underlying mutational process is poorly understood. A fundamental question in this respect is whether insertions and deletions are governed by similar or different processes and, if so, what these differences are. METHODOLOGY/PRINCIPAL FINDINGS: We use publishe...

  10. Construction of Deletion-knockout Mutant Fowlpox Virus (FWPV)

    OpenAIRE

    Laidlaw, Stephen M.; Skinner, Michael A.

    2014-01-01

    The construction of deletion-knockout poxviruses is a useful approach to determining the function of specific virus genes. This protocol is an adaptation of the transient dominant knockout selection protocol published by Falkner and Moss (1990) for use with vaccinia virus. The protocol makes use of the dominant selectable marker Escherichia coli guanine phosphoribosyltransferase (gpt) gene (Mulligan and Berg, 1981), under the control of an early/late poxvirus promoter. The deletion viruses th...

  11. Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

    OpenAIRE

    de Rooij, Jasmijn D.E.; Beuling, Eva; Marry M van den Heuvel-Eibrink; Obulkasim, Askar; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Sonneveld, Edwin; Gibson, Brenda E.S.; Pieters, Rob; Zimmermann, Martin; Zwaan, C. Michel; Fornerod, Maarten

    2015-01-01

    IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations...

  12. Fast detection of deletion breakpoints using quantitative PCR.

    Science.gov (United States)

    Abildinova, Gulshara; Abdrakhmanova, Zhanara; Tuchinsky, Helena; Nesher, Elimelech; Pinhasov, Albert; Raskin, Leon

    2016-06-16

    The routine detection of large and medium copy number variants (CNVs) is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories. PMID:27333265

  13. RNA-Editing with Combined Insertion and Deletion Preserves Regularity

    Directory of Open Access Journals (Sweden)

    E.P. de Vink

    2013-01-01

    Full Text Available We consider two elementary forms of string rewriting called guided insertion/deletion and guided rewriting. The original strings are modified depending on the match with a given set of auxiliary strings, called guides. Guided insertion/deletion considers matching of a string and a guide with respect to a specific correspondence of strings. Guided rewriting considers matching of a string and a guide with respect to an equivalence relation on the alphabet. Guided insertion/deletion is inspired by {RNA}-editing, a biological process by which the original genetic information stored in DNA is modified before its final expression. The formalism here allows for simultaneous insertion and deletion of string elements. Guided rewriting, based on a letter-to-letter relation, is technically more appealing than guided insertion/deletion. We prove that guided rewriting preserves regularity: for every regular language its closure under guided rewriting is regular too. In the proof we will rely on the auxiliary notion of a slice sequence. We establish a correspondence of slice sequences and guide rewrite sequences. Because of their left-to-right nature, slice sequences are more convenient to deal with than guided rewrite sequences in the construction of the finite automata that we encounter in the proofs of regularity. Based on the result for guided rewriting we establish that guided insertion/deletion preserves regularity as well.

  14. Fast detection of deletion breakpoints using quantitative PCR

    Directory of Open Access Journals (Sweden)

    Gulshara Abildinova

    2016-01-01

    Full Text Available Abstract The routine detection of large and medium copy number variants (CNVs is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories.

  15. Exon Deletions of Parkin Gene in Patients with Parkinson Disease

    Institute of Scientific and Technical Information of China (English)

    王涛; 梁直厚; 孙圣刚; 曹学兵; 彭海; 刘红进; 童萼塘

    2004-01-01

    Summary: Mutations in the parkin gene have recently been identified in familial and isolated patients with early-onset Parkinson disease (PD) and that subregions between exon 2 and 4 of the parkin gene are hot spots of deletive mutations. To study the distribution of deletions in the parkin gene among variant subset patients with PD in China, and to explore the role of parkin gene in the pathogenesis of PD, 63 patients were divided into early onset and later onset groups. Exons 1-12 were amplified by PCR, templated by the genomic DNA of patients, and then the deletion distribution detected by agarose electrophoresis. Four patients were found to be carrier of exon deletions in 63 patients with PD. The location of the deletion was on exon 2 (1 case), exon 3 (2 cases) and exon 4 (1 case). All patients were belong to the group of early onset PD. The results showed that parkin gene deletion on exon 2, exon 3 and exon 4 found in Chinese population contributes partly to early onset PD.

  16. Mouse models for preeclampsia: disruption of redox-regulated signaling

    Directory of Open Access Journals (Sweden)

    Chambers Anne E

    2009-01-01

    Full Text Available Abstract The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-O-methyl transferase (Comt-/- in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2 which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha at late pregnancy. We propose that in wild type (Comt++ pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD. Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/- stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD. We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD.

  17. Disrupted Stars in Unusual Galaxies

    Science.gov (United States)

    Kohler, Susanna

    2016-03-01

    Tidal disruption events (TDEs) occur when a star passes a little too close to a supermassive black hole at the center of a galaxy. Tidal forces from the black hole cause the passing star to be torn apart, resulting in a brief flare of radiation as the stars material accretes onto the black hole. A recent study asks the following question: do TDEs occur most frequently in an unusual type of galaxy?A Trend in DisruptionsSo far, we have data from eight candidate TDEs that peaked in optical and ultraviolet wavelengths. The spectra from these observations have shown an intriguing trend: many of these TDEs host galaxies exhibit weak line emission (indicating little or no current star-formation activity), and yet they show strong Balmer absorption lines (indicating star formation activity occurred within the last Gyr). These quiescent, Balmer-strong galaxies likely underwent a period of intense star formation that recently ended.To determine if TDEs are overrepresented in such galaxies, a team of scientists led by Decker French (Steward Observatory, University of Arizona) has quantified the fraction of galaxies in the Sloan Digital Sky Survey (SDSS) that exhibit similar properties to those of TDE hosts.Quantifying OverrepresentationSpectral characteristics of SDSS galaxies (gray) and TDE candidate host galaxies (colored points): line emission vs. Balmer absorption. The lower right-hand box identifies thequiescent, Balmer-strong galaxies which contain most TDE events, yet are uncommon among the galaxy sample as a whole. Click for a better look! [French et al. 2016]French and collaborators compare the optical spectra of the TDE host galaxies to those of nearly 600,000 SDSS galaxies, using two different cutoffs for the Balmer absorption the indicator of past star formation. Their strictest cut, filtering for very high Balmer absorption, selected only 0.2% of the SDSS galaxies, yet 38% of the TDEs are hosted in such galaxies. Using a more relaxed cutoff selects 2.3% of

  18. Partial deletion of the sulfate transporter SLC13A1 is associated with an osteochondrodysplasia in the Miniature Poodle breed.

    Directory of Open Access Journals (Sweden)

    Mark W Neff

    Full Text Available A crippling dwarfism was first described in the Miniature Poodle in Great Britain in 1956. Here, we resolve the genetic basis of this recessively inherited disorder. A case-control analysis (8:8 of genotype data from 173 k SNPs revealed a single associated locus on CFA14 (P(raw <10(-8. All affected dogs were homozygous for an ancestral haplotype consistent with a founder effect and an identical-by-descent mutation. Systematic failure of nine, nearly contiguous SNPs, was observed solely in affected dogs, suggesting a deletion was the causal mutation. A 130-kb deletion was confirmed both by fluorescence in situ hybridization (FISH analysis and by cloning the physical breakpoints. The mutation was perfectly associated in all cases and obligate heterozygotes. The deletion ablated all but the first exon of SLC13A1, a sodium/sulfate symporter responsible for regulating serum levels of inorganic sulfate. Our results corroborate earlier findings from an Slc13a1 mouse knockout, which resulted in hyposulfatemia and syndromic defects. Interestingly, the metabolic disorder in Miniature Poodles appears to share more clinical signs with a spectrum of human disorders caused by SLC26A2 than with the mouse Slc13a1 model. SLC26A2 is the primary sodium-independent sulfate transporter in cartilage and bone and is important for the sulfation of proteoglycans such as aggregan. We propose that disruption of SLC13A1 in the dog similarly causes undersulfation of proteoglycans in the extracellular matrix (ECM, which impacts the conversion of cartilage to bone. A co-dominant DNA test of the deletion was developed to enable breeders to avoid producing affected dogs and to selectively eliminate the mutation from the gene pool.

  19. Cis-regulatory control of the nodal gene, initiator of the sea urchin oral ectoderm gene network

    OpenAIRE

    Nam, Jongmin; Su, Yi-Hsien; Lee, Pei Yun; Robertson, Anthony J; Coffman, James A.; Davidson, Eric H.

    2007-01-01

    Expression of the nodal gene initiates the gene regulatory network which establishes the transcriptional specification of the oral ectoderm in the sea urchin embryo. This gene encodes a TGFβ ligand, and in Strongylocentrotus purpuratus its transcription is activated in the presumptive oral ectoderm at about the 30-cell stage. Thereafter Nodal signaling occurs among all cells of the oral ectoderm territory, and nodal expression is required for expression of oral ectoderm regulatory genes. The ...

  20. Tissue-specific expression of the human alpha 1-antitrypsin gene is controlled by multiple cis-regulatory elements.

    OpenAIRE

    Shen, R F; Li, Y.; Sifers, R N; Wang, H.; Hardick, C; Tsai, S. Y.; Woo, S L

    1987-01-01

    Human alpha 1-antitrypsin (AAT) is expressed in the liver, and a 318 bp fragment immediately flanking the CAP site of the gene was found to be sufficient to drive the expression of a reporter gene (CAT) specifically in hepatoma cells. The enhancing activity however, was orientation-dependent. The DNA fragment was separated into a distal region and a proximal region. A "core enhancer" sequence GTGGTTTC is present within the distal region and is capable of activity enhancement in both orientati...

  1. Tissue-specific expression of the human alpha 1-antitrypsin gene is controlled by multiple cis-regulatory elements.

    Science.gov (United States)

    Shen, R F; Li, Y; Sifers, R N; Wang, H; Hardick, C; Tsai, S Y; Woo, S L

    1987-10-26

    Human alpha 1-antitrypsin (AAT) is expressed in the liver, and a 318 bp fragment immediately flanking the CAP site of the gene was found to be sufficient to drive the expression of a reporter gene (CAT) specifically in hepatoma cells. The enhancing activity however, was orientation-dependent. The DNA fragment was separated into a distal region and a proximal region. A "core enhancer" sequence GTGGTTTC is present within the distal region and is capable of activity enhancement in both orientations when complemented by the proximal region in the sense orientation. The results strongly suggest that there are multiple cis-acting elements in the human AAT gene that confer cell specificity for its expression. Nuclear proteins prepared from the hepatoma cells bound specifically to the proximal region in a band-shifting assay that was resistant to competition by the globin promoter DNA. Foot-printing analysis showed a protected domain within the proximal region that contains a nearly perfect palindromic sequence TGGTTAATATTCACCA, which may be important in the regulation of AAT expression in the liver. PMID:2823229

  2. The contribution of cis-regulatory elements to head-to-head gene pairs’ co-expression pattern

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Transcription regulation is one of the most critical pipelines in biological process,in which cis-elements play the role as gene expression regulators.We attempt to deduce the principles underlying the co-expression of "head-to-head" gene pairs by analyzing activities or behaviors of the shared cis-elements.A network component analysis was performed to estimate the impact of cis-elements on gene promoters and their activities under different conditions.Our discoveries reveal how biological system uses those regulatory elements to control the expression pattern of "head-to-head" gene pairs and the whole transcription regulation system.

  3. Identification of Predictive Cis-Regulatory Elements Using a Discriminative Objective Function and a Dynamic Search Space.

    Directory of Open Access Journals (Sweden)

    Rahul Karnik

    Full Text Available The generation of genomic binding or accessibility data from massively parallel sequencing technologies such as ChIP-seq and DNase-seq continues to accelerate. Yet state-of-the-art computational approaches for the identification of DNA binding motifs often yield motifs of weak predictive power. Here we present a novel computational algorithm called MotifSpec, designed to find predictive motifs, in contrast to over-represented sequence elements. The key distinguishing feature of this algorithm is that it uses a dynamic search space and a learned threshold to find discriminative motifs in combination with the modeling of motifs using a full PWM (position weight matrix rather than k-mer words or regular expressions. We demonstrate that our approach finds motifs corresponding to known binding specificities in several mammalian ChIP-seq datasets, and that our PWMs classify the ChIP-seq signals with accuracy comparable to, or marginally better than motifs from the best existing algorithms. In other datasets, our algorithm identifies novel motifs where other methods fail. Finally, we apply this algorithm to detect motifs from expression datasets in C. elegans using a dynamic expression similarity metric rather than fixed expression clusters, and find novel predictive motifs.

  4. Changes in cis-regulatory elements of a key floral regulator are associated with divergence of inflorescence architectures

    OpenAIRE

    Kusters, E.; Pina, Della, S.; Castel, R; Souer, E.; Koes, R

    2015-01-01

    Higher plant species diverged extensively with regard to the moment (flowering time) and position (inflorescence architecture) at which flowers are formed. This seems largely caused by variation in the expression patterns of conserved genes that specify floral meristem identity (FMI), rather than changes in the encoded proteins. Here, we report a functional comparison of the promoters of homologous FMI genes from Arabidopsis, petunia, tomato and Antirrhinum. Analysis of promoter-reporter cons...

  5. Changes in cis-regulatory elements of a key floral regulator are associated with divergence of inflorescence architectures

    NARCIS (Netherlands)

    E. Kusters; S. Della Pina; R. Castel; E. Souer; R. Koes

    2015-01-01

    Higher plant species diverged extensively with regard to the moment (flowering time) and position (inflorescence architecture) at which flowers are formed. This seems largely caused by variation in the expression patterns of conserved genes that specify floral meristem identity (FMI), rather than ch

  6. A Survey of 6,300 Genomic Fragments for cis-Regulatory Activity in the Imaginal Discs of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Aurélie Jory

    2012-10-01

    Full Text Available Over 6,000 fragments from the genome of Drosophila melanogaster were analyzed for their ability to drive expression of GAL4 reporter genes in the third-instar larval imaginal discs. About 1,200 reporter genes drove expression in the eye, antenna, leg, wing, haltere, or genital imaginal discs. The patterns ranged from large regions to individual cells. About 75% of the active fragments drove expression in multiple discs; 20% were expressed in ventral, but not dorsal, discs (legs, genital, and antenna, whereas ∼23% were expressed in dorsal but not ventral discs (wing, haltere, and eye. Several patterns, for example, within the leg chordotonal organ, appeared a surprisingly large number of times. Unbiased searches for DNA sequence motifs suggest candidate transcription factors that may regulate enhancers with shared activities. Together, these expression patterns provide a valuable resource to the community and offer a broad overview of how transcriptional regulatory information is distributed in the Drosophila genome.

  7. OF SYSTEMS THAT HAVE DISRUPTABLE CONSTRAINS

    Directory of Open Access Journals (Sweden)

    Chernov Yuriy Tikhonovich

    2012-07-01

    Formulas of equivalent static loads, with the help of which the systems are analyzed when constraints are disrupted, are generated. No inertial force is to be derived to obtain equivalent static loads. This is important in view of their application in dynamic analyses . Analysis of the static system in the event of disrupted constraints is based on the equations derived by the authors. The result of the analysis represents an inverse linear relation of static loading and relative stiffness of the system with disrupted constraints. This means that the lower the stiffness of the system, the higher the static loading.

  8. Periodic disruptions in the MT-1 tokamak

    International Nuclear Information System (INIS)

    Disruptive instabilities are common phenomena in toroidal devices, especially in tokamaks. Three types can be distinguished: internal, minor and major disruptions. Periodic minor disruptions in the MT-1 tokamak were measured systematically with values of the limiter safety factor between 4 and 10. The density limit as a function of plasma current and horizontal displacement was investigated. Precursor oscillations always appear before the instability with increasing amplitude but can be observed at the density limit with quasi-stationary amplitude. Phase correlation between precursor oscillations were measured with Mirnov coils and x-ray detectors, and they show good agreement with a simple magnetic island model. (R.P.) 11 refs.; 6 figs

  9. DISRUPTIVE BEHAVIOUR AMONGST DOCTORS, MYTH OR REALITY?

    Directory of Open Access Journals (Sweden)

    Avtar Singh

    2014-01-01

    Full Text Available BACKGROUND : Disruptive behavior in a medical setting is defined as objectionable or offensive interpersonal behavior that leads to disruption of professional activities in the workplace. 1 It has been observed that majority of doctors do not show disruptive behavior in their day today conduct and only few doctors are identified for their disruptive behavior . Special commi ttee on professional conduct and ethics defines disruptive behavior in physicians as aberrant behavior manifested through personal interaction with physicians , hospital personnel , health care professionals , patients , family members or others which interferes with patient care or could reasonably be expected to interfere with the process of delivering quality care. 2 Common forms of disruptive behaviors generally seen amongst young doctors are use of abusive language , yelling or shouting at patients , colleagues and subordinate staff , showing in disciplined behavior and at times indulging in physical abuse. 3 - 4 STUDY DESIGN : Study was conducted at a tertiary care hospital where 614 health care professionals participated which included 108 doctors 432 nurs ing staff and 74 paramedical staff METHOD : Data collection was done by semi structured pretested questionnaire and was entered in Microsoft Excel and analyzed for frequency and percentages . RESULTS : 64 % doctor , 66% nursing staff and 50% of the paramedicals answered that they have seen doctors showing disruptive behavior at one time or the other . Not all the doctors show disruptive behavior but this type of aberrant behavior is seen mainly in2 - 3 percent of doctors only. While answering to the que stion as to the type of disruptive behavior , 57% health care professionals reported that commonest form of disruptive behavior noticed by them amongst doctors was yelling or shouting on junior staff , patients and colleagues . 47% answered that doctors with disruptive behavior do not follow laid down orders or

  10. Disruptive Innovation in Chinese and Indian Businesses

    DEFF Research Database (Denmark)

    markets, has made these emerging economies fertile ground for developing and applying disruptive innovations. A novel mix of key attributes distinctive from those of established technologies or business models, disruptive innovations are typically inferior, yet affordable and "good-enough" products or...... services, which originate in lower-end market segments, but later move up to compete with those provided by incumbent firms. This book sheds new light on disruptive innovations both from and for the bottom of the pyramid in China and India, from the point of view of local entrepreneurs and international...

  11. Report on Criteria for Endocrine Disrupters

    DEFF Research Database (Denmark)

    Holbech, Henrik

    This report has been prepared by the Danish Centre on Endocrine Disrupters as a project contracted by the Danish Environmental Protection Agency. The Danish Centre on Endocrine Disrupters is an interdisciplinary scientific network without walls. The main purpose of the Centre is to build and gather...... overall aim of this project is to provide a science based proposal for criteria for endocrine disrupters. The terms of reference for the project specify elements to be included and/or addressed when developing the criteria (Annex 1). Also, several international reports and papers dealing with assessment...

  12. Disruptions, Disruptivity, and Safer Operating Windows in the High-β Spherical Torus NSTX

    Energy Technology Data Exchange (ETDEWEB)

    Gerhardt, S P; Diallo, A; Gates, D; LeBlanc, B P; Menard, J E; Mueller, D; Sabbagh, S A; Soukhanovskii, V; Tritz, K

    2012-09-27

    This paper discusses disruption rates, disruption causes, and disruptivity statistics in the high- βN National Spherical Torus Experiment (NSTX) [M. Ono, et al. Nuclear Fusion 40, 557 (2000)]. While the overall disruption rate is rather high, configurations with high βN , moderate q*, strong boundary shaping, sufficient rotation, and broad pressure and current profiles are found to have the lowest disruptivity; active n=1 control further reduces the disruptivity. The disruptivity increases rapidly for q*<2.7, which is substantially above the ideal MHD current limit. In quiescent conditions, qmin >1.25 is generally acceptable for avoiding the onset of core rotating n=1 kink/tearing modes; when EPM and ELM disturbances are present, the required qmin for avoiding those modes is raised to ~1.5. The current ramp and early flat-top phase of the discharges are prone to n=1 core rotating modes locking to the wall, leading to a disruption. Small changes to the discharge fueling during this phase can often mitigate the rotation damping associated with these modes and eliminate the disruption. The largest stored energy disruptions are those that occur at high current when a plasma current rampdown is initiated incorrectly.

  13. Runaway electron generation in tokamak disruptions

    International Nuclear Information System (INIS)

    The time evolution of the plasma current during a tokamak disruption is calculated by solving the equations for runaway electron production simultaneously with the induction equation for the toroidal electric field. The resistive diffusion time in a post-disruption plasma is typically comparable to the runaway avalanche growth time. Accordingly, the toroidal electric field induced after the thermal quench of a disruption diffuses radially through the plasma at the same time as it accelerates runaway electrons, which in turn back-react on the electric field. When these processes are accounted for in a self-consistent way, it is found that (1) the efficiency and time scale of runaway generation agrees with JET experiments; (2) the runaway current profile typically becomes more peaked than the pre-disruption current profile; and (3) can easily become radially in the shape of filaments. It is also shown that higher runaway electron generation is expected if the thermal quench is sufficiently fast. (authors)

  14. Operational limits and disruptions in tokamaks

    International Nuclear Information System (INIS)

    This report contains a concise description on status of knowledge in the area of operational limits and disruption characteristics, based on the results of workshops held during the ITER Definition Phase (1988). (author)

  15. Shell Galaxies, Dynamical Friction, and Dwarf Disruption

    CERN Document Server

    Ebrova, Ivana; Canalizo, Gabriela; Bennert, Nicola; Jilkova, Lucie

    2009-01-01

    Using N-body simulations of shell galaxies created in nearly radial minor mergers, we investigate the error of collision dating, resulting from the neglect of dynamical friction and of gradual disruption of the cannibalized dwarf.

  16. Glaciological parameters of disruptive event analysis

    International Nuclear Information System (INIS)

    The following disruptive events caused by ice sheets are considered: continental glaciation, erosion, loading and subsidence, deep ground water recharge, flood erosion, isostatic rebound rates, melting, and periodicity of ice ages

  17. Passive runaway electron suppression in tokamak disruptions

    International Nuclear Information System (INIS)

    Runaway electrons created in disruptions pose a serious problem for tokamaks with large current. It would be desirable to have a runaway electron suppression method which is passive, i.e., a method that does not rely on an uncertain disruption prediction system. One option is to let the large electric field inherent in the disruption drive helical currents in the wall. This would create ergodic regions in the plasma and increase the runaway losses. Whether these regions appear at a suitable time and place to affect the formation of the runaway beam depends on disruption parameters, such as electron temperature and density. We find that it is difficult to ergodize the central plasma before a beam of runaway current has formed. However, the ergodic outer region will make the Ohmic current profile contract, which can lead to instabilities that yield large runaway electron losses

  18. Endocrine Disrupting Chemicals and Disease Susceptibility

    OpenAIRE

    Schug, Thaddeus T.; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J.

    2011-01-01

    Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are tho...

  19. Anastomotic disruption after large bowel resection

    OpenAIRE

    NasirKhan, Mohammad U; Abir, Farshad; Longo, Walter; Kozol, Robert

    2006-01-01

    Anastomotic disruption is a feared and serious complication of colon surgery. Decades of research have identified factors favoring successful healing of anastomoses as well as risk factors for anastomotic disruption. However, some factors, such as the role of mechanical bowel preparation, remain controversial. Despite proper caution and excellent surgical technique, some anastomotic leaks are inevitable. The rapid identification of anastomotic leaks and the timely treatment in these cases are...

  20. Sleep and circadian rhythm disruption in schizophrenia†

    OpenAIRE

    Wulff, Katharina; Dijk, Derk-Jan; Middleton, Benita; Foster, Russell G.; Joyce, Eileen M.

    2012-01-01

    Background Sleep disturbances comparable with insomnia occur in up to 80% of people with schizophrenia, but very little is known about the contribution of circadian coordination to these prevalent disruptions. Aims A systematic exploration of circadian time patterns in individuals with schizophrenia with recurrent sleep disruption. Method We examined the relationship between sleep-wake activity, recorded actigraphically over 6 weeks, along with ambient light exposure and simultaneous circadia...

  1. BUSINESS MODEL PATTERNS FOR DISRUPTIVE TECHNOLOGIES

    OpenAIRE

    BENJAMIN AMSHOFF; CHRISTIAN DÜLME; JULIAN ECHTERFELD; JÜRGEN GAUSEMEIER

    2015-01-01

    Companies nowadays face a myriad of business opportunities as a direct consequence of manifold disruptive technology developments. As a basic characteristic, disruptive technologies lead to a severe shift in value-creation networks giving rise to new market segments. One of the key challenges is to anticipate the business logics within these nascent and formerly unknown markets. Business model patterns promise to tackle this challenge. They can be interpreted as proven business model elements...

  2. On asymmetric collisions with large disruption parameters

    International Nuclear Information System (INIS)

    Collisions between a weak electron bunch and a strong positron bunch are studied within a flat model. Electrons are tracked through the transverse space charge field of the positron bunch, and it is shown that positrons in a storage ring may remain stable after asymmetric collisions with a weak electron bunch in spite of large values of the electron disruption parameter. The plasma oscillations that affect collisions with large disruption parameters may be suppressed by properly matching the electrons. 8 refs., 5 figs

  3. Anastomotic disruption after large bowel resection

    Institute of Scientific and Technical Information of China (English)

    Mohammad U NasirKhan; Farshad Abir; Walter Longo; Robert Kozol

    2006-01-01

    Anastomotic disruption is a feared and serious complication of colon surgery. Decades of research have identified factors favoring successful healing of anastomoses as well as risk factors for anastomotic disruption. However, some factors, such as the role of mechanical bowel preparation, remain controversial.Despite proper caution and excellent surgical technique,some anastomotic leaks are inevitable. The rapid identification of anastomotic leaks and the timely treatment in these cases are paramount.

  4. Technoligical Life Cycles Regional Clusters Facing Disruption

    OpenAIRE

    Bent Dalum; Pedersen, Christian Ø. R.; Gert Villumsen

    2002-01-01

    The phenomenon of technological life cycles is argued to be of great importance in the development of regional clusters. New 'disruptive' technologies may initiate the emergence of new regional industrial clusters and/or create new opportunities for further development of existing ones. However, they may also result in stagnation and decline of the latter. The term disruptive refers to such significant changes in the basic technologies that may change the industrial landscape, even in the sho...

  5. Behaviour of disruption generated runaways in JET

    International Nuclear Information System (INIS)

    Experiments have established the regions of parameter space in JET that lead to runaway generation in disruptions. Previous measurements on the structure of the runaway beam have been confirmed. The delay in runaway generation following temperature collapse is found to be caused by the very high density generated by the disruption. It is shown that runaway generation in JET can be best modelled and understood by including avalanche processes. (author)

  6. Disruptive Technologies and the Emergence of Competition

    OpenAIRE

    Adner, Ron; Zemsky, Peter

    2003-01-01

    We formalize the phenomenon of disruptive technologies (Christensen, 1997) that initially serve isolated market niches and, as they mature, expand to displace established technologies from mainstream segments. Using a model of horizontal and vertical differentiation with discrete customer segmentation, we show how the threat of disruption varies with the rate of technological advance, the number of firms using each technology, segments sizes, marginal costs, and the ability of firms to price ...

  7. ENDOCRINE DISRUPTING EFFECTS OF BUTYLPARABEN: A REVIEW

    OpenAIRE

    Pallabi Goswami; J.C Kalita

    2013-01-01

    In recent years, there has been an increasing concern in the field of endocrine disruption over the presence of various endocrine disrupting chemicals in Pharmaceuticals and Personal care products (PPCPs). This concern has also been as PPCPs are most widely used and had led to introduction of thousands of new and complex chemicals that enter the environment in large quantities. The effect of the chemicals has not only been restricted to human who are exposed directly to the chemicals or the a...

  8. Skin Barrier Defects Caused by Keratinocyte-Specific Deletion of ADAM17 or EGFR Are Based on Highly Similar Proteome and Degradome Alterations.

    Science.gov (United States)

    Tholen, Stefan; Wolf, Cristina; Mayer, Bettina; Knopf, Julia D; Löffek, Stefanie; Qian, Yawen; Kizhakkedathu, Jayachandran N; Biniossek, Martin L; Franzke, Claus-Werner; Schilling, Oliver

    2016-05-01

    Keratinocyte-specific deletion of ADAM17 in mice impairs terminal differentiation of keratinocytes leading to severe epidermal barrier defects. Mice deficient for ADAM17 in keratinocytes phenocopy mice with a keratinocyte-specific deletion of epidermal growth factor receptor (EGFR), which highlights the role of ADAM17 as a "ligand sheddase" of EGFR ligands. In this study, we aim for the first proteomic/degradomic approach to characterize the disruption of the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation. Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17 and EGFR deficiency. These include massive proteome alterations of structural and regulatory components important for barrier formation such as transglutaminases, involucrin, filaggrin, and filaggrin-2. Cleavage site analysis using terminal amine isotopic labeling of substrates revealed increased proteolytic processing of S100 fused-type proteins including filaggrin-2. Alterations in proteolytic processing are supported by altered abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion, among them kallikreins, cathepsins, and their inhibitors. This study highlights the essential role of proteolytic processing for maintenance of a functional epidermal barrier. Furthermore, it suggests that most defects in formation of the postnatal epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR. PMID:27089454

  9. N-hypermannose glycosylation disruption enhances recombinant protein production by regulating secretory pathway and cell wall integrity in Saccharomyces cerevisiae.

    Science.gov (United States)

    Tang, Hongting; Wang, Shenghuan; Wang, Jiajing; Song, Meihui; Xu, Mengyang; Zhang, Mengying; Shen, Yu; Hou, Jin; Bao, Xiaoming

    2016-01-01

    Saccharomyces cerevisiae is a robust host for heterologous protein expression. The efficient expression of cellulases in S. cerevisiae is important for the consolidated bioprocess that directly converts lignocellulose into valuable products. However, heterologous proteins are often N-hyperglycosylated in S. cerevisiae, which may affect protein activity. In this study, the expression of three heterologous proteins, β-glucosidase, endoglucanase and cellobiohydrolase, was found to be N-hyperglycosylated in S. cerevisiae. To block the formation of hypermannose glycan, these proteins were expressed in strains with deletions in key Golgi mannosyltransferases (Och1p, Mnn9p and Mnn1p), respectively. Their extracellular activities improved markedly in the OCH1 and MNN9 deletion strains. Interestingly, truncation of the N-hypermannose glycan did not increase the specific activity of these proteins, but improved the secretion yield. Further analysis showed OCH1 and MNN9 deletion up-regulated genes in the secretory pathway, such as protein folding and vesicular trafficking, but did not induce the unfolded protein response. The cell wall integrity was also affected by OCH1 and MNN9 deletion, which contributed to the release of secretory protein extracellularly. This study demonstrated that mannosyltransferases disruption improved protein secretion through up-regulating secretory pathway and affecting cell wall integrity and provided new insights into glycosylation engineering for protein secretion. PMID:27156860

  10. Functional Profiling Using the Saccharomyces Genome Deletion Project Collections.

    Science.gov (United States)

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-01-01

    The ability to measure and quantify the fitness of an entire organism requires considerably more complex approaches than simply using traditional "omic" methods that examine, for example, the abundance of RNA transcripts, proteins, or metabolites. The yeast deletion collections represent the only systematic, comprehensive set of null alleles for any organism in which such fitness measurements can be assayed. Generated by the Saccharomyces Genome Deletion Project, these collections allow the systematic and parallel analysis of gene functions using any measurable phenotype. The unique 20-bp molecular barcodes engineered into the genome of each deletion strain facilitate the massively parallel analysis of individual fitness. Here, we present functional genomic protocols for use with the yeast deletion collections. We describe how to maintain, propagate, and store the deletion collections and how to perform growth fitness assays on single and parallel screening platforms. Phenotypic fitness analyses of the yeast mutants, described in brief here, provide important insights into biological functions, mechanisms of drug action, and response to environmental stresses. It is important to bear in mind that the specific assays described in this protocol represent some of the many ways in which these collections can be assayed, and in this description particular attention is paid to maximizing throughput using growth as the phenotypic measure. PMID:27587776

  11. Functional Genomics Using the Saccharomyces cerevisiae Yeast Deletion Collections.

    Science.gov (United States)

    Nislow, Corey; Wong, Lai Hong; Lee, Amy Huei-Yi; Giaever, Guri

    2016-01-01

    Constructed by a consortium of 16 laboratories, the Saccharomyces genome-wide deletion collections have, for the past decade, provided a powerful, rapid, and inexpensive approach for functional profiling of the yeast genome. Loss-of-function deletion mutants were systematically created using a polymerase chain reaction (PCR)-based gene deletion strategy to generate a start-to-stop codon replacement of each open reading frame by homologous recombination. Each strain carries two molecular barcodes that serve as unique strain identifiers, enabling their growth to be analyzed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays or through the use of next-generation sequencing technologies. Functional profiling of the deletion collections, using either strain-by-strain or parallel assays, provides an unbiased approach to systematically survey the yeast genome. The Saccharomyces yeast deletion collections have proved immensely powerful in contributing to the understanding of gene function, including functional relationships between genes and genetic pathways in response to diverse genetic and environmental perturbations. PMID:27587784

  12. An intersegmental neuronal architecture for spinal wave propagation under deletions.

    Science.gov (United States)

    Pérez, Toni; Tapia, Jesus A; Mirasso, Claudio R; García-Ojalvo, Jordi; Quevedo, Jorge; Cuellar, Carlos A; Manjarrez, Elias

    2009-08-19

    Recent studies have established and characterized the propagation of traveling electrical waves along the cat spinal cord during scratching, but the neuronal architecture that allows for the persistence of such waves even during periods of absence of bursts of motoneuron activity (deletions) is still unclear. Here we address this problem both theoretically and experimentally. Specifically, we monitored during long lasting periods of time the global electrical activity of spinal neurons during scratching. We found clear deletions of unaltered cycle in extensor activity without associated deletions of the traveling spinal wave. Furthermore, we also found deletions with a perturbed cycle associated with a concomitant absence of the traveling spinal wave. Numerical simulations of an asymmetric two-layer model of a central-pattern generator distributed longitudinally along the spinal cord qualitatively reproduce the sinusoidal traveling waves, and are able to replicate both classes of deletions. We believe these findings shed light into the longitudinal organization of the central-pattern generator networks in the spinal cord. PMID:19692599

  13. Disruption of PHO13 improves ethanol production via the xylose isomerase pathway.

    Science.gov (United States)

    Bamba, Takahiro; Hasunuma, Tomohisa; Kondo, Akihiko

    2016-03-01

    Xylose is the second most abundant sugar in lignocellulosic materials and can be converted to ethanol by recombinant Saccharomyces cerevisiae yeast strains expressing heterologous genes involved in xylose assimilation pathways. Recent research demonstrated that disruption of the alkaline phosphatase gene, PHO13, enhances ethanol production from xylose by a strain expressing the xylose reductase (XR) and xylitol dehydrogenase (XDH) genes; however, the yield of ethanol is poor. In this study, PHO13 was disrupted in a recombinant strain harboring multiple copies of the xylose isomerase (XI) gene derived from Orpinomyces sp., coupled with overexpression of the endogenous xylulokinase (XK) gene and disruption of GRE3, which encodes aldose reductase. The resulting YΔGP/XK/XI strain consumed 2.08 g/L/h of xylose and produced 0.88 g/L/h of volumetric ethanol, for an 86.8 % theoretical ethanol yield, and only YΔGP/XK/XI demonstrated increase in cell concentration. Transcriptome analysis indicated that expression of genes involved in the pentose phosphate pathway (GND1, SOL3, TAL1, RKI1, and TKL1) and TCA cycle and respiratory chain (NDE1, ACO1, ACO2, SDH2, IDH1, IDH2, ATP7, ATP19, SDH4, SDH3, CMC2, and ATP15) was upregulated in the YΔGP/XK/XI strain. And the expression levels of 125 cell cycle genes were changed by deletion of PHO13. PMID:26769491

  14. Disruption of a Large Intergenic Noncoding RNA in Subjects with Neurodevelopmental Disabilities

    Science.gov (United States)

    Talkowski, Michael E.; Maussion, Gilles; Crapper, Liam; Rosenfeld, Jill A.; Blumenthal, Ian; Hanscom, Carrie; Chiang, Colby; Lindgren, Amelia; Pereira, Shahrin; Ruderfer, Douglas; Diallo, Alpha B.; Lopez, Juan Pablo; Turecki, Gustavo; Chen, Elizabeth S.; Gigek, Carolina; Harris, David J.; Lip, Va; An, Yu; Biagioli, Marta; MacDonald, Marcy E.; Lin, Michael; Haggarty, Stephen J.; Sklar, Pamela; Purcell, Shaun; Kellis, Manolis; Schwartz, Stuart; Shaffer, Lisa G.; Natowicz, Marvin R.; Shen, Yiping; Morton, Cynthia C.; Gusella, James F.; Ernst, Carl

    2012-01-01

    Large intergenic noncoding (linc) RNAs represent a newly described class of ribonucleic acid whose importance in human disease remains undefined. We identified a severely developmentally delayed 16-year-old female with karyotype 46,XX,t(2;11)(p25.1;p15.1)dn in the absence of clinically significant copy number variants (CNVs). DNA capture followed by next-generation sequencing of the translocation breakpoints revealed disruption of a single noncoding gene on chromosome 2, LINC00299, whose RNA product is expressed in all tissues measured, but most abundantly in brain. Among a series of additional, unrelated subjects referred for clinical diagnostic testing who showed CNV affecting this locus, we identified four with exon-crossing deletions in association with neurodevelopmental abnormalities. No disruption of the LINC00299 coding sequence was seen in almost 14,000 control subjects. Together, these subjects with disruption of LINC00299 implicate this particular noncoding RNA in brain development and raise the possibility that, as a class, abnormalities of lincRNAs may play a significant role in human developmental disorders. PMID:23217328

  15. Mechanical algal disruption for efficient biodiesel extraction

    Science.gov (United States)

    Krehbiel, Joel David

    Biodiesel from algae provides several benefits over current biodiesel feedstocks, but the energy requirements of processing algae into a useable fuel are currently so high as to be prohibitive. One route to improving this is via disruption of the cells prior to lipid extraction, which can significantly increase energy recovery. Unfortunately, several obvious disruption techniques require more energy than can be gained. This dissertation examines the use of microbubbles to improve mechanical disruption of algal cells using experimental, theoretical, and computational methods. New laboratory experiments show that effective ultrasonic disruption of algae is achieved by adding microbubbles to an algal solution. The configuration studied flows the solution through a tube and insonifies a small section with a high-pressure ultrasound wave. Previous biomedical research has shown effective cell membrane damage on animal cells with similar methods, but the present research is the first to extend such study to algal cells. Results indicate that disruption increases with peak negative pressure between 1.90 and 3.07 MPa and with microbubble concentration up to 12.5 x 107 bubbles/ml. Energy estimates of this process suggest that it requires only one-fourth the currently most-efficient laboratory-scale disruption process. Estimates of the radius near each bubble that causes disruption (i.e. the disruption radius) suggest that it increases with peak negative pressure and is near 9--20 microm for all cases tested. It is anticipated that these procedures can be designed for better efficiency and efficacy, which will be facilitated by identifying the root mechanisms of the bubble-induced disruption. We therefore examine whether bubble expansion alone creates sufficient cell deformation for cell rupture. The spherically-symmetric Marmottant model for bubble dynamics allows estimation of the flow regime under experimental conditions. Bubble expansion is modeled as a point source of

  16. Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire.

    Science.gov (United States)

    Rusconi, Daniela; Negri, Gloria; Colapietro, Patrizia; Picinelli, Chiara; Milani, Donatella; Spena, Silvia; Magnani, Cinzia; Silengo, Margherita Cirillo; Sorasio, Lorena; Curtisova, Vaclava; Cavaliere, Maria Luigia; Prontera, Paolo; Stangoni, Gabriela; Ferrero, Giovanni Battista; Biamino, Elisa; Fischetto, Rita; Piccione, Maria; Gasparini, Paolo; Salviati, Leonardo; Selicorni, Angelo; Finelli, Palma; Larizza, Lidia; Gervasini, Cristina

    2015-06-01

    Rubinstein-Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55% of cases) and EP300 (~8%) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30-50 %) and deletions (~10%). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23% of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype-phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype. PMID:25805166

  17. Dissecting the phenotypes of Dravet syndrome by gene deletion.

    Science.gov (United States)

    Rubinstein, Moran; Han, Sung; Tai, Chao; Westenbroek, Ruth E; Hunker, Avery; Scheuer, Todd; Catterall, William A

    2015-08-01

    Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Nav1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Nav1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Nav1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Nav1.1 in parvalbumin-expressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types. PMID:26017580

  18. Functional analysis of hepatitis B virus pre-s deletion variants associated with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Lin Chih-Ming

    2012-02-01

    Full Text Available Abstract Background Naturally occurring pre-S deletion mutants have been identified in hepatitis B carriers and shown to be associated with the development of hepatocellular carcinoma. The phenotypes of these pre-S deletion genomes remain unclear, and they were investigated in this study. Methods The pre-S deletion genomes: (1 pre-S1 deletion, (2 deletion spanning pre-S1 and pre-S2, (3 pre-S2 N-terminal deletion, and (4 pre-S2 internal deletion were constructed and analyzed by transfection into Huh-7 cells. Results Functional analyses reveal that these mutants were divided into two groups: S promoter deletion and non-S promoter deletion variants. Compared with the wild-type genome, S promoter deletion variants led to an inverse ratio of pre-S1 mRNA and pre-S2/S mRNA, and intracellular accumulation of surface proteins. An interesting finding is that a small amount of L proteins was detected in the medium from S promoter deletion variant-transfected cells. Non-S promoter deletion variants conversely displayed a wild-type like mRNA and protein pattern. The secretion of surface proteins from non-S promoter deletion variants was inhibited less than from S promoter deletion variant. Immunofluorescence analysis showed mutant surface proteins colocalized with ER and exhibited an atypical distribution: granular staining pattern in the S-promoter deletion variants and perinuclear staining pattern in the non-S promoter deletion variants. Conclusion This study shows that these pre-S deletion genomes exhibit two different phenotypes in mRNA transcription, surface protein expression and secretion. This diversity seems to result from the deletion of S promoter rather than result from the deletion of pre-S1 or pre-S2.

  19. Ku80-Deleted Cells are Defective at Base Excision Repair

    OpenAIRE

    Li, Han; Marple, Teresa; Hasty, Paul

    2013-01-01

    Ku80 forms a heterodimer with Ku70, called Ku, that repairs DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. As a consequence of deleting NHEJ, Ku80-mutant cells are hypersensitive to agents that cause DNA DSBs like ionizing radiation. Here we show that Ku80 deletion also decreased resistance to ROS and alkylating agents that typically cause base lesions and single-strand breaks (SSBs). This is unusual since base excision repair (BER), not NHEJ, typically repa...

  20. Binding numbers of fractional k-deleted graphs

    OpenAIRE

    KOTANI, Keiko

    2010-01-01

    Let k be an integer with $k \\ge 2$. We show that if G be a graph such that $|G| > 4k+1 -4\\sqrt {k-1}$ and $bind(G)> {(2k-1)(n-1) \\over k(n-2)},$ then G is a fractional k-deleted graph. We also show that in the case where k is even, if G be a graph such that $|G| > 4k+1 -4\\sqrt {k}$ and $bind(G)> {(2k-1)(n-1) \\over k(n-2)+1},$ then G is a fractional k-deleted graph.

  1. Disruptions and vertical displacement events in JET

    International Nuclear Information System (INIS)

    Major disruptions and vertical displacement events (VDEs) represent a serious problem for the integrity of large devices such as ITER and a reactor. This arises from the localized power deposition on the divertor target and first wall, the production of runaway electrons in the post-disruptive plasma and the substantial forces transmitted to the vacuum vessel by eddy and halo currents. Extensive experiments have been performed in JET to characterize the phenomena associated with disruptions and VDEs and to investigate the underlying physics. In addition, the installation of a disruption feedback stabilization system based on a set of four internal saddle coils driven by high power (3 kA/1.5 kV), high frequency (0-10 kHz) amplifiers has allowed initial experiments on the control of disruptions by suppression of the n = 1 mhd precursor. This system has also been used to study fundamental aspects of the physics of error field induced modes, which is of direct application to ITER (author). 3 refs, 8 figs

  2. A Genome-Wide Transcription An alysis Reveals a Close Correlation of Promoter INDEL Polymorphism and Heterotic Gene Expression in Rice Hybrids

    Institute of Scientific and Technical Information of China (English)

    Hui-Yong Zhang; Li-Geng Ma; Xing Wang Deng; Hang He; Liang-Bi Chen; Lei Li; Man-Zhong Liang; Xiang-Feng Wang; Xi-Gang Liu; Guang-Ming He; Run-Sheng Chen

    2008-01-01

    Heterosis,or hybrid vigor,refers to the phenomenon in which hybrid progeny of two inbred varieties exhibits enhanced growth or agronomic performance.Although a century-long history of research has generated several hypotheses regarding the genetic basis of heterosis,the molecular mechanisms underlying heterosis and heterotic gene expression remain elusive.Here,we report a genome-wide gene expression analysis of two heterotic crosses in rice,taking advantage of its fully sequenced genomes.Approximately 7-9%of the genes were differentially expressed in the seedling shoots from two sets of heterotic crosses,including many transcription factor genes,and exhibited multiple modes of gene action.Comparison of the putative promoter regions of the ortholog genes between inbred parents revealed extensive sequence variation,particularly smallinsertions/deletions(INDELs),many of which result in the formation/disruption of putative cis-regulatory elements.Together,these results suggest that a combinatoriaI interplay between expression of transcription factors and polymorphic promoter cis-regulatory elements in the hybrids is one plausible molecular mechanism underlying heterotic gene action and thus heterosis in rice.

  3. Mechanical algal disruption for efficient biodiesel extraction

    Science.gov (United States)

    Krehbiel, Joel David

    Biodiesel from algae provides several benefits over current biodiesel feedstocks, but the energy requirements of processing algae into a useable fuel are currently so high as to be prohibitive. One route to improving this is via disruption of the cells prior to lipid extraction, which can significantly increase energy recovery. Unfortunately, several obvious disruption techniques require more energy than can be gained. This dissertation examines the use of microbubbles to improve mechanical disruption of algal cells using experimental, theoretical, and computational methods. New laboratory experiments show that effective ultrasonic disruption of algae is achieved by adding microbubbles to an algal solution. The configuration studied flows the solution through a tube and insonifies a small section with a high-pressure ultrasound wave. Previous biomedical research has shown effective cell membrane damage on animal cells with similar methods, but the present research is the first to extend such study to algal cells. Results indicate that disruption increases with peak negative pressure between 1.90 and 3.07 MPa and with microbubble concentration up to 12.5 x 107 bubbles/ml. Energy estimates of this process suggest that it requires only one-fourth the currently most-efficient laboratory-scale disruption process. Estimates of the radius near each bubble that causes disruption (i.e. the disruption radius) suggest that it increases with peak negative pressure and is near 9--20 microm for all cases tested. It is anticipated that these procedures can be designed for better efficiency and efficacy, which will be facilitated by identifying the root mechanisms of the bubble-induced disruption. We therefore examine whether bubble expansion alone creates sufficient cell deformation for cell rupture. The spherically-symmetric Marmottant model for bubble dynamics allows estimation of the flow regime under experimental conditions. Bubble expansion is modeled as a point source of

  4. A model for disruption generated runaway electrons

    International Nuclear Information System (INIS)

    One of the possible consequences of disruptions in tokamaks is the generation of runaway electrons which can impact plasma facing components and cause damage, owing to high local energy deposition. This problem becomes more serious as the machine size and plasma current increase. Since large size and high currents are characteristics of proposed future machines, control of runaway generation is an important design consideration. A lumped circuit model for disruption runaway electron generation indicates that impurity concentration and type, as well as plasma motion, can strongly influence runaway behaviour. A comparison of disruption data from several runs on JET and DIII-D with model results demonstrate the effects of impurities, and plasma motion, on runaway number density and energy. The model is also applied to the calculation of runaway currents for ITER. (author). 16 refs, 13 figs

  5. Disc formation from stellar tidal disruptions

    CERN Document Server

    Bonnerot, Clément; Lodato, Giuseppe; Price, Daniel J

    2015-01-01

    The potential of tidal disruption of stars to probe otherwise quiescent supermassive black holes cannot be exploited, if their dynamics is not fully understood. So far, the observational appearance of these events has been commonly derived from analytical extrapolations of the debris dynamical properties just after the stellar disruption. In this paper, we perform hydrodynamical simulations of stars in highly eccentric orbits, that follow the stellar debris after disruption and investigate their ultimate fate. We demonstrate that gas debris circularize on an orbital timescale because relativistic apsidal precession causes the stream to self-cross. The higher the eccentricity and/or the deeper the encounter, the faster is the circularization. If the internal energy deposited by shocks during stream self-interaction is readily radiated, the gas forms a narrow ring at the circularization radius. It will then proceed to accrete viscously at a super-Eddington rate, puffing up under radiation pressure. If instead c...

  6. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Groth, Julie Jespersen; Potthoff, Daniel; Clausen, Jens;

    2009-01-01

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...... the three main subproblems in railway disruption management: timetable adjustment, and rolling stock and crew re-scheduling. Next to a general description of these problems, we give an overview of the existing literature and we present some details of the specific situations at DSB S-tog and NS. These...... are the railway operators in the suburban area of Copenhagen, Denmark, and on the main railway lines in The Netherlands, respectively. Finally, we address the integration of the re-scheduling processes of the timetable, and the resources rolling stock and crew....

  7. Mermaid syndrome with amniotic band disruption.

    Science.gov (United States)

    Managoli, Sanjeev; Chaturvedi, Pushpa; Vilhekar, Krishna Y; Iyenger, Janaki

    2003-01-01

    An association of Amniotic Band Disruption Sequence and Mermaid Syndrome in a newborn having multiple congenital anomalies is being reported. The newborn had aberrant string like tissues attached to the amputed fingers and toes. Adhesions of amniotic bands had disrupted the fetal parts especially anteriorly in the midline, causing multiple anomalies. Apart from these features of Amniotic Band Disruption Sequence, the newborn had complete fusion of the lower limbs by cutaneous tissue, a characteristic of Mermaid Syndrome (Sirenomelia). Associated malformations were anal stenosis, rectal atresia, small horseshoe kidney, hypoplastic urinary bladder and a bicomuate uterus. The single umbilical artery had a high origin, arising directly from the aorta just distal to the celiac axis, which is unique to sirenomelia. Theories put forward regarding the etiopathogenesis of both the conditions are discussed. PMID:12619964

  8. An Improved Single-Step Cloning Strategy Simplifies the Agrobacterium tumefaciens-Mediated Transformation (ATMT)-Based Gene-Disruption Method for Verticillium dahliae.

    Science.gov (United States)

    Wang, Sheng; Xing, Haiying; Hua, Chenlei; Guo, Hui-Shan; Zhang, Jie

    2016-06-01

    The soilborne fungal pathogen Verticillium dahliae infects a broad range of plant species to cause severe diseases. The availability of Verticillium genome sequences has provided opportunities for large-scale investigations of individual gene function in Verticillium strains using Agrobacterium tumefaciens-mediated transformation (ATMT)-based gene-disruption strategies. Traditional ATMT vectors require multiple cloning steps and elaborate characterization procedures to achieve successful gene replacement; thus, these vectors are not suitable for high-throughput ATMT-based gene deletion. Several advancements have been made that either involve simplification of the steps required for gene-deletion vector construction or increase the efficiency of the technique for rapid recombinant characterization. However, an ATMT binary vector that is both simple and efficient is still lacking. Here, we generated a USER-ATMT dual-selection (DS) binary vector, which combines both the advantages of the USER single-step cloning technique and the efficiency of the herpes simplex virus thymidine kinase negative-selection marker. Highly efficient deletion of three different genes in V. dahliae using the USER-ATMT-DS vector enabled verification that this newly-generated vector not only facilitates the cloning process but also simplifies the subsequent identification of fungal homologous recombinants. The results suggest that the USER-ATMT-DS vector is applicable for efficient gene deletion and suitable for large-scale gene deletion in V. dahliae. PMID:26780432

  9. Disruptive event analysis: volcanism and igneous intrusion

    Energy Technology Data Exchange (ETDEWEB)

    Crowe, B.M.

    1980-08-01

    An evaluation is made of the disruptive effects of volcanic activity with respect to long term isolation of radioactive waste through deep geologic storage. Three major questions are considered. First, what is the range of disruption effects of a radioactive waste repository by volcanic activity. Second, is it possible, by selective siting of a repository, to reduce the risk of disruption by future volcanic activity. And third, can the probability of repository disruption by volcanic activity be quantified. The main variables involved in the evaluation of the consequences of repository disruption by volcanic activity are the geometry of the magma-repository intersection (partly controlled by depth of burial) and the nature of volcanism. Potential radionuclide dispersal by volcanic transport within the biosphere ranges in distance from several kilometers to global. Risk from the most catastrophic types of eruptions can be reduced by careful site selection to maximize lag time prior to the onset of activity. Certain areas or volcanic provinces within the western United States have been sites of significant volcanism and should be avoided as potential sites for a radioactive waste repository. Examples of projection of future sites of active volcanism are discussed for three areas of the western United States. Probability calculations require two types of data: a numerical rate or frequency of volcanic activity and a numerical evaluation of the areal extent of volcanic disruption for a designated region. The former is clearly beyond the current state of art in volcanology. The latter can be approximated with a reasonable degree of satisfaction. In this report, simplified probability calculations are attempted for areas of past volcanic activity.

  10. Disruptive event analysis: volcanism and igneous intrusion

    International Nuclear Information System (INIS)

    An evaluation is made of the disruptive effects of volcanic activity with respect to long term isolation of radioactive waste through deep geologic storage. Three major questions are considered. First, what is the range of disruption effects of a radioactive waste repository by volcanic activity. Second, is it possible, by selective siting of a repository, to reduce the risk of disruption by future volcanic activity. And third, can the probability of repository disruption by volcanic activity be quantified. The main variables involved in the evaluation of the consequences of repository disruption by volcanic activity are the geometry of the magma-repository intersection (partly controlled by depth of burial) and the nature of volcanism. Potential radionuclide dispersal by volcanic transport within the biosphere ranges in distance from several kilometers to global. Risk from the most catastrophic types of eruptions can be reduced by careful site selection to maximize lag time prior to the onset of activity. Certain areas or volcanic provinces within the western United States have been sites of significant volcanism and should be avoided as potential sites for a radioactive waste repository. Examples of projection of future sites of active volcanism are discussed for three areas of the western United States. Probability calculations require two types of data: a numerical rate or frequency of volcanic activity and a numerical evaluation of the areal extent of volcanic disruption for a designated region. The former is clearly beyond the current state of art in volcanology. The latter can be approximated with a reasonable degree of satisfaction. In this report, simplified probability calculations are attempted for areas of past volcanic activity

  11. Two generations of identical twins with ELN deletion

    OpenAIRE

    Katumba-Lunyenya, Jasper

    2009-01-01

    We report a family with three generations of an ELN deletion. The grandfather was normal except for two inguinal herniotomies. The first generation identical twins had supravalvular aortic and multiple peripheral pulmonary artery stenoses. The second generation twins died during the neonatal period of myocardial infarcts.

  12. 44 CFR 5.27 - Deletion of identifying details.

    Science.gov (United States)

    2010-10-01

    ... details. 5.27 Section 5.27 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY... identifying details. To the extent required to prevent a clearly unwarranted invasion of personal privacy, FEMA may delete identifying details when making available or publishing an opinion, statement of...

  13. 34 CFR 5.16 - Deletion of identifying details.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Deletion of identifying details. 5.16 Section 5.16... details. Whenever any final opinion, order, or other materials required to be made available pursuant to... other identifying details will constitute a clearly unwarranted invasion of personal privacy, the...

  14. Frequency of heterozygous TET2 deletions in myeloproliferative neoplasms

    Directory of Open Access Journals (Sweden)

    Joseph Tripodi

    2010-09-01

    Full Text Available Joseph Tripodi1, Ronald Hoffman1, Vesna Najfeld2, Rona Weinberg31The Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine and 2Department of Medicine and Pathology, Mount Sinai School of Medicine, 3The Myeloproliferative Disorders Program, Cellular Therapy Laboratory, The New York Blood Center, New York, NY, USAAbstract: The Philadelphia chromosome (Ph-negative myeloproliferative neoplasms (MPNs, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a group of clonal hematopoietic stem cell disorders with overlapping clinical and cytogenetic features and a variable tendency to evolve into acute leukemia. These diseases not only share overlapping chromosomal abnormalities but also a number of acquired somatic mutations. Recently, mutations in a putative tumor suppressor gene, ten-eleven translocation 2 (TET2 on chromosome 4q24 have been identified in 12% of patients with MPN. Additionally 4q24 chromosomal rearrangements in MPN, including TET2 deletions, have also been observed using conventional cytogenetics. The goal of this study was to investigate the frequency of genomic TET2 rearrangements in MPN using fluorescence in situ hybridization as a more sensitive method for screening and identifying genomic deletions. Among 146 MPN patients, we identified two patients (1.4% who showed a common 4q24 deletion, including TET2. Our observations also indicated that the frequency of TET2 deletion is increased in patients with an abnormal karyotype (5%.Keywords: TET2, myeloproliferative neoplasms, fluorescence in situ hybridization, cytogenetics

  15. Expanding Our Understanding of mtDNA Deletions.

    Science.gov (United States)

    Picard, Martin; Vincent, Amy E; Turnbull, Doug M

    2016-07-12

    Clonal expansion of mtDNA deletions compromises mitochondrial function in human disease and aging, but how deleterious mtDNA genomes propagate has remained unclear. In this issue (Gitschlag et al., 2016) and in a recent Nature publication, C. elegans studies implicate the mitochondrial unfolded protein response (UPR(mt)) and offer mechanistic insights into this process. PMID:27411002

  16. Commentary: The Thrill of Professionalization and the Agony of Deletes

    Science.gov (United States)

    Waite, Susan Field; Leavell, Judy A.

    2006-01-01

    Although some teacher educators hoped that the creation and use of standards would help to professionalize teaching, the discourse of standards and accountability is now being used to erode teacher education. Many teacher educators who anticipated the thrill of professionalization through standards are now experiencing the agony of deletes,…

  17. Deletion Mutations Keep Kinase Inhibitors in the Loop.

    Science.gov (United States)

    Freed, Daniel M; Park, Jin H; Radhakrishnan, Ravi; Lemmon, Mark A

    2016-04-11

    Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and HER2 cause primary resistance to common inhibitors, suggesting strategies for improved inhibitor selection. PMID:27070691

  18. Genetics Home Reference: 22q11.2 deletion syndrome

    Science.gov (United States)

    ... Seattle, Washington Children's Hospital of Philadelphia Cincinnati Children's Hospital Medical Center Disease InfoSearch: 22q11.2 Deletion Syndrome Emory University School of Medicine Genetics Education Materials for School Success (GEMSS) MalaCards: chromosome 22q11. ...

  19. Efficient Generation of Unmarked Deletions in Legionella pneumophila▿ †

    OpenAIRE

    Bryan, Andrew; Harada, Kaoru; Michele S Swanson

    2011-01-01

    Unmarked gene deletions facilitate studies of Legionella pneumophila multicomponent processes, such as motility and exonuclease activity. For this purpose, FRT-flanked alleles constructed in Escherichia coli using λ-Red recombinase were transferred to L. pneumophila by natural transformation. Resistance cassettes were then efficiently excised using the Flp site-specific recombinase encoded on a plasmid that is readily lost.

  20. Distinct effects of tafazzin deletion in differentiated and undifferentiated mitochondria

    NARCIS (Netherlands)

    D. Acehan; Z. Khuchua; R.H. Houtkooper; A. Malhotra; J. Kaufman; F.M. Vaz; M. Ren; H.A. Rockman; D.L. Stokes; M. Schlame

    2009-01-01

    Tafazzin is a conserved mitochondrial protein that is required to maintain normal content and composition of cardiolipin. We used electron tomography to investigate the effect of tafazzin deletion on mitochondrial structure and found that cellular differentiation plays a crucial role in the manifest

  1. Tidal disruption of stars by SMBHs

    Science.gov (United States)

    Komossa, S.

    2016-06-01

    The tidal disruption and subsequent accretion of stars by supermassive black holes produces spectacular flares in the X-ray sky. First found with ROSAT, ongoing and upcoming sky surveys will find these events in the 1000s. In X-rays, tidal disruption events (TDEs) provide us with powerful new probes of accretion physics under extreme conditions, of the formation of disk winds, of relativistic effects near the SMBH, and of the presence of supermassive binary black holes. This talk reviews the status of observations, and discusses future prospects. XMM-Newton will continue to play an important role in identifying new events and carry out spectroscopic follow-ups.

  2. Airline Disruption Management - Perspectives, Experiences and Outlook

    DEFF Research Database (Denmark)

    Kohl, Niklas; Larsen, Allan; Larsen, Jesper;

    2007-01-01

    Over the past decade, airlines have become more concerned with developing an optimal flight schedule, with very little slack left to accommodate for any form of variation from the optimal solution. During operation the planned schedules often have to be revised due to disruptions caused by for ex...... part we report on experiences from a large research and development project on airline disruption management. Within the project the first prototype of a multiple resource decision support system at the operations control center in a major airline, has been implemented....

  3. Disruptive Technologies and Networking in Telecom Industries

    DEFF Research Database (Denmark)

    Madsen, Erik Strøjer; Hartington, Simon Preuthun

    2015-01-01

    developed around the introduction of the smart phone and looking closer into the reactions of major players such as Apple, Google, Microsoft and Nokia, we find evidence supporting the finding in the literature of an inadequate strategies among incumbent companies. Large incumbent companies are focused too...... telecommunication industry and finds significant similarities between the industry development and the literature on disruptive technology, which finds that incumbent companies are not able to react in a successful way when disruptions occur in their industry. By studying how the telecommunication industry...

  4. Disruptive technologies and networking in telecom industries

    DEFF Research Database (Denmark)

    Madsen, Erik Strøjer; Hartington, Simon

    developed around the introduction of the smart phone and looking closer into the reactions of major players such as Apple, Google, Microsoft and Nokia, we find evidence supporting the finding in the literature of an inadequate strategies among incumbent companies. Large incumbent companies are focused too...... telecommunication industry and finds significant similarities between the industry development and the literature on disruptive technology, which finds that incumbent companies are not able to react in a successful way when disruptions occur in their industry. By studying how the telecommunication industry...

  5. Abundance Anomalies In Tidal Disruption Events

    OpenAIRE

    Kochanek, C. S.

    2015-01-01

    The ~10% of tidal disruption events (TDEs) due to stars more massive than the Sun should show abundance anomalies due to stellar evolution in helium, carbon and nitrogen, but not oxygen. Helium is always enhanced, but only by up to ~25% on average because it becomes inaccessible once it is sequestered in the high density core as the star leaves the main sequence. However, portions of the debris associated with the disrupted core of a main sequence star can be enhanced in helium by factors of ...

  6. Engineering aspects of disruption current decay

    International Nuclear Information System (INIS)

    Engineering features associated with the configuration of a tokamak can affect the amount of energy that produces melting and damage to the limiters or internal wall surfaces as the result of a major disruption. During the current decay period of a major thermal disruption, the energy that can damage a wall or limiter comes from the external magnetic field. By providing a good conducting torus near the plasma and increasing the plasma circuit resistance, this magnetic energy (transferred by way of the plasma circuit) can be minimized. This report addresses engineering design features to reduce the energy deposited on the inner torus surface that produces melting of the structures

  7. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

    International Nuclear Information System (INIS)

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2f/f) and their corresponding wild-type background mice (MyhCre.Tgfbr2WT/WT) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process

  8. Disruption of TGF-β signaling in smooth muscle cell prevents flow-induced vascular remodeling

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Fu [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Chambon, Pierre [Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104, INSERM U596, ULP, Collége de France) and Institut Clinique de la Souris, ILLKIRCH, Strasbourg (France); Tellides, George [Department of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (United States); Kong, Wei [Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing (China); Zhang, Xiaoming, E-mail: rmygxgwk@163.com [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China); Li, Wei [Department of Vascular Surgery, Peking University People’s Hospital, Beijing (China)

    2014-11-07

    Highlights: • TGF-β signaling in SMC contributes to the flow-induced vascular remodeling. • Disruption of TGF-β signaling in SMC can prevent this process. • Targeting SM-specific Tgfbr2 could be a novel therapeutic strategy for vascular remodeling. - Abstract: Transforming growth factor-β (TGF-β) signaling has been prominently implicated in the pathogenesis of vascular remodeling, especially the initiation and progression of flow-induced vascular remodeling. Smooth muscle cells (SMCs) are the principal resident cells in arterial wall and are critical for arterial remodeling. However, the role of TGF-β signaling in SMC for flow-induced vascular remodeling remains unknown. Therefore, the goal of our study was to determine the effect of TGF-β pathway in SMC for vascular remodeling, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) deletion mice model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2{sup f/f}) and their corresponding wild-type background mice (MyhCre.Tgfbr2{sup WT/WT}) underwent partial ligation of left common carotid artery for 1, 2, or 4 weeks. Then the carotid arteries were harvested and indicated that the disruption of Tgfbr2 in SMC provided prominent inhibition of vascular remodeling. And the thickening of carotid media, proliferation of SMC, infiltration of macrophage, and expression of matrix metalloproteinase (MMP) were all significantly attenuated in Tgfbr2 disruption mice. Our study demonstrated, for the first time, that the TGF-β signaling in SMC plays an essential role in flow-induced vascular remodeling and disruption can prevent this process.

  9. Evolution of the Insertion-Deletion Mutation Rate Across the Tree of Life.

    Science.gov (United States)

    Sung, Way; Ackerman, Matthew S; Dillon, Marcus M; Platt, Thomas G; Fuqua, Clay; Cooper, Vaughn S; Lynch, Michael

    2016-01-01

    Mutations are the ultimate source of variation used for evolutionary adaptation, while also being predominantly deleterious and a source of genetic disorders. Understanding the rate of insertion-deletion mutations (indels) is essential to understanding evolutionary processes, especially in coding regions, where such mutations can disrupt production of essential proteins. Using direct estimates of indel rates from 14 phylogenetically diverse eukaryotic and bacterial species, along with measures of standing variation in such species, we obtain results that imply an inverse relationship of mutation rate and effective population size. These results, which corroborate earlier observations on the base-substitution mutation rate, appear most compatible with the hypothesis that natural selection reduces mutation rates per effective genome to the point at which the power of random genetic drift (approximated by the inverse of effective population size) becomes overwhelming. Given the substantial differences in DNA metabolism pathways that give rise to these two types of mutations, this consistency of results raises the possibility that refinement of other molecular and cellular traits may be inversely related to species-specific levels of random genetic drift. PMID:27317782

  10. Somatic amplifications and deletions in genome of papillary thyroid carcinomas.

    Science.gov (United States)

    Passon, Nadia; Bregant, Elisa; Sponziello, Marialuisa; Dima, Maria; Rosignolo, Francesca; Durante, Cosimo; Celano, Marilena; Russo, Diego; Filetti, Sebastiano; Damante, Giuseppe

    2015-11-01

    Somatic gene copy number variation contributes to tumor progression. Using comparative genomic hybridization (CGH) array, the presence of genomic imbalances was evaluated in a series of 27 papillary thyroid carcinomas (PTCs). To detect only somatic imbalances, for each sample, the reference DNA was from normal thyroid tissue of the same patient. The presence of the BRAF V600E mutation was also evaluated. Both amplifications and deletions showed an uneven distribution along the entire PTC cohort; amplifications were more frequent than deletions (mean values of 17.5 and 7.2, respectively). Number of aberration events was not even among samples, the majority of them occurring only in a small fraction of PTCs. Most frequent amplifications were detected at regions 2q35, 4q26, and 4q34.1, containing FN1, PDE5A, and GALNTL6 genes, respectively. Most frequent deletions occurred at regions 6q25.2, containing OPMR1 and IPCEF1 genes and 7q14.2, containing AOAH and ELMO1 genes. Amplification of FN1 and PDE5A genomic regions was confirmed by quantitative PCR. Frequency of amplifications and deletions was in relationship with clinical features and BRAF mutation status of tumor. In fact, according to the American Joint Committee on Cancer stage and American Thyroid Association (ATA) risk classification, amplifications are more frequent in higher risk samples, while deletions tend to prevail in the lower risk tumors. Analysis of single aberrations according to the ATA risk grouping shows that amplifications containing PDE5A, GALNTL6, DHRS3, and DOCK9 genes are significantly more frequent in the intermediate/high risk group than in the low risk group. Thus, our data would indicate that analysis of somatic genome aberrations by CGH array can be useful to identify additional prognostic variables. PMID:25863487

  11. Rare copy number deletions predict individual variation in intelligence.

    Directory of Open Access Journals (Sweden)

    Ronald A Yeo

    Full Text Available Phenotypic variation in human intellectual functioning shows substantial heritability, as demonstrated by a long history of behavior genetic studies. Many recent molecular genetic studies have attempted to uncover specific genetic variations responsible for this heritability, but identified effects capture little variance and have proven difficult to replicate. The present study, motivated an interest in "mutation load" emerging from evolutionary perspectives, examined the importance of the number of rare (or infrequent copy number variations (CNVs, and the total number of base pairs included in such deletions, for psychometric intelligence. Genetic data was collected using the Illumina 1MDuoBeadChip Array from a sample of 202 adult individuals with alcohol dependence, and a subset of these (N = 77 had been administered the Wechsler Abbreviated Scale of Intelligence (WASI. After removing CNV outliers, the impact of rare genetic deletions on psychometric intelligence was investigated in 74 individuals. The total length of the rare deletions significantly and negatively predicted intelligence (r = -.30, p = .01. As prior studies have indicated greater heritability in individuals with relatively higher parental socioeconomic status (SES, we also examined the impact of ethnicity (Anglo/White vs. Other, as a proxy measure of SES; these groups did not differ on any genetic variable. This categorical variable significantly moderated the effect of length of deletions on intelligence, with larger effects being noted in the Anglo/White group. Overall, these results suggest that rare deletions (between 5% and 1% population frequency or less adversely affect intellectual functioning, and that pleotropic effects might partly account for the association of intelligence with health and mental health status. Significant limitations of this research, including issues of generalizability and CNV measurement, are discussed.

  12. Deletion affecting band 7q36 not associated with holoprosencephaly

    Energy Technology Data Exchange (ETDEWEB)

    Ebrahim, S.A.D.; Krivchenia, E.; Mohamed, A.N. [Wayne State Univ., Detroit, MI (United States)] [and others

    1994-09-01

    Although the appearance of 7q36 aberrations have been postulated to be responsible for holoprosencephaly (HPE), the presence of a de novo 7q36 deletion in fetus without HPE has not been reported. We report the first case of a fetus with 7q36 deletion but lacking HPE. Ultrasound examination of a 25-year-old G3P1 Caucasian female showed small head circumference with microcephaly at 28 weeks. Decreased amniotic fluid volume, bilateral renal dilatation and abnormal facial features were also noted. Chromosome analysis after cordocentesis showed an abnormal female karyotype with a deletion involving the chromosome band 7q36, 46,XX,del(7)(q36). Chromosome studies on the biological parents were normal. In view of the chromosome finding and after extensive counseling, the couple elected to terminate the pregnancy. The chromosome findings were confirmed by fetal blood chromosome analysis at termination. Post-mortem examination confirmed dysmorphic features including a depressed nasal bridge and large flat ears with no lobules, but no cleft lip or palate was noted. Internal abnormalities included a bicuspid pulmonary valve and abnormally located lungs. The brain weighed 190g (249 {plus_minus} 64g expected) and had symmetric cerebral hemispheres without evidence of HPE or other gross or microscopic malformation, except focal cerebellar cortical dysplasia. In summary, our patient showed a deletion of the same chromosomal band implicated in HPE but lacked HPE. This finding indicates that 7q36 deletion may be seen in the absence of HPE and suggests that other genetic mechanisms may be responsible for HPE in this setting.

  13. Analysis of Noncanonical Calcium-Dependent Protein Kinases in Toxoplasma gondii by Targeted Gene Deletion Using CRISPR/Cas9.

    Science.gov (United States)

    Long, Shaojun; Wang, Qiuling; Sibley, L David

    2016-05-01

    Calcium-dependent protein kinases (CDPKs) are expanded in apicomplexan parasites, especially in Toxoplasma gondii where 14 separate genes encoding these enzymes are found. Although previous studies have shown that several CDPKs play a role in controlling invasion, egress, and cell division in T. gondii, the roles of most of these genes are unexplored. Here we developed a more efficient method for gene disruption using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) that was modified to completely delete large, multiexonic genes from the genome and to allow serial replacement by recycling of the selectable marker using Cre-loxP. Using this system, we generated a total of 24 mutants in type 1 and 2 genetic backgrounds to ascertain the functions of noncanonical CDPKs. Remarkably, although we were able to confirm the essentiality of CDPK1 and CDPK7, the majority of CDPKs had no discernible phenotype for growth in vitro or infection in the mouse model. The exception to this was CDPK6, loss of which leads to reduced plaquing, fitness defect in a competition assay, and reduced tissue cyst formation in chronically infected mice. Our findings highlight the utility of CRISPR/Cas9 for rapid serial gene deletion and also suggest that additional models are needed to reveal the functions of many genes in T. gondii. PMID:26755159

  14. Intronic deletions of tva receptor gene decrease the susceptibility to infection by avian sarcoma and leukosis virus subgroup A.

    Science.gov (United States)

    Chen, Weiguo; Liu, Yang; Li, Hongxing; Chang, Shuang; Shu, Dingming; Zhang, Huanmin; Chen, Feng; Xie, Qingmei

    2015-01-01

    The group of avian sarcoma and leukosis virus (ASLV) in chickens contains six highly related subgroups, A to E and J. Four genetic loci, tva, tvb, tvc and tvj, encode for corresponding receptors that determine the susceptibility to the ASLV subgroups. The prevalence of ASLV in hosts may have imposed strong selection pressure toward resistance to ASLV infection, and the resistant alleles in all four receptor genes have been identified. In this study, two new alleles of the tva receptor gene, tva(r5) and tva(r6), with similar intronic deletions were identified in Chinese commercial broilers. These natural mutations delete the deduced branch point signal within the first intron, disrupting mRNA splicing of the tva receptor gene and leading to the retention of intron 1 and introduction of premature TGA stop codons in both the longer and shorter tva isoforms. As a result, decreased susceptibility to subgroup A ASLV in vitro and in vivo was observed in the subsequent analysis. In addition, we identified two groups of heterozygous allele pairs which exhibited quantitative differences in host susceptibility to ASLV-A. This study demonstrated that defective splicing of the tva receptor gene can confer genetic resistance to ASLV subgroup A in the host. PMID:25873518

  15. Phenotype microarray analysis of Escherichia coli K-12 mutants with deletions of all two-component systems.

    Science.gov (United States)

    Zhou, Lu; Lei, Xiang-He; Bochner, Barry R; Wanner, Barry L

    2003-08-01

    Two-component systems are the most common mechanism of transmembrane signal transduction in bacteria. A typical system consists of a histidine kinase and a partner response regulator. The histidine kinase senses an environmental signal, which it transmits to its partner response regulator via a series of autophosphorylation, phosphotransfer, and dephosphorylation reactions. Much work has been done on particular systems, including several systems with regulatory roles in cellular physiology, communication, development, and, in the case of bacterial pathogens, the expression of genes important for virulence. We used two methods to investigate two-component regulatory systems in Escherichia coli K-12. First, we systematically constructed mutants with deletions of all two-component systems by using a now-standard technique of gene disruption (K. A. Datsenko and B. L. Wanner, Proc. Natl. Acad. Sci. USA 97:6640-6645, 2000). We then analyzed these deletion mutants with a new technology called Phenotype MicroArrays, which permits assays of nearly 2,000 growth phenotypes simultaneously. In this study we tested 100 mutants, including mutants with individual deletions of all two-component systems and several related genes, including creBC-regulated genes (cbrA and cbrBC), phoBR-regulated genes (phoA, phoH, phnCDEFGHIJKLMNOP, psiE, and ugpBAECQ), csgD, luxS, and rpoS. The results of this battery of nearly 200,000 tests provided a wealth of new information concerning many of these systems. Of 37 different two-component mutants, 22 showed altered phenotypes. Many phenotypes were expected, and several new phenotypes were also revealed. The results are discussed in terms of the biological roles and other information concerning these systems, including DNA microarray data for a large number of the same mutants. Other mutational effects are also discussed. PMID:12897016

  16. Conditional deletion of epithelial IKKβ impairs alveolar formation through apoptosis and decreased VEGF expression during early mouse lung morphogenesis

    Directory of Open Access Journals (Sweden)

    Li Changgong

    2011-10-01

    Full Text Available Abstract Background Alveolar septation marks the beginning of the transition from the saccular to alveolar stage of lung development. Inflammation can disrupt this process and permanently impair alveolar formation resulting in alveolar hypoplasia as seen in bronchopulmonary dysplasia in preterm newborns. NF-κB is a transcription factor central to multiple inflammatory and developmental pathways including dorsal-ventral patterning in fruit flies; limb, mammary and submandibular gland development in mice; and branching morphogenesis in chick lungs. We have previously shown that epithelial overexpression of NF-κB accelerates lung maturity using transgenic mice. The purpose of this study was to test our hypothesis that targeted deletion of NF-κB signaling in lung epithelium would impair alveolar formation. Methods We generated double transgenic mice with lung epithelium-specific deletion of IKKβ, a known activating kinase upstream of NF-κB, using a cre-loxP transgenic recombination strategy. Lungs of resulting progeny were analyzed at embryonic and early postnatal stages to determine specific effects on lung histology, and mRNA and protein expression of relevant lung morphoreulatory genes. Lastly, results measuring expression of the angiogenic factor, VEGF, were confirmed in vitro using a siRNA-knockdown strategy in cultured mouse lung epithelial cells. Results Our results showed that IKKβ deletion in the lung epithelium transiently decreased alveolar type I and type II cells and myofibroblasts and delayed alveolar formation. These effects were mediated through increased alveolar type II cell apoptosis and decreased epithelial VEGF expression. Conclusions These results suggest that epithelial NF-κB plays a critical role in early alveolar development possibly through regulation of VEGF.

  17. Double disruption of the proteinase genes, tppA and pepE, increases the production level of human lysozyme by Aspergillus oryzae.

    Science.gov (United States)

    Jin, Feng Jie; Watanabe, Taisuke; Juvvadi, Praveen Rao; Maruyama, Jun-ichi; Arioka, Manabu; Kitamoto, Katsuhiko

    2007-10-01

    In this study, we investigated the effects of proteinase gene disruption on heterologous protein production by Aspergillus oryzae. The human lysozyme (HLY) was selected for recombinant production as a model for the heterologous protein. A tandem HLY construct fused with alpha-amylase (AmyB) was expressed by A. oryzae in which the Kex2 cleavage site was inserted at the upstream of HLY. HLY was successfully processed from AmyB and produced in the medium. We performed a systematic disruption analysis of five proteinase genes (pepA, pepE, alpA, tppA, and palB) in the HLY-producing strain with the adeA selectable marker. Comparative analysis indicated that disruption of the tppA gene encoding a tripeptidyl peptidase resulted in the highest increase (36%) in the HLY production. We further deleted the tppA gene in the pepE or palB disruptant with another selectable marker, argB. Consequently, a double disruption of the tppA and pepE genes led to a 63% increase in the HLY production compared to the control strain. This is the first study to report that the double disruption of the tppA and pepE genes improved the production level of a heterologous protein by filamentous fungi. PMID:17622525

  18. Heavy Metals Acting as Endocrine Disrupters

    Directory of Open Access Journals (Sweden)

    Bogdan Georgescu

    2011-10-01

    Full Text Available Last years researches focused on several natural and synthetic compounds that may interfere with the major functionsof the endocrine system and were termed endocrine disrupters. Endocrine disrupters are defined as chemicalsubstances with either agonist or antagonist endocrine effects in human and animals. These effects may be achievedby interferences with the biosynthesis or activity of several endogenous hormones. Recently, it was demonstratedthat heavy metals such as cadmium (Cd, arsen (As, mercury (Hg, nickel (Ni, lead (Pb and zinc (Zn may exhibitendocrine-disrupting activity in animal experiments. Emerging evidence of the intimate mechanisms of action ofthese heavy metals is accumulating. It was revealed, for example, that the Zn atom from the Zn fingers of theestrogen receptor can be replaced by several heavy metal molecules such as copper, cobalt, Ni and Cd. By replacingthe Zn atom with Ni or copper, binding of the estrogen receptor to the DNA hormone responsive elements in the cellnucleus is prevented. In both males and females, low-level exposure to Cd interferes with the biological effects ofsteroid hormones in reproductive organs. Arsen has the property to bind to the glucocorticoid receptor thusdisturbing glucocorticoids biological effects. With regard to Hg, this may induce alterations in male and femalefertility, may affect the function of the hypothalamo-pituitary-thyroid axis or the hypothalamo-pituitary-adrenal axis,and disrupt biosynthesis of steroid hormones.

  19. Analysis of recent fuel-disruption experiments

    International Nuclear Information System (INIS)

    Recent USDOE-sponsored DEH, FGR, and TREAT F series fuel-disruption experiments are analyzed with existing analytical models. The experiments are interpreted and the results used to evaluate the models. Calculations are presented using the FRAS3 fission-gas-behavior code and the DiMelfi-Deitrich fuel-response model

  20. 75 FR 30306 - Responding To Disruptive Patients

    Science.gov (United States)

    2010-06-01

    ... recommendations is not disruptive under this section. Unfunded Mandates The Unfunded Mandates Reform Act requires... patient care area (e.g., private exam room near an exit); (3) Arranging for medical and any other services..., Health professions, Health records, Homeless, Medical and dental schools, Medical devices,...

  1. Towards a Framework of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    2014-01-01

    of governance regimes and platform layers is deterministic of whether disruptive derivatives are permitted to flourish. This framework has been employed in a comparative case study between centralized (i.e., PayPal) and decentralized (i.e., Coinkite) digital payment platforms to illustrate its...

  2. Maternal Characteristics Predicting Young Girls' Disruptive Behavior

    Science.gov (United States)

    van der Molen, Elsa; Hipwell, Alison E.; Vermeiren, Robert; Loeber, Rolf

    2011-01-01

    Little is known about the relative predictive utility of maternal characteristics and parenting skills on the development of girls' disruptive behavior. The current study used five waves of parent- and child-report data from the ongoing Pittsburgh Girls Study to examine these relationships in a sample of 1,942 girls from age 7 to 12 years.…

  3. JET disruption studies in support of ITER

    Czech Academy of Sciences Publication Activity Database

    Riccardo, V.; Arnoux, G.; Cahyna, Pavel; Hender, T.C.; Huber, A.; Jachmich, S.; Kiptily, V.; Koslowski, R.; Krlín, Ladislav; Lehnen, M.; Loarte, A.; Nardon, E.; Papřok, R.; Tskhakaya, D.

    2010-01-01

    Roč. 52, č. 12 (2010), s. 124018. ISSN 0741-3335. [European Physical Society Conference on Plasma Physics/37th/. Dublin, 21.06.2010-25.06.2010] Institutional research plan: CEZ:AV0Z20430508 Keywords : ITER * JET * disruption * runaway electrons Subject RIV: BL - Plasma and Gas Discharge Physics Impact factor: 2.466, year: 2010

  4. Traffic disruption route Einstein near building 170

    CERN Multimedia

    A Lopez - TS/CE

    2005-01-01

    The TS/CE Group informs you that, for the duration of the work at Building 170, there may be some disruption to traffic on route Einstein in the vicinity of Building 170. The work is due to take place from the 14th to 18th February. For more information, please contact 165029. A. Lopez TS/CE

  5. The Relative Ineffectiveness of Criminal Network Disruption

    Science.gov (United States)

    Duijn, Paul A. C.; Kashirin, Victor; Sloot, Peter M. A.

    2014-02-01

    Researchers, policymakers and law enforcement agencies across the globe struggle to find effective strategies to control criminal networks. The effectiveness of disruption strategies is known to depend on both network topology and network resilience. However, as these criminal networks operate in secrecy, data-driven knowledge concerning the effectiveness of different criminal network disruption strategies is very limited. By combining computational modeling and social network analysis with unique criminal network intelligence data from the Dutch Police, we discovered, in contrast to common belief, that criminal networks might even become `stronger', after targeted attacks. On the other hand increased efficiency within criminal networks decreases its internal security, thus offering opportunities for law enforcement agencies to target these networks more deliberately. Our results emphasize the importance of criminal network interventions at an early stage, before the network gets a chance to (re-)organize to maximum resilience. In the end disruption strategies force criminal networks to become more exposed, which causes successful network disruption to become a long-term effort.

  6. The Relative Ineffectiveness of Criminal Network Disruption

    NARCIS (Netherlands)

    P.A.C. Duijn; V. Kashirin; P.M.A. Sloot

    2014-01-01

    Researchers, policymakers and law enforcement agencies across the globe struggle to find effective strategies to control criminal networks. The effectiveness of disruption strategies is known to depend on both network topology and network resilience. However, as these criminal networks operate in se

  7. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten Visby; Nielsen, Helena Skyt;

    2015-01-01

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... achievement of peers by about 1.7–2.3% of a standard deviation....

  8. Empathy in Boys with Disruptive Behavior Disorders

    Science.gov (United States)

    de Wied, Minet; Goudena, Paul P.; Matthys, Walter

    2005-01-01

    Background: The present study examined empathy in 8- to 12-year-old clinically referred boys with disruptive behavior disorders (DBD) (n = 25) and age-matched normal controls (n = 24). Method: Situational empathy was assessed by children's emotional and cognitive responses to six empathy-inducing vignettes (displaying sadness, anger or happiness).…

  9. Pesticides Provoke Endocrine Disruption A Review

    International Nuclear Information System (INIS)

    Increasing numbers of environmental chemicals,including pesticides, have the ability to produce endocrine disruption by various mechanisms. such substances may affect hormone secretion from an endocrine gland and may alter the rate of hormone elimination from the body. environmental chemicals may also disrupt regulatory feedback mechanisms that exist between two endocrine organs; or may interact with a hormone receptor either by mimicking or antagonizing the actions of the natural hormone. these chemicals are referred to endocrine disruptive chemicals (EDC's). EDC's act to alter the blood hormone levels or the subsequent action of hormones . the use of radioimmunoassay(RIA) constitutes a superior and unrivalled tool for the determination and quantification of hormones.the endocrine system participates in virtually all important functions of an organism, such as sexual differentiation before birth, sexual maturation during puberty, reproduction in adulthood, growth, metabolism, digestion, cardiovascular function and excretion. hormones are also implicated in the etiology of certain cancers of hormone- dependent tissues, such as those of the breast, uterus, and prostate gland. therefore, endocrine disruption can potentially produce widespread effects. scientists should not stick to the past belief which presumes that pesticides have limited effect on some hormones. A paradigm shift in which a wider vision of understanding of the wholesome complex effects of pesticides on the whole body rather than a narrow limited understanding should take place

  10. Study of Endocrine Disrupting Chemicals in Environment

    Directory of Open Access Journals (Sweden)

    Zoltán Juvancz

    2008-06-01

    Full Text Available Endocrine disrupting chemicals (EDC cause more and more seriousenvironmental pollutions. The EDCs show only ng-μg/l concentration level in theenvironment, therefore their determinations require multistep sample preparationprocesses and highly sophisticated instrumentation. This paper discuss the EDC effects,and show examples for determination of such compounds.

  11. Is Online Learning a Disruptive Innovation?

    Science.gov (United States)

    Meyer, Katrina A.

    2011-01-01

    In their desire to plan for the future, planners must assess the role of both internal and external influences on the institution. What then should people make of the idea that technology is disruptive? This perception fuels the views of Barone and Hagner (2001), who claimed that technology would "transform" higher education; Duderstadt (2000),…

  12. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. Grøne; Krægpøth, Morten; Nielsen, Helena Skyt;

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We i...

  13. E-Learning: Between Augmentation and Disruption?

    Science.gov (United States)

    Heilesen, Simon B.; Josephsen, Jens

    2008-01-01

    Based on a framework for analysis combining diffusion theory, content layer analysis and sense making, this paper discusses the theme of "e-learning as augmentation or disruption" from the point of view of technological innovation. Two cases of on-campus blended learning at Roskilde University, Denmark, are introduced to illustrate the discussion.…

  14. The Structure of Childhood Disruptive Behaviors

    Science.gov (United States)

    Martel, Michelle M.; Gremillion, Monica; Roberts, Bethan; von Eye, Alexander; Nigg, Joel T.

    2010-01-01

    Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) frequently co-occur. Comorbidity of these 2 childhood disruptive behavior domains has not been satisfactorily explained at either a structural or etiological level. The current study evaluated a bifactor model, which allows for a "g" factor in addition to…

  15. Development of Disruptive Open Access Journals

    Science.gov (United States)

    Anderson, Terry; McConkey, Brigette

    2009-01-01

    Open access (OA) publication has emerged, with disruptive effects, as a major outlet for scholarly publication. OA publication is usually associated with on-line distribution and provides access to scholarly publications to anyone, anywhere--regardless of their ability to pay subscription fees or their association with an educational institution.…

  16. 75 FR 69881 - Responding to Disruptive Patients

    Science.gov (United States)

    2010-11-16

    ... that may: (1) Have an annual effect on the economy of $100 million or more or adversely affect in a material way the economy, a sector of the economy, productivity, competition, jobs, the environment, public... when a patient is disruptive and the procedures for implementing those measures. 75 FR 30,306....

  17. The Debris Streams from Tidal Disruption Events

    Science.gov (United States)

    Coughlin, Eric

    2016-01-01

    When a star comes within a critical distance of a supermassive black hole, the tidal force exerted by the hole overcomes the stellar self-gravity. The star is subsequently torn apart, creating a stream of tidally-shredded debris that initially recedes from the hole, eventually returns to pericenter, forms an accretion disk and generates a highly luminous event that can sometimes be accompanied by the production of relativistic jets. This entire process is known as a tidal disruption event (TDE), and dozens of these events have already been observed. I will discuss my most recent work that has analyzed the tidal disruption process, and in particular I will focus on the results of numerical and analytical investigations that show that the streams of debris produced during TDEs can be gravitationally unstable. Specifically, I will describe how compressive motions augment the importance of self-gravity not long after the star is disrupted, resulting in the fragmentation of the debris stream into small-scale clumps. These findings will be discussed in the context of the observational signatures of tidal disruption events, and I will also relate these results to my past investigations concerning accretion disk formation and jet launching during TDEs.

  18. Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer

    Science.gov (United States)

    Bikle, Daniel D.; Jiang, Yan; Nguyen, Thai; Oda, Yuko; Tu, Chia-ling

    2016-01-01

    1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis (epidVdr−∕− and epidCasr−∕−). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β–catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr−∕− mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the epidVdr−∕− or epidCasr−∕−. But in mice with epidermal specific deletion of both Vdr and Casr (epidVdr−∕−/epidCasr−∕− [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β–catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed. PMID:27462278

  19. Disruption of a cystine transporter downregulates expression of genes involved in sulfur regulation and cellular respiration.

    Science.gov (United States)

    Simpkins, Jessica A; Rickel, Kirby E; Madeo, Marianna; Ahlers, Bethany A; Carlisle, Gabriel B; Nelson, Heidi J; Cardillo, Andrew L; Weber, Emily A; Vitiello, Peter F; Pearce, David A; Vitiello, Seasson P

    2016-01-01

    Cystine and cysteine are important molecules for pathways such as redox signaling and regulation, and thus identifying cellular deficits upon deletion of the Saccharomyces cerevisiae cystine transporter Ers1p allows for a further understanding of cystine homeostasis. Previous complementation studies using the human ortholog suggest yeast Ers1p is a cystine transporter. Human CTNS encodes the protein Cystinosin, a cystine transporter that is embedded in the lysosomal membrane and facilitates the export of cystine from the lysosome. When CTNS is mutated, cystine transport is disrupted, leading to cystine accumulation, the diagnostic hallmark of the lysosomal storage disorder cystinosis. Here, we provide biochemical evidence for Ers1p-dependent cystine transport. However, the accumulation of intracellular cystine is not observed when the ERS1 gene is deleted from ers1-Δ yeast, supporting the existence of modifier genes that provide a mechanism in ers1-Δ yeast that prevents or corrects cystine accumulation. Upon comparison of the transcriptomes of isogenic ERS1+ and ers1-Δ strains of S. cerevisiae by DNA microarray followed by targeted qPCR, sixteen genes were identified as being differentially expressed between the two genotypes. Genes that encode proteins functioning in sulfur regulation, cellular respiration, and general transport were enriched in our screen, demonstrating pleiotropic effects of ers1-Δ. These results give insight into yeast cystine regulation and the multiple, seemingly distal, pathways that involve proper cystine recycling. PMID:27142334

  20. Characteristics of dr1790 disruptant and its functional analysis in Deinococcus radiodurans

    Directory of Open Access Journals (Sweden)

    Jianhui Cheng

    2015-06-01

    Full Text Available Deinococcus radiodurans (DR is an extremophile that is well known for its resistance to radiation, oxidants and desiccation. The gene dr1790 of D. radiodurans was predicted to encode a yellow-related protein. The primary objective of the present study was to characterize the biological function of the DR1790 protein, which is a member of the ancient yellow/major royal jelly (MRJ protein family, in prokaryotes. Fluorescence labeling demonstrated that the yellow-related protein encoded by dr1790 is a membrane protein. The deletion of the dr1790 gene decreased the cell growth rate and sensitivity to hydrogen peroxide and radiation and increased the membrane permeability of D. radiodurans. Transcript profiling by microarray and RT-PCR analyses of the dr1790 deletion mutant suggested that some genes that are involved in protein secretion and transport were strongly suppressed, while other genes that are involved in protein quality control, such as chaperones and proteases, were induced. In addition, the expression of genes with predicted functions that are involved in antioxidant systems, electron transport, and energy metabolism was significantly altered through the disruption of dr1790. Moreover, the results of proteomic analyses using 2-DE and MS also demonstrated that DR1790 contributed to D. radiodurans survival. Taken together, these results indicate that the DR1790 protein from the ancient yellow protein family plays a pleiotropic role in the survival of prokaryotic cells and contributes to the extraordinary resistance of D. radiodurans against oxidative and radiation stresses.

  1. Loss of Usp9x disrupts cortical architecture, hippocampal development and TGFβ-mediated axonogenesis.

    Directory of Open Access Journals (Sweden)

    Shane Stegeman

    Full Text Available The deubiquitylating enzyme Usp9x is highly expressed in the developing mouse brain, and increased Usp9x expression enhances the self-renewal of neural progenitors in vitro. USP9X is a candidate gene for human neurodevelopmental disorders, including lissencephaly, epilepsy and X-linked intellectual disability. To determine if Usp9x is critical to mammalian brain development we conditionally deleted the gene from neural progenitors, and their subsequent progeny. Mating Usp9x(loxP/loxP mice with mice expressing Cre recombinase from the Nestin promoter deleted Usp9x throughout the entire brain, and resulted in early postnatal lethality. Although the overall brain architecture was intact, loss of Usp9x disrupted the cellular organization of the ventricular and sub-ventricular zones, and cortical plate. Usp9x absence also led to dramatic reductions in axonal length, in vivo and in vitro, which could in part be explained by a failure in Tgf-β signaling. Deletion of Usp9x from the dorsal telencephalon only, by mating with Emx1-cre mice, was compatible with survival to adulthood but resulted in reduction or loss of the corpus callosum, a dramatic decrease in hippocampal size, and disorganization of the hippocampal CA3 region. This latter phenotypic aspect resembled that observed in Doublecortin knock-out mice, which is an Usp9x interacting protein. This study establishes that Usp9x is critical for several aspects of CNS development, and suggests that its regulation of Tgf-β signaling extends to neurons.

  2. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues.

    OpenAIRE

    Cortopassi, G A; Shibata, D.; Soong, N W; Arnheim, N

    1992-01-01

    An assay that selectively amplifies a specific deletion of the mitochondrial genome has been used to study the extent of the deletion's accumulation in a variety of human tissues. The deletion occurs at much higher levels in nervous and muscle tissues than in all other tissues studied. The variation in deletion level between the same tissues in different persons of similar age appears to be less than the variation among tissues within an individual. Tests for artifactual explanations of the l...

  3. Screening for clinically significant non-deletional alpha thalassaemia mutations by pyrosequencing

    OpenAIRE

    Haywood, Anna; Dreau, Helene; Timbs, Adele; Schuh, Anna; Old, John; Henderson, Shirley

    2010-01-01

    Abstract Non-deletional ?+-thalassaemia is associated with a higher degree of morbidity and mortality than deletional forms of ?+-thalassaemia. Screening for the common deletional forms of ?-thalassaemia by Gap-PCR is widely practiced; however, the detection of non-deletional ?-thalassaemia mutations is technically more labour-intensive and expensive, as it requires DNA sequencing. In addition, the presence of four very closely homologous alpha globin genes and the frequent co-exis...

  4. Disruptive behavior in school. Wired up - the relationship between disruptive behavior and new technology.

    OpenAIRE

    Solberg, Stine

    2014-01-01

    Background: The thesis is part of the research project Disruptive behavior in school, led by professor Liv Duesund at the Department of Special Needs Education, University of Oslo. Professor Duesund is the supervisor of the thesis. It is a cooperation project between University of Oslo and University of California, Berkeley and compares the educational cultures of Norway an the United States (Duesund, 2013). The focus is on disruptive behavior, and in what ways behavior can vary in the two ...

  5. Mitochondrial DNA deletion mutations in adult mouse cardiac side population cells

    Energy Technology Data Exchange (ETDEWEB)

    Lushaj, Entela B., E-mail: lushaj@surgery.wisc.edu [Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792 (United States); Lozonschi, Lucian; Barnes, Maria; Anstadt, Emily; Kohmoto, Takushi [Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792 (United States)

    2012-06-01

    We investigated the presence and potential role of mitochondrial DNA (mtDNA) deletion mutations in adult cardiac stem cells. Cardiac side population (SP) cells were isolated from 12-week-old mice. Standard polymerase chain reaction (PCR) was used to screen for the presence of mtDNA deletion mutations in (a) freshly isolated SP cells and (b) SP cells cultured to passage 10. When present, the abundance of mtDNA deletion mutation was analyzed in single cell colonies. The effect of different levels of deletion mutations on SP cell growth and differentiation was determined. MtDNA deletion mutations were found in both freshly isolated and cultured cells from 12-week-old mice. While there was no significant difference in the number of single cell colonies with mtDNA deletion mutations from any of the groups mentioned above, the abundance of mtDNA deletion mutations was significantly higher in the cultured cells, as determined by quantitative PCR. Within a single clonal cell population, the detectable mtDNA deletion mutations were the same in all cells and unique when compared to deletions of other colonies. We also found that cells harboring high levels of mtDNA deletion mutations (i.e. where deleted mtDNA comprised more than 60% of total mtDNA) had slower proliferation rates and decreased differentiation capacities. Screening cultured adult stem cells for mtDNA deletion mutations as a routine assessment will benefit the biomedical application of adult stem cells.

  6. Common Deletion (CD) in mitochondrial DNA of irradiated rat heart

    International Nuclear Information System (INIS)

    The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3rd until the 15th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels. (author)

  7. Common Deletion (CD) in mitochondrial DNA of irradiated rat heart

    Energy Technology Data Exchange (ETDEWEB)

    Siqueira, Raquel Gomes; Ferreira-Machado, Samara C.; Almeida, Carlos E.V. de, E-mail: raquelgsiqueira@gmail.com [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Ciencias Radiologicas; Silva, Dayse A. da; Carvalho, Elizeu F. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Diagnosticos por DNA; Melo, Luiz D.B. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biofisica Carlos Chagas Filho. Lab. de Parasitologia Molecular

    2014-05-15

    The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3rd until the 15th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels. (author)

  8. Growing networks with preferential addition and deletion of edges

    CERN Document Server

    Deijfen, Maria

    2015-01-01

    A preferential attachment model for a growing network incorporating deletion of edges is studied and the expected asymptotic degree distribution is analyzed. At each time step $t=1,2,\\ldots$, with probability $\\pi_1>0$ a new vertex with one edge attached to it is added to the network and the edge is connected to an existing vertex chosen proportionally to its degree, with probability $\\pi_2$ a vertex is chosen proportionally to its degree and an edge is added between this vertex and a randomly chosen other vertex, and with probability $\\pi_3=1-\\pi_1-\\pi_21/3$, the fraction $p_k$ decays exponentially at rate $(\\pi_1+\\pi_2)/2\\pi_3$. There is hence a non-trivial upper bound for how much deletion the network can incorporate without loosing the power-law behavior of the degree distribution. The analytical results are supported by simulations.

  9. Longitudinal association between marital disruption and child BMI and obesity.

    Science.gov (United States)

    Arkes, Jeremy

    2012-08-01

    This research examines whether family disruptions (i.e., divorces and separation) contribute to children's weight problems. The sample consists of 7,299 observations for 2,333 children, aged 5-14, over the 1986-2006 period, from a US representative sample from the Child and Young Adult Survey accompanying the National Longitudinal Survey of Youth (NLSY). The study uses individual-fixed-effects models in a longitudinal framework to compare children's BMI and weight problems before and after a disruption. Furthermore, besides doing a before-after comparison for children, the study also estimates the effects at various periods relative to the disruption in order to examine whether children are affected before the disruption and whether any effects change as time passes from the disruption, as some effects may be temporary or slow to develop. Despite having a larger sample than the previous studies, the results provide no evidence that, on average, children's BMI and BMI percentile scores (measured with continuous outcomes) are affected before the disruption, after the disruption, and as time passes from the disruption, relative to a baseline period a few years before the disruption. However, children experiencing a family disruption do have an increased risk of obesity (having a BMI percentile score of 95 or higher) in the two years leading up to the disruption as well as after the disruption, and as time passes from the disruption. PMID:22484366

  10. Anthropogenic tracers, endocrine disrupting chemicals, and endocrine disruption in Minnesota lakes

    Science.gov (United States)

    Writer, J.H.; Barber, L.B.; Brown, G.K.; Taylor, H.E.; Kiesling, R.L.; Ferrey, M.L.; Jahns, N.D.; Bartell, S.E.; Schoenfuss, H.L.

    2010-01-01

    Concentrations of endocrine disrupting chemicals and endocrine disruption in fish were determined in 11 lakes across Minnesota that represent a range of trophic conditions and land uses (urban, agricultural, residential, and forested) and in which wastewater treatment plant discharges were absent. Water, sediment, and passive polar organic integrative samplers (POCIS) were analyzed for steroidal hormones, alkylphenols, bisphenol A, and other organic and inorganic molecular tracers to evaluate potential non-point source inputs into the lakes. Resident fish from the lakes were collected, and caged male fathead minnows were deployed to evaluate endocrine disruption, as indicated by the biological endpoints of plasma vitellogenin and gonadal histology. Endocrine disrupting chemicals, including bisphenol A, 17??-estradiol, estrone, and 4-nonylphenol were detected in 90% of the lakes at part per trillion concentrations. Endocrine disruption was observed in caged fathead minnows and resident fish in 90% of the lakes. The widespread but variable occurrence of anthropogenic chemicals in the lakes and endocrine disruption in fish indicates that potential sources are diverse, not limited to wastewater treatment plant discharges, and not entirely predictable based on trophic status and land use. ?? 2010.

  11. Delete-free Reachability Analysis for Temporal and Hierarchical Planning

    OpenAIRE

    Bit-Monnot, Arthur; Smith, David E.; Do, Minh

    2016-01-01

    Reachability analysis is a crucial part of the heuristic computation for many state of the art classical and temporal planners. In this paper, we study the difficulty that arises in assessing the reachability of actions in planning problems containing sets of interdependent actions, notably including problems with required concurrency as well as hierarchical planning problems. In temporal planners, this complication has been addressed by augmenting a delete-free relaxation with additional rel...

  12. Optimizing Gateway™ technology (Invitrogen) to construct Rhizobium leguminosarum deletion mutants

    OpenAIRE

    Lanza Lucio, Monica; Alborno, Marcelo; Rey Navarro, Luis; Imperial Ródenas, Juan

    2010-01-01

    The study of the role of different genes in Rhizobium leguminosarum requires the generation of mutants by homologous recombination. In this communication we describe a novel approach to obtain deletion mutants of genes in Rhizobium using Gateway TM Cloning technology (Invitrogen) and a new vector (pK18-attR), both conjugative and Rhizobium specific, that carries the recombination tails of Gateway system. This tool is a new alternative to the classic approach based on cloning using rest...

  13. 78 FR 71582 - Procurement List; Proposed Additions and Deletions

    Science.gov (United States)

    2013-11-29

    ...-583-9479--SS NSN: 8415-01-583-9480--SR NSN: 8415-01-583-9483--SL NSN: 8415-01-583-9485--MS NSN: 8415...: 8415-01-584-1640--SS NSN: 8415-01-584-1641--SR NSN: 8415-01-584-1642--SL NSN: 8415-01-584-1643--MS NSN... for deletion from the Procurement List: Products Stamp Pad Ink NSN: 7510-01-316-7516--Refill...

  14. Schizophrenia in an Adult With 6p25 Deletion Syndrome

    OpenAIRE

    Caluseriu, O; Mirza, G.; J. Ragoussis; Chow, E. W. C.; MacCrimmon, D.; Bassett, A S

    2006-01-01

    Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld–Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. Th...

  15. Multidrug Resistance of a Porin Deletion Mutant of Mycobacterium smegmatis

    OpenAIRE

    Stephan, Joachim; Mailaender, Claudia; Etienne, Gilles; Daffé, Mamadou; Niederweis, Michael

    2004-01-01

    Mycobacteria contain an outer membrane of unusually low permeability which contributes to their intrinsic resistance to many agents. It is assumed that small and hydrophilic antibiotics cross the outer membrane via porins, whereas hydrophobic antibiotics may diffuse through the membrane directly. A mutant of Mycobacterium smegmatis lacking the major porin MspA was used to examine the role of the porin pathway in antibiotic sensitivity. Deletion of the mspA gene caused high-level resistance of...

  16. Scenario-Based Stochastic Programs: Strategies for Deleting Scenarios

    OpenAIRE

    Dupacova, J.

    1995-01-01

    The proposed strategies for deleting scenarios are based on postoptimality analysis of the optimal value function with respect to probabilities of the included scenarios. These strategies can be used to reduce the size of the large scenario based problems or of the problems constructed in the course of specific numerical procedures, such as stochastic decomposition or scenario aggregation. A convex nonsmooth optimization problem is replaced by a sequence of line search problems along rec...

  17. Molecular basis of human growth hormone gene deletions

    International Nuclear Information System (INIS)

    Crossover sites resulting from unequal recombination within the human growth hormone (GH) gene cluster that cause GH1 gene deletions and isolated GH deficiency type 1A were localized in nine patients. In eight unrelated subjects homozygous for 6.7-kilobase (kb) deletions, the breakpoints are within two blocks of highly homologous DNA sequences that lie 5' and 3' to the GH1 gene. In seven of these eight cases, the breakpoints map within a 1,250-base-pair (bp) region composed of 300-bp Alu sequences of 86% homology and flanking non-Alu sequences that are 600 and 300 bp in length and are of 96% and 88% homology, respectively. In the eighth patient, the breakpoints are 5' to these Alu repeats and are most likely within a 700-bp-region of 96% homologous DNA sequences. In the ninth patient homozygous for a 7.6-kb deletion, the breakpoints are contained with a 29-bp perfect repeat lying 5' to GH1 and the human chorionic somatomammotropin pseudogene (CSHP1). Together, these results indicate that the presence of highly homologous DNA sequences flanking GH1 predispose to recurrent unequal recombinational events presumably through chromosomal misalignment

  18. Science and policy on endocrine disrupters must not be mixed

    DEFF Research Database (Denmark)

    Bergman, Åke; Andersson, Anna-Maria; Becher, Georg;

    2013-01-01

    The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a r...

  19. Endocrine disrupters. The case of estrogen xenobiotics

    Directory of Open Access Journals (Sweden)

    N. Olea Serrano

    2001-06-01

    Full Text Available Interest of the scientific community in chemical substances able to alter the hormone balance –endocrine disrupters- has grown with increasing evidence of the consequences for animal populations of exposure to these substances. As has occurred on previous occasions, observational data on animal populations have been sufficiently suggestive to cause concerns among clinicians that similar effects may be produced in human populations. Although data on the effects on populations of animals are more easily generated than those on individuals, clinical observations on human individuals alongside the few existing epidemiological studies have shown a certain parallelism. Indeed, in vitro and in vivo models have been able to designate many chemical compounds as hormonal mimics, including both natural and human-produced compounds to which there are exposure risks. The present work reviews the conceptual premises of endocrine disruption and the development of the use of this term.

  20. Disruption problematics in segmented-blanket concepts

    International Nuclear Information System (INIS)

    In tokamaks, the hostile operating environment originated by plasma disruption events requires that the first-wall/blanket/shield components sustain the large induced electromagnetic (EM) forces without significant structural deformation and within allowable material stresses. As a consequence, there is a need to improve the safety features of the segmented-blanket design concepts in order to satisfy the disruption problematics.The present paper describes recent investigations on internal blanket reinforcement systems needed in order to improve the first-wall/blanket/shield structural design for next-step and commercial fusion reactors. Particularly in the context of SEAFP and ITER activities, representative 3-D CAD models of the inboard and outboard blanket regions and the related magnetomechanical simulations are illustrated. (orig.)

  1. Disruption of cytoplasmic microtubules by ultraviolet radiation

    International Nuclear Information System (INIS)

    Ultraviolet (UV) irradiation of cultured human skin fibroblasts causes the disassembly of their microtubules. Using indirect immunofluorescence microscopy, we have now investigated whether damage to the microtubule precursor pool may contribute to the disruption of microtubules. Exposure to polychromatic UV radiation inhibits the reassembly of microtubules during cellular recovery from cold treatment. In addition, the ability of taxol to promote microtubule polymerization and bundling is inhibited in UV-irradiated cells. However, UV irradiation of taxol-pretreated cells or in situ detergent-extracted microtubules fails to disrupt the microtubule network. These data suggest that damage to dimeric tubulin, or another soluble factor(s) required for polymerization, contributes to the disassembly of microtubules in UV-irradiated human skin fibroblasts

  2. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Jespersen-Groth, Julie; Potthoff, Daniel; Clausen, Jens;

    the three main subproblems in railway disruption management: timetable adjustment, and rolling stock and crew re-scheduling. Next to a general description of these problems, we give an overview of the existing literature and we present some details of the specific situations at DSB S-tog and NS. These...... are the railway operators in the suburban area of Copenhagen, Denmark, and on the main railway lines in the Netherlands, respectively. Since not much research has been carried out yet on Operations Research models for disruption management in the railway context, models and techniques that have been...... developed for related problems in the airline world are discussed as well. Finally, we address the integration of the re-scheduling processes of the timetable, and the resources rolling stock and crew....

  3. The hexagon hypothesis: Six disruptive scenarios.

    Science.gov (United States)

    Burtles, Jim

    2015-01-01

    This paper aims to bring a simple but effective and comprehensive approach to the development, delivery and monitoring of business continuity solutions. To ensure that the arguments and principles apply across the board, the paper sticks to basic underlying concepts rather than sophisticated interpretations. First, the paper explores what exactly people are defending themselves against. Secondly, the paper looks at how defences should be set up. Disruptive events tend to unfold in phases, each of which invites a particular style of protection, ranging from risk management through to business continuity to insurance cover. Their impact upon any business operation will fall into one of six basic scenarios. The hexagon hypothesis suggests that everyone should be prepared to deal with each of these six disruptive scenarios and it provides them with a useful benchmark for business continuity. PMID:26420396

  4. Molecular Characterization of Heterologous HIV-1gp120 Gene Expression Disruption in Mycobacterium bovis BCG Host Strain: A Critical Issue for Engineering Mycobacterial Based-Vaccine Vectors

    Directory of Open Access Journals (Sweden)

    Joan Joseph

    2010-01-01

    Full Text Available Mycobacterium bovis Bacillus Calmette-Guérin (BCG as a live vector of recombinant bacterial vaccine is a promising system to be used. In this study, we evaluate the disrupted expression of heterologous HIV-1gp120 gene in BCG Pasteur host strain using replicative vectors pMV261 and pJH222. pJH222 carries a lysine complementing gene in BCG lysine auxotrophs. The HIV-1 gp120 gene expression was regulated by BCG hsp60 promoter (in plasmid pMV261 and Mycobacteria spp. α-antigen promoter (in plasmid pJH222. Among 14 rBCG:HIV-1gp120 (pMV261 colonies screened, 12 showed a partial deletion and two showed a complete deletion. However, deletion was not observed in all 10 rBCG:HIV-1gp120 (pJH222 colonies screened. In this study, we demonstrated that E. coli/Mycobacterial expression vectors bearing a weak promoter and lysine complementing gene in a recombinant lysine auxotroph of BCG could prevent genetic rearrangements and disruption of HIV 1gp120 gene expression, a key issue for engineering Mycobacterial based vaccine vectors.

  5. Disruption strategies for online child pornography networks

    OpenAIRE

    Joffres, Kilauea

    2012-01-01

    The advent of the Internet has allowed for the creation of online child pornography networks, in which websites link to one another and facilitate access to child pornographic materials. This project seeks to use social network analysis tools to identify effective disruption strategies against online child pornography networks. For this purpose, four networks of child exploitation material were extracted using a specially designed web-crawler. These networks were then submitted to three diffe...

  6. Disruption of vitamin A metabolism by dioxin

    OpenAIRE

    Högberg, Pi

    2003-01-01

    Vitamin A (retinoids) is a nutrient that plays a central role in development and remains essential for cell growth and differentiation throughout life. Dioxins are polychlorinated organic pollutants known to negatively affect the storage and body clearance of retinoids. This work aimed at studying mechanisms and consequences of dioxin-induced retinoid disruption in vivo. As model compound we used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and as model species adult male S...

  7. A model of major disruption in tokamaks

    International Nuclear Information System (INIS)

    A mechanism for the onset of the major disruption is proposed which considers the effect of magnetic stochasticity on the growth of the m=2 tearing mode. The toroidicity can cause stochasticity near the separatrix of the m=2 magnetic island which enhances the current viscosity, resulting in explosive growth. The threshold condition and the time scale of rapid growth are studied. The role of the toroidal coupling to the m=1 component is also discussed. (author)

  8. Mechanical properties and disruption of dental biofilms

    OpenAIRE

    Rmaile, Amir

    2013-01-01

    A literature review of dental plaque biofilms formation, progression and detachment mechanisms is presented in this thesis. Various strategies that have been employed to reduce or eliminate dental biofilms are discussed. The focus of the thesis was on the mechanical properties and disruption of dental biofilms, especially from hard-to-access areas of the oral cavity, such as the interproximal (IP) sites between the teeth. Various methods to measure mechanical properties of dental biofilms wer...

  9. Pathological tau disrupts ongoing network activity

    OpenAIRE

    Menkes-Caspi, Noa; Yamin, Hagar G; Kellner, Vered; Spires-Jones, Tara L; Cohen, Dana; Stern, Edward A.

    2015-01-01

    Pathological tau leads to dementia and neurodegeneration in tauopathies, including Alzheimer's disease. It has been shown to disrupt cellular and synaptic functions, yet its effects on the function of the intact neocortical network remain unknown. Using in vivo intracellular and extracellular recordings, we measured ongoing activity of neocortical pyramidal cells during various arousal states in the rTg4510 mouse model of tauopathy, prior to significant cell death, when only a fraction of the...

  10. Will disruptive innovations cure health care?

    Science.gov (United States)

    Christensen, C M; Bohmer, R; Kenagy, J

    2000-01-01

    It's no secret that health care delivery is convoluted, expensive, and often deeply dissatisfying to consumers. But what is less obvious is that a way out of this crisis exists. Simpler alternatives to expensive care are already here--everything from $5 eyeglasses that people can use to correct their own vision to angioplasty instead of open-heart surgery. Just as the PC replaced the mainframe and the telephone replaced the telegraph operator, disruptive innovations are changing the landscape of health care. Nurse practitioners, general practitioners, and even patients can do things in less-expensive, decentralized settings that could once be performed only by expensive specialists in centralized, inconvenient locations. But established institutions--teaching hospitals, medical schools, insurance companies, and managed care facilities--are fighting these innovations tooth and nail. Instead of embracing change, they're turning the thumbscrews on their old processes--laying off workers, delaying payments, merging, and adding layers of overhead workers. Not only is this at the root of consumer dissatisfaction with the present system, it sows the seeds of its own destruction. The history of disruptive innovations tells us that incumbent institutions will be replaced with ones whose business models are appropriate to the new technologies and markets. Instead of working to preserve the existing systems, regulators, physicians, and pharmaceutical companies need to ask how they can enable more disruptive innovations to emerge. If the natural process of disruption is allowed to proceed, the result will be higher quality, lower cost, more convenient health care for everyone. PMID:11143147

  11. The Impact of Disruptive Innovations in Orthopaedics

    OpenAIRE

    Hansen, Erik; Bozic, Kevin J.

    2009-01-01

    The US healthcare system is currently facing daunting demographic and economic challenges. Because musculoskeletal disorders and disease represent a substantial and growing portion of this healthcare burden, novel approaches will be needed to continue to provide high-quality, affordable, and accessible orthopaedic care to our population. The concept of “disruptive innovations,” which has been studied and popularized by Harvard Business School Professor Clayton Christensen, may offer a potenti...

  12. Cloning and disruption of Ustilago maydis genes.

    OpenAIRE

    Fotheringham, S.; Holloman, W K

    1989-01-01

    We have demonstrated that genes from Ustilago maydis can be cloned by direct complementation of mutants through the use of genomic libraries made in a high-frequency transformation vector. We isolated a gene involved in amino acid biosynthesis as an illustrative example and showed that integrative and one-step disruption methods can be used to create null mutations in the chromosomal copy of the gene by homologous recombination. The results of this investigation make it clear that one-step ge...

  13. Action-Specific Disruption of Perceptual Confidence

    OpenAIRE

    Stephen M. Fleming; Maniscalco, Brian; Ko, Yoshiaki; Amendi, Namema; Ro, Tony; Lau, Hakwan

    2015-01-01

    Theoretical models of perception assume that confidence is related to the quality or strength of sensory processing. Counter to this intuitive view, we showed in the present research that the motor system also contributes to judgments of perceptual confidence. In two experiments, we used transcranial magnetic stimulation (TMS) to manipulate response-specific representations in the premotor cortex, selectively disrupting postresponse confidence in visual discrimination judgments. Specifically,...

  14. Disrupted neural synchronization in toddlers with autism

    OpenAIRE

    Dinstein, Ilan; Pierce, Karen; Eyler, Lisa; Solso, Stephanie; Malach, Rafael; Behrmann, Marlene; Courchesne, Eric

    2011-01-01

    Autism is often described as a disorder of neural synchronization. However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms. Here, we show that disrupted synchronization is evident in the spontaneous cortical activity of naturally sleeping toddlers with autism, but not in toddlers with language delay or typical development. Toddlers with autism exhibited significantly weaker inter...

  15. Five disruptive technology directions for 5G

    DEFF Research Database (Denmark)

    Boccardi, Federico; W. Heath Jr., Robert; Lozano, Angel;

    2014-01-01

    New research directions will lead to fundamental changes in the design of future fifth generation (5G) cellular networks. This article describes five technologies that could lead to both architectural and component disruptive design changes: device-centric architectures, millimeter wave, massive...... MIMO, smarter devices, and native support for machine-to-machine communications. The key ideas for each technology are described, along with their potential impact on 5G and the research challenges that remain....

  16. Language adapts to signal disruption in interaction

    OpenAIRE

    Macuch Silva, V.; Roberts, S

    2016-01-01

    Linguistic traits are often seen as reflecting cognitive biases and constraints (e.g. Christiansen & Chater, 2008). However, language must also adapt to properties of the channel through which communication between individuals occurs. Perhaps the most basic aspect of any communication channel is noise. Communicative signals can be blocked, degraded or distorted by other sources in the environment. This poses a fundamental problem for communication. On average, channel disruption accompanies p...

  17. Robust scheduling and disruption recovery for airlines

    OpenAIRE

    Eggenberg, Niklaus; Salani, Matteo

    2009-01-01

    Airline planning include complex and structured operations that must be planned in advance in order to exploit the available resources, provide a reliable and competitive service and forecast system's performances. Decisions regarding operations are based on data which is frequently due to uncertainty. Moreover, unpredicted events may disrupt the current schedule and force managers to take reactive decisions to recover to an operational state. On the other hand, proactive decisions, i.e. deci...

  18. Disruptive Discourses: Kenyan Maasai Schoolgirls Make Themselves

    OpenAIRE

    Switzer, Heather

    2009-01-01

    This abridged discussion of Maasai schoolgirls and disruptive discourses comes from my dissertation (in progress), Making the Maasai Schoolgirl: Developing Modernities on the Margins, an ethnographic case study of development at the local level that examines an emergent social category in contemporary Kenyan Maasai society: the “schoolgirl.” It is only recently, in the past generation, that Maasai females have attended school in any number, and access remains relatively limited. The dissertat...

  19. Influence of Dynamic Capabilities in Creating Disruptive Innovation

    OpenAIRE

    Čiutienė, R; Thattakath, E

    2014-01-01

    The aim of this paper is to demonstrate the influence of Dynamic Capabilities in creating Disruptive Innovation. For doing so the concepts of Dynamic Capabilities and Disruptive Innovation are reviewed. The criteria of an innovation named Disruptive Innovation are obtained by comparative study between the various innovation types. To demonstrate the role of Dynamic Capabilities in creating Disruptive Innovation, the Innovation Lifecycle is demonstrated with respect to Dynamic Capabilities. Th...

  20. Fortum, how an incumbent should deal with a disruptive innovation

    OpenAIRE

    Noteboom, Arno

    2014-01-01

    Solar PV as a disruptive innovation is changing the established energy industry. It forces energy incumbents to compete on a new market, and on new features. This research sets out to investigate how Fortum should be dealing with this disruptive innovation. This study is conducted in two parts, first it is analysed what the effects are of solar PV being labelled disruptive. This determines whether Fortum should at all be participating in this new disruptive market. The second part analyse...

  1. Influence of Dynamic Capabilities in Creating Disruptive Innovation

    OpenAIRE

    Čiutienė, R; Thattakath, E

    2015-01-01

    The aim of this paper is to demonstrate the influence of Dynamic Capabilities in creating Disruptive Innovation. For doing so the concepts of Dynamic Capabilities and Disruptive Innovation are reviewed. The criteria of an innovation named Disruptive Innovation are obtained by comparative study between the various innovation types. To demonstrate the role of Dynamic Capabilities in creating Disruptive Innovation, the Innovation Lifecycle is demonstrated with respect to Dynamic Capabilities. Th...

  2. Fungal tools for the degradation of endocrine disrupting compounds

    OpenAIRE

    Kabiersch, Grit

    2013-01-01

    Endocrine disrupting compounds are synthetic or natural compounds that mimic the action of hormones and thus disrupt or alter functions of the endocrine system usually through direct interactions with nuclear receptors. The main objective of this work was to develop strategies of how to degrade endocrine disrupting compounds and how to monitor the removal of the endocrine disrupting effect with focus on the estrogenic compound bisphenol A and on the virilizing compound tributyltin. Bisph...

  3. Risk Evaluation of Endocrine-Disrupting Chemicals

    Science.gov (United States)

    Gioiosa, Laura; Palanza, Paola; vom Saal, Frederick S.

    2015-01-01

    We review here our studies on early exposure to low doses of the estrogenic endocrine-disrupting chemical bisphenol A (BPA) on behavior and metabolism in CD-1 mice. Mice were exposed in utero from gestation day (GD) 11 to delivery (prenatal exposure) or via maternal milk from birth to postnatal day 7 (postnatal exposure) to 10 µg/kg body weight/d of BPA or no BPA (controls). Bisphenol A exposure resulted in long-term disruption of sexually dimorphic behaviors. Females exposed to BPA pre- and postnatally showed increased anxiety and behavioral profiles similar to control males. We also evaluated metabolic effects in prenatally exposed adult male offspring of dams fed (from GD 9 to 18) with BPA at doses ranging from 5 to 50 000 µg/kg/d. The males showed an age-related significant change in a number of metabolic indexes ranging from food intake to glucose regulation at BPA doses below the no observed adverse effect level (5000 µg/kg/d). Consistent with prior findings, low but not high BPA doses produced significant effects for many outcomes. These findings provide further evidence of the potential risks that developmental exposure to low doses of the endocrine disrupter BPA may pose to human health, with fetuses and infants being highly vulnerable. PMID:26740806

  4. Disruptive Innovation Can Prevent the Next Pandemic.

    Science.gov (United States)

    Shaikh, Affan T; Ferland, Lisa; Hood-Cree, Robert; Shaffer, Loren; McNabb, Scott J N

    2015-01-01

    Public health surveillance (PHS) is at a tipping point, where the application of novel processes, technologies, and tools promise to vastly improve efficiency and effectiveness. Yet twentieth century, entrenched ideology and lack of training results in slow uptake and resistance to change. The term disruptive innovation - used to describe advances in technology and processes that change existing markets - is useful to describe the transformation of PHS. Past disruptive innovations used in PHS, such as distance learning, the smart phone, and field-based laboratory testing have outpaced older services, practices, and technologies used in the traditional classroom, governmental offices, and personal communication, respectively. Arguably, the greatest of these is the Internet - an infrastructural innovation that continues to enable exponential benefits in seemingly limitless ways. Considering the Global Health Security Agenda and facing emerging and reemerging infectious disease threats, evolving environmental and behavioral risks, and ever changing epidemiologic trends, PHS must transform. Embracing disruptive innovation in the structures and processes of PHS can be unpredictable. However, it is necessary to strengthen and unlock the potential to prevent, detect, and respond. PMID:26442242

  5. Extensor Mechanism Disruption in Knee Dislocation.

    Science.gov (United States)

    O'Malley, Michael; Reardon, Patrick; Pareek, Ayoosh; Krych, Aaron; Levy, Bruce A; Stuart, Michael J

    2016-05-01

    Disruption of the knee extensor mechanism is a challenging injury with no clear consensus on optimal treatment. Although rare in the setting of knee dislocations, these injuries should not be overlooked. Acute, complete rupture of either the quadriceps or patellar tendon necessitates primary repair with or without augmentation. Surgical management may also be required in the setting of a partial tear if a significant extensor lag is present or nonoperative treatment has failed. Tendon augmentation is used during primary repair if the native tissue is inadequate or after a failed primary repair. The purpose of this study is to evaluate extensor mechanism disruption incidence, injury patterns, associated injuries, and surgical options, including a novel tendon augmentation technique. This procedure consists of primary patellar or quadriceps tendon repair with semitendinosus autograft augmentation utilizing a distal or proximal patellar socket. Advantages of repair with tendon augmentation include accelerated rehabilitation, decreased risk of patellar fracture from transverse or longitudinal bone tunnels, and less hardware complications. We recommend consideration of this technique for selected cases of acute extensor mechanism disruption in the setting of tibiofemoral dislocation. PMID:26636488

  6. Novel features of 3q29 deletion syndrome: Results from the 3q29 registry

    OpenAIRE

    Glassford, Megan R.; Jill A. Rosenfeld; Freedman, Alexa A.; Michael E Zwick; ,; Mulle, Jennifer G.

    2016-01-01

    3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 Mb deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet‐based survey instruments. We report here on data collected during...

  7. In vitro deletions in the partition locus of plasmid pSC101.

    OpenAIRE

    Kalla, S R; Gustafsson, P

    1984-01-01

    Deletion mutants in the 375-base-pair EcoRI-AvaI fragment carrying the partition locus of plasmid pSC101 were formed by the combined action of exonuclease III and nuclease S1. Six deletion mutants were isolated, and the endpoints of the deletions were sequenced. One of the deletions extended 69 base pairs from the EcoRI site without impairing plasmid stability. The other five deletions caused the plasmid to be unstable and extended 199 to 251 base pairs from the EcoRI site.

  8. The Impact of Marital Conflict and Disruption on Children's Health

    Science.gov (United States)

    Houseknecht, Sharon K.; Hango, Darcy W.

    2006-01-01

    This article investigates the effect of inconsistency between parental marital conflict and disruption on children's health. Inconsistent situations arise when minimal marital conflict precedes disruption or when marital conflict is high but there is no disruption. Using data from the National Longitudinal Survey of Youth, two alternative…

  9. Disruptive Behaviour of Students in Primary Education and Emotional Intelligence

    Science.gov (United States)

    Esturgo-Deu, M. Estrella; Sala-Roca, Josefina

    2010-01-01

    This study analyses the relation between disruptive behaviours and the emotional abilities of children in primary education. To do this, disruptive behaviour and emotional abilities were evaluated in 1422 pupils aged between 6 and 12 years of age at 11 education centres using EQIjv. No relation was found between disruptive behaviours and age, but…

  10. Phenotypic reversion of an IS1-mediated deletion mutation: a combined role for point mutations and deletions in transposon evolution.

    Science.gov (United States)

    Lida, S; Marcoli, R; Bickle, T A

    1982-01-01

    We have physically characterised a deletion mutant of the R plasmid R100 which has lost all of the antibiotic resistances, including chloramphenicol resistance (Cmr), coded by its IS1-flanked r-determinant. The deletion was mediated by one of the flanking IS1 elements and terminates within the carboxyl terminus of the Cmr gene. DNA sequence analysis showed that the mutated gene would produce a protein 20 amino acids longer than the wild-type due to fusion with an open reading frame in the IS element. Surprisingly for a deletion mutation, rare, spontaneous Cmr revertants could be recovered. Two of the four revertants studied had frame shifts due to the insertion of a single AT base pair at the same position; the revertants would code for a protein five amino acids shorter than the wild-type. The other two revertants had acquired duplications of the 34-bp inverted terminal repeat sequences of the IS1 element and would direct the synthesis of a protein six amino acids longer than the wild-type. The reverted Cmr markers were still capable of transposition. These observations suggest a role for point mutations and small DNA rearrangements in the formation of new gene organisations produced by mobile genetic elements. PMID:6329702

  11. Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin

    Energy Technology Data Exchange (ETDEWEB)

    Thanh, L.T.; Man, Nguyen Thi; Morris, G.E. [Wales Institute, Clwyd (United Kingdom)] [and others

    1995-08-28

    We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.

  12. DNA-based detection of chromosome deletion and amplification: diagnostic and mechanistic significance

    International Nuclear Information System (INIS)

    This paper describes a few of the many possible examples in which application of a molecular cytogenetic approach can ultimately lead to a new, important understanding about the statics and dynamics of human chromosome structure. In the case of retinoblastoma, cytological observations of deletions and linkage analysis have positioned the retinoblastoma locus to bank 13q14. This locus is grossly deleted in some spontaneous tumors. It is still necessary to locate more precisely and characterize the nature of the retinoblastoma locus, as well as the basis for the heterogeneity in deletions removing one copy of this locus. One is left with the possibility that those deletions that may be observed cytologically reflect but the tip of the iceberg of deletions; detection of others may require molecular probes. A related question is the nature of the DNA sequences at the deletion boundaries and the role they play in promoting these deletions

  13. Lysis delay and burst shrinkage of coliphage T7 by deletion of terminator Tφ reversed by deletion of early genes.

    Science.gov (United States)

    Nguyen, Huong Minh; Kang, Changwon

    2014-02-01

    Bacteriophage T7 terminator Tϕ is a class I intrinsic terminator coding for an RNA hairpin structure immediately followed by oligo(U), which has been extensively studied in terms of its transcription termination mechanism, but little is known about its physiological or regulatory functions. In this study, using a T7 mutant phage, where a 31-bp segment of Tϕ was deleted from the genome, we discovered that deletion of Tϕ from T7 reduces the phage burst size but delays lysis timing, both of which are disadvantageous for the phage. The burst downsizing could directly result from Tϕ deletion-caused upregulation of gene 17.5, coding for holin, among other Tϕ downstream genes, because infection of gp17.5-overproducing Escherichia coli by wild-type T7 phage showed similar burst downsizing. However, the lysis delay was not associated with cellular levels of holin or lysozyme or with rates of phage adsorption. Instead, when allowed to evolve spontaneously in five independent adaptation experiments, the Tϕ-lacking mutant phage, after 27 or 29 passages, recovered both burst size and lysis time reproducibly by deleting early genes 0.5, 0.6, and 0.7 of class I, among other mutations. Deletion of genes 0.5 to 0.7 from the Tϕ-lacking mutant phage decreased expression of several Tϕ downstream genes to levels similar to that of the wild-type phage. Accordingly, phage T7 lysis timing is associated with cellular levels of Tϕ downstream gene products. This suggests the involvement of unknown factor(s) besides the known lysis proteins, lysozyme and holin, and that Tϕ plays a role of optimizing burst size and lysis time during T7 infection. IMPORTANCE Bacteriophages are bacterium-infecting viruses. After producing numerous progenies inside bacteria, phages lyse bacteria using their lysis protein(s) to get out and start a new infection cycle. Normally, lysis is tightly controlled to ensure phage progenies are maximally produced and released at an optimal time. Here, we have

  14. Novel CIC point mutations and an exon-spanning, homozygous deletion identified in oligodendroglial tumors by a comprehensive genomic approach including transcriptome sequencing.

    Directory of Open Access Journals (Sweden)

    Sophie Eisenreich

    Full Text Available Oligodendroglial tumors form a distinct subgroup of gliomas, characterized by a better response to treatment and prolonged overall survival. Most oligodendrogliomas and also some oligoastrocytomas are characterized by a unique and typical unbalanced translocation, der(1,19, resulting in a 1p/19q co-deletion. Candidate tumor suppressor genes targeted by these losses, CIC on 19q13.2 and FUBP1 on 1p31.1, were only recently discovered. We analyzed 17 oligodendrogliomas and oligoastrocytomas by applying a comprehensive approach consisting of RNA expression analysis, DNA sequencing of CIC, FUBP1, IDH1/2, and array CGH. We confirmed three different genetic subtypes in our samples: i the "oligodendroglial" subtype with 1p/19q co-deletion in twelve out of 17 tumors; ii the "astrocytic" subtype in three tumors; iii the "other" subtype in two tumors. All twelve tumors with the 1p/19q co-deletion carried the most common IDH1 R132H mutation. In seven of these tumors, we found protein-disrupting point mutations in the remaining allele of CIC, four of which are novel. One of these tumors also had a deleterious mutation in FUBP1. Only by integrating RNA expression and array CGH data, were we able to discover an exon-spanning homozygous microdeletion within the remaining allele of CIC in an additional tumor with 1p/19q co-deletion. Therefore we propose that the mutation rate might be underestimated when looking at sequence variants alone. In conclusion, the high frequency and the spectrum of CIC mutations in our 1p/19q-codeleted tumor cohort support the hypothesis that CIC acts as a tumor suppressor in these tumors, whereas FUBP1 might play only a minor role.

  15. Tidal disruption events from supermassive black hole binaries

    CERN Document Server

    Coughlin, Eric R; Nixon, Chris; Begelman, Mitchell C

    2016-01-01

    We investigate the pre-disruption gravitational dynamics and post-disruption hydrodynamics of the tidal disruption of stars by supermassive black hole (SMBH) binaries. We focus on binaries with relatively low mass primaries ($10^6M_{\\odot}$), moderate mass ratios, and separations with reasonably long gravitational wave inspiral times (tens of Myr). First, we generate a large ensemble (between 1 and 10 million) of restricted three-body integrations to quantify the statistical properties of tidal disruptions by circular SMBH binaries of initially-unbound stars. Compared to the reference case of a disruption by a single SMBH, the binary potential induces significant variance into the specific energy and angular momentum of the star at the point of disruption. Second, we use Newtonian numerical hydrodynamics to study the detailed evolution of the fallback debris from 120 disruptions randomly selected from the three-body ensemble (excluding only the most deeply penetrating encounters). We find that the overall mor...

  16. Parameterized Algorithms for Deletion to (r,ell)-Graphs

    OpenAIRE

    Kolay, Sudeshna; Panolan, Fahad

    2015-01-01

    For fixed integers r,ell geq 0, a graph G is called an (r,ell)-graph if the vertex set V(G) can be partitioned into r independent sets and ell cliques. This brings us to the following natural parameterized questions: Vertex (r,ell)-Partization and Edge (r,ell)-Partization. An input to these problems consist of a graph G and a positive integer k and the objective is to decide whether there exists a set S subseteq V(G) (S subseteq E(G)) such that the deletion of S from G results in an (r,ell)-g...

  17. Chlorambucil effectively induces deletion mutations in mouse germ cells.

    OpenAIRE

    Russell, L B; Hunsicker, P R; Cacheiro, N L; Bangham, J W; Russell, W. L.; Shelby, M D

    1989-01-01

    The chemotherapeutic agent chlorambucil was found to be more effective than x-rays or any chemical investigated to date in inducing high yields of mouse germ-line mutations that appear to be deletions or other structural changes. Induction of mutations involving seven specific loci was studied after exposures of various male germ-cell stages to chlorambucil at 10-25 mg/kg. A total of 60,750 offspring was scored. Mutation rates in spermatogonial stem cells were not significantly increased over...

  18. Targeted deletions of cyclooxygenase-2 and atherogenesis in mice

    DEFF Research Database (Denmark)

    Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene;

    2010-01-01

    hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a...... shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low...

  19. Coherent photon-photon processes in disruptive and non-disruptive relativistic heavy-ion collisions

    International Nuclear Information System (INIS)

    Using an impact parameter formulation, differential probability distributions and cross sections for the production of lepton pairs via the photon-photon mechanism are calculated for relativistic heavy-ion collisions. The characteristic features of lepton pair production in disruptive as well as in non-disruptive A-A collisions are studied. Cross sections can be large, the very low k perpendicularto -values of the pairs will help to distinguish these pairs from the ones originating from other sources like Drell-Yan or thermal production. (orig.)

  20. Pheromone disruption of Argentine ant trail integrity.

    Science.gov (United States)

    Suckling, D M; Peck, R W; Manning, L M; Stringer, L D; Cappadonna, J; El-Sayed, A M

    2008-12-01

    Disruption of Argentine ant trail following and reduced ability to forage (measured by bait location success) was achieved after presentation of an oversupply of trail pheromone, (Z)-9-hexadecenal. Experiments tested single pheromone point sources and dispersion of a formulation in small field plots. Ant walking behavior was recorded and digitized by using video tracking, before and after presentation of trail pheromone. Ants showed changes in three parameters within seconds of treatment: (1) Ants on trails normally showed a unimodal frequency distribution of walking track angles, but this pattern disappeared after presentation of the trail pheromone; (2) ants showed initial high trail integrity on a range of untreated substrates from painted walls to wooden or concrete floors, but this was significantly reduced following presentation of a point source of pheromone; (3) the number of ants in the pheromone-treated area increased over time, as recruitment apparently exceeded departures. To test trail disruption in small outdoor plots, the trail pheromone was formulated with carnuba wax-coated quartz laboratory sand (1 g quartz sand/0.2 g wax/1 mg pheromone). The pheromone formulation, with a half-life of 30 h, was applied by rotary spreader at four rates (0, 2.5, 7.5, and 25 mg pheromone/m(2)) to 1- and 4-m(2) plots in Volcanoes National Park, Hawaii. Ant counts at bait cards in treated plots were significantly reduced compared to controls on the day of treatment, and there was a significant reduction in ant foraging for 2 days. These results show that trail pheromone disruption of Argentine ants is possible, but a much more durable formulation is needed before nest-level impacts can be expected. PMID:19034574

  1. Abundance anomalies in tidal disruption events

    Science.gov (United States)

    Kochanek, C. S.

    2016-05-01

    The ˜10 per cent of tidal disruption events (TDEs) due to stars more massive than M* ≳ M⊙ should show abundance anomalies due to stellar evolution in helium, carbon and nitrogen, but not oxygen. Helium is always enhanced, but only by up to ˜25 per cent on average because it becomes inaccessible once it is sequestered in the high-density core as the star leaves the main sequence. However, portions of the debris associated with the disrupted core of a main-sequence star can be enhanced in helium by factors of 2-3 for debris at a common orbital period. These helium abundance variations may be a contributor to the observed diversity of hydrogen and helium line strengths in TDEs. A still more striking anomaly is the rapid enhancement of nitrogen and the depletion of carbon due to the CNO cycle - stars with M* ≳ M⊙ quickly show an increase in their average N/C ratio by factors of 3-10. Because low-mass stars evolve slowly and high-mass stars are rare, TDEs showing high N/C will almost all be due to ˜1-2 M⊙ stars disrupted on the main sequence. Like helium, portions of the debris will show still larger changes in C and N, and the anomalies decline as the star leaves the main sequence. The enhanced [N/C] abundance ratio of these TDEs provides the first natural explanation for the rare, nitrogen-rich quasars and may also explain the strong nitrogen emission seen in ultraviolet spectra of ASASSN-14li.

  2. Laser Microbial Killing and Biofilm Disruption

    Science.gov (United States)

    Krespi, Yosef P.; Kizhner, Victor

    2009-06-01

    Objectives: To analyze the ability of NIR lasers to reduce bacterial load and demonstrate the capability of fiber-based Q-switched Nd:YAG laser disrupting biofilm. Study Design: NIR diode laser was tested in vitro and in vivo using pathogenic microorganisms (S. aureus, S. pneumoniae, P. aeruginosa). In addition biofilms were grown from clinical Pseudomonas isolates and placed in culture plates, screws, tympanostomy tubes and PET sutures. Methods: In the animal experiments acute rhinosinusitis model was created by packing the rabbit nose with bacteria soaked solution. The nasal pack was removed in two days and nose was exposed to laser irradiation. A 940 nm diode laser with fiber diffuser was used. Nasal cultures were obtained before and after the laser treatments. Animals were sacrificed fifteen days following laser treatment and bacteriologic/histologic results analyzed. Q-switched Nd:YAG laser generated shockwave pulses were delivered on biofilm using special probes over culture plates, screws, tubes, and PET sutures for the biofilm experiments. Results: Average of two log bacteria reduction was achieved with NIR laser compared to controls. Histologic studies demonstrated preservation of tissue integrity without significant damage to mucosa. Biofilms were imaged before, during and after treatment using a confocal microscope. During laser-generated shockwave application, biofilm was initially seen to oscillate and eventually break off. Large and small pieces of biofilm were totally and instantly removed from the surface to which they were attached in seconds. Conclusions: Significant bacterial reduction was achieved with NIR laser therapy in this experimental in vitro and animal study. In addition we disrupted Pseudomonas aeruginosa biofilms using Q-switched Nd:YAG laser and special probes generating plasma and shockwave. This new and innovative method of bacteria killing and biofilm disruption without injuring host tissue may have clinical application in the

  3. Electrical disruption in toroidal plasma of hydrogen

    International Nuclear Information System (INIS)

    The initial phase of ionization of a toroidal plasma produced in hydrogen was investigated using zero-dimensional model. The model describes the temporal evolution of plasma by spatial medium of particle density and temperature, on whole plasma volume. The energy and particle (electrons and ions) balance equations are considered. The electron loss is due to ambipolar diffusion in the presence of magnetic field. The electron energy loss involves ionization, Coulomb interaction and diffusion. The ohmic heating converter gives the initial voltage necessary to disruption. (M.C.K.)

  4. Enhanced Cloud Disruption by Magnetic Field Interaction

    CERN Document Server

    Gregori, G; Ryu, D; Jones, T W; Miniati, Francesco; Ryu, Dongsu

    1999-01-01

    We present results from the first three-dimensional numerical simulations of moderately supersonic cloud motion through a tenuous, magnetized medium. We show that the interaction of the cloud with a magnetic field perpendicular to its motion has a great dynamical impact on the development of instabilities at the cloud surface. Even for initially spherical clouds, magnetic field lines become trapped in surface deformations and undergo stretching. The consequent field amplification that occurs there and particularly its variation across the cloud face then dramatically enhance the growth rate of Rayleigh-Taylor unstable modes, hastening the cloud disruption.

  5. Ballooning instability precursors to high β disruptions

    International Nuclear Information System (INIS)

    Strongly ballooning modes have been found as precursors to high β disruptions on TFTR. The modes are typically localized to a region spanning about 60 degree in the toroidal direction. The toroidal localization is associated with lower frequency, global Magneto-Hydro-Dynamic (MHD) activity, typically an ideal n = 1 kink mode. They have moderate to high frequency (f = 10--20 frot), implying toroidal mode numbers in the range n = 10--20. The growth rates for the modes are large, of order 104/sec

  6. Multimedia data mining and analytics disruptive innovation

    CERN Document Server

    Baughman, Aaron; Pan, Jia-Yu; Petrushin, Valery A

    2015-01-01

    This authoritative text/reference provides fresh insights into the cutting edge of multimedia data mining, reflecting how the research focus has shifted towards networked social communities, mobile devices and sensors. Presenting a detailed exploration into the progression of the field, the book describes how the history of multimedia data processing can be viewed as a sequence of disruptive innovations. Across the chapters, the discussion covers the practical frameworks, libraries, and open source software that enable the development of ground-breaking research into practical applications.

  7. MHD perturbation amplitudes required to trigger disruptions

    Czech Academy of Sciences Publication Activity Database

    de Vries, P.C.; Pautasso, G.; Nardon, E.; Cahyna, Pavel; Gerasimov, S.; Maraschek, M.; Lehnen, M.; Huijsmans, G.T.A.; Hender, T.C.

    Vol. 38F. Mulhouse : European Physical Society, 2014 - (Ratynskaia, S.; Mantica, P.; Benuzzi-Mounaix, A.; Dilecce, G.; Bingham, R.; Hirsch, M.; Kemnitz, B.; Klinger, T.), O5.133-O5.133 ISBN 2-914771-90-8. - (Europhysics conference abstracts. 38F). [European Physical Society Conference on Plasma Physics/41./. Berlin (DE), 23.06.2014-27.06.2014] Institutional support: RVO:61389021 Keywords : Disruption * locked mode * magnetic island Subject RIV: BL - Plasma and Gas Discharge Physics http://ocs.ciemat.es/EPS2014PAP/pdf/O5.133.pdf

  8. Helical Disruptions in Small Loops of DNA

    International Nuclear Information System (INIS)

    The thermodynamical stability of DNA minicircles is investigated by means of path integral techniques. Hydrogen bonds between base pairs on complementary strands can be broken by thermal fluctuations and temporary fluctuational openings along the double helix are essential to biological functions such as transcription and replication of the genetic information. Helix unwinding and bubble formation patterns are computed in circular sequences with variable radius in order to analyze the interplay between molecule size and appearance of helical disruptions. The latter are found in minicircles with < 100 base pairs and appear as a strategy to soften the stress due to the bending and torsion of the helix

  9. Traumatic ureteropelvic disruption in the child

    International Nuclear Information System (INIS)

    Traumatic disruption of the ureter from the renal pelvis is a rare injury because the ureteropelvic junction is situated deep in the retroperitoneum and is thus protected by the spine and paraspinal muscles. The mechanism for this injury is thought to be the stretching of the proximal ureter by sudden extreme hyperextension of the trunk. As a non-fatal injury, this occurs only in the child because of the greater elasticity and mobility of the young skeleton. At The Children's Hospital we have seen 3 cases of avulsion of the ureter from the pelvis following blunt trauma. (orig.)

  10. The disruptive effect of Think Aloud

    OpenAIRE

    Nielsen, Janni; Yssing , Carsten

    2004-01-01

    Thinking Aloud Thinking Aloud is the most commonly used technique used to test users´ interaction with computers. The assumption is that Think Aloud gives access to what goes on in the users´ minds. However, interfaces are multi modal and play heavily on user´s visual perception. Reflecting upon Think Aloud (TA), we ask the question: what happens when users are required to verbalise their visual perceptions and interactions? We argue that TA may have a disruptive effect, suggesting that other...

  11. Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy

    Energy Technology Data Exchange (ETDEWEB)

    Bianchi, Marzia; Rizza, Teresa; Verrigni, Daniela [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Martinelli, Diego [Division of Metabolism, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Tozzi, Giulia; Torraco, Alessandra; Piemonte, Fiorella [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Dionisi-Vici, Carlo [Division of Metabolism, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Nobili, Valerio [Gastroenterology and Liver Unit, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Francalanci, Paola; Boldrini, Renata; Callea, Francesco [Dept. Pathology, ' Bambino Gesu' Children' s Hospital, Rome (Italy); Santorelli, Filippo Maria [UOC Neurogenetica e Malattie Neuromuscolari, Fondazione Stella Maris, Pisa (Italy); Bertini, Enrico [Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, ' Bambino Gesu' Children' s Hospital, Rome (Italy); and others

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Expanded array of mtDNA deletions. Black-Right-Pointing-Pointer Pearson syndrome with prominent hepatopathy associated with single mtDNA deletions. Black-Right-Pointing-Pointer Detection of deletions in fibroblasts and blood avoids muscle and liver biopsy. Black-Right-Pointing-Pointer Look for mtDNA deletions before to study nuclear genes related to mtDNA depletion. -- Abstract: Hepatic involvement in mitochondrial cytopathies rarely manifests in adulthood, but is a common feature in children. Multiple OXPHOS enzyme defects in children with liver involvement are often associated with dramatically reduced amounts of mtDNA. We investigated two novel large scale deletions in two infants with a multisystem disorder and prominent hepatopathy. Amount of mtDNA deletions and protein content were measured in different post-mortem tissues. The highest levels of deleted mtDNA were in liver, kidney, pancreas of both patients. Moreover, mtDNA deletions were detected in cultured skin fibroblasts in both patients and in blood of one during life. Biochemical analysis showed impairment of mainly complex I enzyme activity. Patients manifesting multisystem disorders in childhood may harbour rare mtDNA deletions in multiple tissues. For these patients, less invasive blood specimens or cultured fibroblasts can be used for molecular diagnosis. Our data further expand the array of deletions in the mitochondrial genomes in association with liver failure. Thus analysis of mtDNA should be considered in the diagnosis of childhood-onset hepatopathies.

  12. Blocking rolling circle replication with a UV lesion creates a deletion hotspot.

    Science.gov (United States)

    Seigneur, M; Ehrlich, S D; Michel, B

    1997-11-01

    UV light irradiation increases genetic instability by causing mutations and deletions. The mechanism of UV-induced rearrangements was investigated making use of deletion-prone plasmids. Chimeric plasmids carrying pBR322 and M13 replication origins undergo deletions that join the M13 replication origin to a random nucleotide. A restriction fragment was UV irradiated, introduced into such a hybrid plasmid and deletions formed at the M13 origin were analysed. In most of the deletant molecules, the M13 replication nick site was linked to a nucleotide in the irradiated fragment, showing that UV lesions are deletion hotspots. These deletions were independent of the UvrABC excision repair proteins, suggesting that the deletogenic structure is the lesion itself and not a repair intermediate. They were not found in the absence of M13 replication, indicating that they result from the encounter of the M13 replication fork with the UV lesion. Furthermore, UV-induced deletions occurred independently of pBR322 replication. We conclude that, in contrast to pBR322 replication forks, M13 replication forks blocked by UV lesions are deletion prone. We propose that the deletion-prone properties of a UV-arrested polymerase depend on the associated helicase. PMID:9402026

  13. Geometric figure-ground cues override standard depth from accretion-deletion.

    Science.gov (United States)

    Tanrikulu, Ömer Daglar; Froyen, Vicky; Feldman, Jacob; Singh, Manish

    2016-03-01

    Accretion-deletion is widely considered a decisive cue to surface depth ordering, with the accreting or deleting surface interpreted as behind an adjoining surface. However, Froyen, Feldman, and Singh (2013) have shown that when accretion-deletion occurs on both sides of a contour, accreting-deleting regions can also be perceived as in front and as self-occluding due to rotation in three dimensions. In this study we ask whether geometric figure-ground cues can override the traditional "depth from accretion-deletion" interpretation even when accretion-deletion takes place only on one side of a contour. We used two tasks: a relative-depth task (front/back), and a motion-classification task (translation/rotation). We conducted two experiments, in which texture in only one set of alternating regions was moving; the other set was static. Contrary to the traditional interpretation of accretion-deletion, the moving convex and symmetric regions were perceived as figural and rotating in three dimensions in roughly half of the trials. In the second experiment, giving different motion directions to the moving regions (thereby weakening motion-based grouping) further weakened the traditional accretion-deletion interpretation. Our results show that the standard "depth from accretion-deletion" interpretation is overridden by static geometric cues to figure-ground. Overall, the results demonstrate a rich interaction between accretion-deletion, figure-ground, and structure from motion that is not captured by existing models of depth from motion. PMID:26982528

  14. Genome-Wide Generation of Yeast Gene Deletion Strains

    Directory of Open Access Journals (Sweden)

    Steven L. Kelly

    2006-04-01

    Full Text Available In the year 2001 a collection of yeast strains will be completed that are deleted in the 6000 open reading frames selected as putative genes by the initial bioinformatic analysis of the Saccharomyces cerevisiae genome. The collection was produced by the transatlantic yeast gene deletion project, a collaboration involving researchers in the USA, Canada and Europe. The European effort was part of EUROFAN (European Functional Analysis Network where some of the strains could feed into various functional analysis nodes dealing with specific areas of cell biology. With approximately 40% of human genes involved in heritable disease having a homologue in yeast and with the use of yeast in various drug discovery strategies, not least due to the dramatic increase in fungal infections, these strains will be valuable in trans-genomic studies and in specialised interest studies in individual laboratories. A detailed analysis of the project by the consortium is in preparation, here we discuss the yeast strains, reported findings and approaches to using this resource.

  15. Systematic discovery of complex insertions and deletions in human cancers.

    Science.gov (United States)

    Ye, Kai; Wang, Jiayin; Jayasinghe, Reyka; Lameijer, Eric-Wubbo; McMichael, Joshua F; Ning, Jie; McLellan, Michael D; Xie, Mingchao; Cao, Song; Yellapantula, Venkata; Huang, Kuan-lin; Scott, Adam; Foltz, Steven; Niu, Beifang; Johnson, Kimberly J; Moed, Matthijs; Slagboom, P Eline; Chen, Feng; Wendl, Michael C; Ding, Li

    2016-01-01

    Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research. PMID:26657142

  16. Disruptive mood dysregulation disorder: current insights

    Directory of Open Access Journals (Sweden)

    Baweja R

    2016-08-01

    Full Text Available Raman Baweja, Susan D Mayes, Usman Hameed, James G Waxmonsky Department of Psychiatry, Penn State University College of Medicine, Hershey, PA, USA Abstract: Disruptive mood dysregulation disorder (DMDD was introduced as a new diagnostic entity under the category of depressive disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5. It was included in DSM-5 primarily to address concerns about the misdiagnosis and consequent overtreatment of bipolar disorder in children and adolescents. DMDD does provide a home for a large percentage of referred children with severe persistent irritability that did not fit well into any DSM, Fourth Edition (DSM-IV diagnostic category. However, it has been a controversial addition to the DSM-5 due to lack of published validity studies, leading to questions about its validity as a distinct disorder. In this article, the authors discuss the diagnostic criteria, assessment, epidemiology, criticism of the diagnosis, and pathophysiology, as well as treatment and future directions for DMDD. They also review the literature on severe mood dysregulation, as described by the National Institute of Mental Health, as the scientific support for DMDD is based primarily on studies of severe mood dysregulation. Keywords: disruptive mood dysregulation disorder, persistent irritability, temper outbursts 

  17. Abundance Anomalies In Tidal Disruption Events

    CERN Document Server

    Kochanek, C S

    2015-01-01

    The ~10% of tidal disruption events (TDEs) due to stars more massive than the Sun should show abundance anomalies due to stellar evolution in helium, carbon and nitrogen, but not oxygen. Helium is always enhanced, but only by up to ~25% on average because it becomes inaccessible once it is sequestered in the high density core as the star leaves the main sequence. However, portions of the debris associated with the disrupted core of a main sequence star can be enhanced in helium by factors of 2-3 for debris at a common orbital period. These helium abundance variations may be a contributor to the observed diversity of hydrogen and helium line strengths in TDEs. A still more striking anomaly is the rapid enhancement of nitrogen and the depletion of carbon due to the CNO cycle -- stars more massive than the Sun quickly show an increase in their average N/C ratio by factors of 3-10. Because low mass stars evolve slowly and high mass stars are rare, TDEs showing high N/C will almost all be due to 1-2Msun stars disr...

  18. Onset conditions for disruptions during VDEs

    Science.gov (United States)

    Manickam, Janardhan; Gerhardt, Stefan; Boozer, Allen; NSTX Team

    2011-10-01

    The Vertical Displacement Event, VDE, evolves on a slow timescale relative to the ideal MHD Alfvenic timescale. At some point the kink mode is strongly destabilized, leading to the final disruption. In most cases this occurs when q-edge is slightly less than two. Non-axisymmetric halo currents are often observed, well before the disruption. The evolution of the plasma during the VDE is modeled as a sequence of shrinking equilibria, where the core current profile remains constant so that the safety-factor at the axis, q-axis, remains fixed and the q-edge systematically decreases. Stability analysis shows that the plasma is indeed stable or has a small growth-rate until q- edge drops below 2, at which point the growth-rate rises rapidly, approaching γTA = 1 . The kink mode is characterized by m / n = 2 / 1 , where m and n are the poloidal and toroidal mode numbers. The surface currents associated with the MHD perturbation are computed. These may be related to the non-axisymmetric component of the halo currents and may be providing stability at modest growth-rates. This model is compared with observations on NSTX. This manuscript has been authored by Princeton University and collaborators under Contract Number(s) DE-AC02-09CH11466.

  19. Features, Events, and Processes: Disruptive Events

    International Nuclear Information System (INIS)

    The purpose of this analysis report is to evaluate and document the inclusion or exclusion of the disruptive events features, events, and processes (FEPs) with respect to modeling used to support the total system performance assessment for license application (TSPA-LA). A screening decision, either ''Included'' or ''Excluded,'' is given for each FEP, along with the technical basis for screening decisions. This information is required by the U.S. Nuclear Regulatory Commission (NRC) at 10 CFR 63.114 (d), (e), and (f) [DIRS 156605]. The FEPs addressed in this report deal with both seismic and igneous disruptive events, such as fault displacements through the repository and an igneous intrusion into the repository. For included FEPs, this analysis summarizes the implementation of the FEP in TSPA-LA (i.e., how the FEP is included). For excluded FEPs, this analysis provides the technical basis for exclusion from TSPA-LA (i.e., why the FEP is excluded). Previous versions of this report were developed to support the total system performance assessments (TSPA) for various prior repository designs. This revision addresses the repository design for the license application (LA)

  20. Features, Events, and Processes: Disruptive Events

    Energy Technology Data Exchange (ETDEWEB)

    P. Sanchez

    2004-11-08

    The purpose of this analysis report is to evaluate and document the inclusion or exclusion of the disruptive events features, events, and processes (FEPs) with respect to modeling used to support the total system performance assessment for license application (TSPA-LA). A screening decision, either ''Included'' or ''Excluded,'' is given for each FEP, along with the technical basis for screening decisions. This information is required by the U.S. Nuclear Regulatory Commission (NRC) at 10 CFR 63.114 (d), (e), and (f) [DIRS 156605]. The FEPs addressed in this report deal with both seismic and igneous disruptive events, such as fault displacements through the repository and an igneous intrusion into the repository. For included FEPs, this analysis summarizes the implementation of the FEP in TSPA-LA (i.e., how the FEP is included). For excluded FEPs, this analysis provides the technical basis for exclusion from TSPA-LA (i.e., why the FEP is excluded). Previous versions of this report were developed to support the total system performance assessments (TSPA) for various prior repository designs. This revision addresses the repository design for the license application (LA).

  1. Disruptive Conduct: The Impact of Disruptive Technologies on Social Relations in Higher Education

    Science.gov (United States)

    Flavin, Michael

    2016-01-01

    Higher education institutions (HEIs) have invested significantly in digital technologies for learning and teaching. However, technologies provided by HEIs have not been universally successful in terms of adoption and usage. Meanwhile, both students and lecturers use disruptive technologies to support learning and teaching. This article examines…

  2. Comparison of Advanced Machine Learning Tools for Disruption Prediction and Disruption Studies

    Czech Academy of Sciences Publication Activity Database

    Odstrčil, Michal; Murari, A.; Mlynář, Jan

    2013-01-01

    Roč. 41, č. 7 (2013), s. 1751-1759. ISSN 0093-3813 R&D Projects: GA ČR GAP205/10/2055 Institutional support: RVO:61389021 Keywords : Learning Machines * Support Vector Machines * Neural Network * ASDEX Upgrade * JET * Disruption mitigation * Tokamaks * ITER Subject RIV: BL - Plasma and Gas Discharge Physics Impact factor: 0.950, year: 2013

  3. Genetic deletion of S-opsin prevents rapid cone degeneration in a mouse model of Leber congenital amaurosis.

    Science.gov (United States)

    Zhang, Tao; Enemchukwu, Nduka O; Jones, Alex; Wang, Shixian; Dennis, Emily; Watt, Carl B; Pugh, Edward N; Fu, Yingbin

    2015-03-15

    Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal synthesis and cause Leber congenital amaurosis (LCA), a severe hereditary blindness occurring in early childhood. The pathology is attributed to a combination of 11-cis-retinal deficiency and photoreceptor degeneration. The mistrafficking of cone membrane-associated proteins including cone opsins (M- and S-opsins), cone transducin (Gαt2), G-protein-coupled receptor kinase 1 (GRK1) and guanylate cyclase 1 (GC1) has been suggested to play a role in cone degeneration. However, their precise role in cone degeneration is unclear. Here we investigated the role of S-opsin (Opn1sw) in cone degeneration in Lrat(-) (/-), a murine model for LCA, by genetic ablation of S-opsin. We show that deletion of just one allele of S-opsin from Lrat(-) (/-) mice is sufficient to prevent the rapid cone degeneration for at least 1 month. Deletion of both alleles of S-opsin prevents cone degeneration for an extended period (at least 12 months). This genetic prevention is accompanied by a reduction of endoplasmic reticulum (ER) stress in Lrat(-) (/-) photoreceptors. Despite cone survival in Opn1sw(-/-)Lrat(-) (/-) mice, cone membrane-associated proteins (e.g. Gαt2, GRK1 and GC1) continue to have trafficking problems. Our results suggest that cone opsins are the 'culprit' linking 11-cis-retinal deficiency to cone degeneration in LCA. This result has important implications for the current gene therapy strategy that emphasizes the need for a combinatorial therapy to both improve vision and slow photoreceptor degeneration. PMID:25416279

  4. Deletion of P399E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency

    International Nuclear Information System (INIS)

    Highlights: → Mutations in human POR cause congenital adrenal hyperplasia. → We are reporting a novel 3 amino acid deletion mutation in POR P399E401del. → POR mutation P399E401del decreased P450 activities by 60-85%. → Impairment of steroid metabolism may be caused by multiple hits. → Severity of aromatase inhibition is related to degree of in utero virilization. -- Abstract: P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399E401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399E401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17α-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399E401 revealed reduced stability and flexibility of the mutant. In conclusion, P399E401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399E401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.

  5. CCAAT/enhancer binding protein β deletion increases mitochondrial function and protects mice from LXR-induced hepatic steatosis

    International Nuclear Information System (INIS)

    Highlights: ► LXR agonist activation increases liver TG accumulation by increasing lipogenesis. ► C/EBPβ−/− mouse prevents LXR activation-mediated induction of hepatic lipogenesis. ► C/EBPβ deletion increases mitochondrial transport chain function. ► Beneficial effects of LXR activation on liver cholesterol metabolism did not change. ► C/EBPβ inhibition might have important therapeutic potential. -- Abstract: Drugs designed specifically to activate liver X receptors (LXRs) have beneficial effects on lowering cholesterol metabolism and inflammation but unfortunately lead to severe hepatic steatosis. The transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of liver gene expression but little is known about its involvement in LXR-based steatosis and cholesterol metabolism. The present study investigated the role of C/EBPβ expression in LXR agonist (T0901317)-mediated alteration of hepatic triglyceride (TG) and lipogenesis in mice. C/EBPβ deletion in mice prevented LXR agonist-mediated induction of lipogenic gene expression in liver in conjunction with significant reduction of liver TG accumulation. Surprisingly, C/EBPβ−/− mice showed a major increase in liver mitochondrial electron chain function compared to WT mice. Furthermore, LXR activation in C/EBPβ−/− mice increased the expression of liver ATP-binding cassette transporter ABCG1, a gene implicated in cholesterol efflux and reducing blood levels of total and LDL-cholesterol. Together, these findings establish a central role for C/EBPβ in the LXR-mediated steatosis and mitochondrial function, without impairing the influence of LXR activation on lowering LDL and increasing HDL-cholesterol. Inactivation of C/EBPβ might therefore be an important therapeutic strategy to prevent LXR activation-mediated adverse effects on liver TG metabolism without disrupting its beneficial effects on cholesterol metabolism.

  6. Mucopolysaccharidosis type IVA: Common double deletion in the N-Acetylgalactosamine-6-sulfatase gene (GALNS)

    Energy Technology Data Exchange (ETDEWEB)

    Hori, Toshinori; Tomatsu, Shunji; Fukuda, Seiji [Gifu Univ. School of Medicine, Gifu (Japan)] [and others

    1995-04-10

    Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase (GALNS). We found two separate deletions of nearly 8.0 and 6.0 kb in the GALNS gene, including some exons. There are Alu repetitive elements near the breakpoints of the 8.0-kb deletion, and this deletion resulted from an Alu-Alu recombination. The other 6.0-kb deletion involved illegitimate recombinational events between incomplete short direct repeats of 8 bp at deletion breakpoints. The same rearrangement has been observed in a heteroallelic state in four unrelated patients. This is the first documentation of a common double deletion a gene that is not a member of a gene cluster. 39 refs., 5 figs.

  7. Complementarity of quantum correlations in cloning and deleting of quantum states

    Science.gov (United States)

    Sazim, Sk; Chakrabarty, Indranil; Datta, Annwesha; Pati, Arun K.

    2015-06-01

    We quantify the amount of correlation generated between two different output modes in imperfect cloning and deletion processes. We use three different measures of quantum correlations and investigate their role in determining the fidelity of cloning and deletion. We obtain a bound on the total correlation generated in the successive processes of cloning and deleting operations. This bound displays a different kind of complementary relationship between the quantum correlations required in generating a copy of a quantum state and the amount of correlation required to bring it back to the original state by deleting and vice versa. Our result shows that the better we clone (delete) a state, the more difficult it will be to bring the state back to its original form by the process of deleting (cloning).

  8. STUDY OF DELETION OF P16 GENE IN THE PROGRESSION OF BRAIN ASTROCYTOMAS

    Institute of Scientific and Technical Information of China (English)

    Zhai Guang; Yuan Xianhou

    1998-01-01

    Objective:To study the relationship between deletion of P16 gene and occurrence and progression of astrocytomas. Methods: The techniques of polymerase chain reaction (PCR) and immunohistochemistry were used to detect the deletion of exon2 of P16 gene and expression of P16 gene in 52 cases of Brain astrocytoma.Results: The deletion rate of exon2 of P16 gene in the tumors analyzed was 34.6%. Most of them with deletion of exon2 of p16 gene were high grade astrocytomas (grade Ⅲ 42%, grade Ⅳ 50%). 61.5% of the tumors were absent from expression of p16 and the deletion rate of p16 protein increased with the grade of astrocytoma (X2=10.83, P<0.005). Conclusion: Deletion of p16 gene and protein may correlate with the malignant progression of astrocytoma.

  9. The rates and patterns of deletions in the human factor IX gene

    Energy Technology Data Exchange (ETDEWEB)

    Ketterling, R.P.; Vielhaber, E.L.; Lind, T.J.; Thorland, E.C.; Sommer S.S. (Mayo Clinic/Foundation, Rochester, MN (United States))

    1994-02-01

    Deletions are commonly observed in genes with either segments of highly homologous sequences or excessive gene length. However, in the factor IX gene and in most genes, deletions (of [ge]21 bp) are uncommon. The authors have analyzed DNA from 290 families with hemophilia B (203 independent mutations) and have found 12 deletions >20 bp. Eleven of these are >2 kb (range >3-163 kb), and one is 1.1 kb. The junctions of the four deletions that are completely contained within the factor IX gene have been determined. A novel mutation occurred in patient HB128: the data suggest that a 26.8-kb deletion occurred between two segments of alternating purines and pyrimidines and that a 2.3-kb sense strand segment derived from the deleted region was inserted. For a sample of 203 independent mutations, the authors estimate the [open quotes]baseline[close quotes] rates of deletional mutation per base pair per generation as a function of size. The rate for large (>2 kb)I deletions is exceedingly low. For every mutational event in which a given base is at the junction of a large deletion, there are an estimated 58 microdeletions (<20 bp) and 985 single-base substitutions at that base. Analysis of the nine reported deletion junctions in the factor IX gene literature reveals that (i) five are associated with inversion, orphan sequences, or sense strand insertions; (ii) four are simple deletions that display an excess of short direct repeats at their junctions; (iii) there is no dramatic clustering of junctions within the gene; and (iv) with the exception of alternating purines and pyrimidines, deletion junctions are not preferentially associated with repetitive DNA. 58 refs., 5 figs., 5 tabs.

  10. A Chinese familial growth hormone deficiency with a deletion of 7.1 kb of DNA.

    OpenAIRE

    He, Y A; Chen, S S; Wang, Y. X; Lin, X. Y.; D. F. Wang

    1990-01-01

    Using restriction endonuclease analysis and a human growth hormone cDNA probe, we have found a Chinese family with a human growth hormone gene deletion. Two affected sibs are homozygous for a deletion of approximately 7.1 kb of DNA, which contains the normal human growth hormone gene. The patients' parents and grandmothers are heterozygous for the deleted gene. Their grandfathers are normal and homozygous for the hGH-N gene. All of them have normal stature.

  11. SIMULATING THE SUPPLY DISRUPTION FOR THE COORDINATED SUPPLY CHAIN

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    There are many disruptive accidents in the supply chain operations system and achieving the coordination of supply chain is main objective for supply chain research. While disruptive accidents have increasingly influenced the coordinated operation of the supply chain, existing research literature on the supply chain coordination is setting in a stationary environment. The answer for how the disruptive accidents affect the coordinated supply chain is given in this paper. Based on the benchmark supply chain which is coordinated by the negative incentive mechanism, we study the impacts of supply disruption on the supply chain system by using simulation approach in which two different distribution function of random variable are used to express the supply disruption. Comparison between these two simulation results and possible coordination mechanism under the supply disruption are proposed. From the perspective of supply chain risk management, we provide the inspiration for the manager.

  12. Induction of Mitochondrial DNA Deletion by Ionizing Radiation in Human Lung Fibroblast IMR-90 Cells

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Hyeon Soo; Jung, U Hee; Park, Hae Ran; Jo, Sung Kee [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2009-06-15

    Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging and also contributes to their unfavorable effects in cultured cells and animal tissues. This study was conducted to investigate the effect of ionizing radiation (IR) on mtDNA deletion and the involvement of reactive oxygen species (ROS) in this process in human lung fibroblast (IMR-90) cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated with {sup 137}Cs -rays and the intracellular ROS level was determined by 2',7'-dichlorofluorescein diacetate (DCFH-DA) and mtDNA common deletion (4977bp) was detected by nested PCR. Old cells at PD 55 and H{sub 2}O{sub 2}-treated young cells were compared as the positive control. IR increased the intracellular ROS level and mtDNA 4977 bp deletion in IMR-90 cells dose-dependently. The increases of ROS level and mtDNA deletion were also observed in old cells and H{sub 2}O{sub 2}-treated young cells. To confirm the increased ROS level is essential for mtDNA deletion in irradiated cells, the effects of N-acetylcysteine (NAC) on IRinduced ROS and mtDNA deletion were examined. 5 mM NAC significantly attenuated the IR-induced ROS increase and mtDNA deletion. These results suggest that IR induces the mtDNA deletion and this process is mediated by ROS in IMR-90 cells.

  13. Cognitive and structural neuroimaging characteristics of schizophrenia patients with large, rare copy number deletions.

    Science.gov (United States)

    Kenneth Martin, Andrew; Robinson, Gail; Reutens, David; Mowry, Bryan

    2014-12-30

    Large (>500 Kb), rare (frequency <1%) deletions are associated with risk for schizophrenia. The aim of the study was to characterise patients with these deletions using measures of cognition, grey-matter volume and white-matter integrity. Patients with schizophrenia and large, rare deletions (SZ-del) (n=17) were assessed on a test of intelligence, the Wechsler Abbreviated Scale of Intelligence (WASI), and compared with age- and sex-matched schizophrenia patients without large, rare deletions (SZ-nodel) (n=65), and healthy controls (HCs) (n=50). Regional grey-matter differences were investigated using voxel-based morphometry (SZ-del=9; SZ-nodel=26; HC=19). White-matter integrity was assessed using fractional anisotropy (SZ-del=9; SZ-nodel=24; HC=15). Compared with schizophrenia patients without large, rare deletions, those with large, rare deletions had lower IQ; greater grey-matter volume in clusters with peaks in the left and right cerebellum, left hippocampus, and right rectal gyrus; and increased white-matter anisotropy in the body and genu of the corpus callosum. Compared with healthy controls, patients with large, rare deletions had reduced grey matter volume in the right calcarine gyrus. In sum, patients with large, rare deletions had structural profiles intermediate to those observed in healthy controls and schizophrenia patients without large, rare deletions, but had greater impairment in intelligence. PMID:25453991

  14. Distal Deletion of Chromosome 11q Encompassing Jacobsen Syndrome without Platelet Abnormality

    OpenAIRE

    Sheth, Frenny J.; Datar, Chaitanya; Andrieux, Joris; Pandit, Anand; Nayak, Darshana; Rahman, Mizanur; Sheth, Jayesh J.

    2014-01-01

    Terminal 11q deletion, known as Jacobsen syndrome (JBS), is a rare genetic disorder associated with numerous dysmorphic features. We studied two cases with multiple congenital anomalies that were cytogenetically detected with deletions on 11q encompassing JBS region: 46,XX,der(11) del(11)(q24). Array comparative genomic hybridization (aCGH) analysis confirmed partial deletion of 11.8–11.9 Mb at 11q24.1q25 (case 1) and 13.9–14 Mb deletion at 11q23.3q25 together with 7.3–7.6 Mb duplication at 1...

  15. Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression

    Directory of Open Access Journals (Sweden)

    Hanamura Ichiro

    2006-10-01

    Full Text Available Abstract Background A high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. Previously, we determined that p18INK4c, an essential gene for normal plasma cell differentiation, was bi-allelically deleted in five of sixteen multiple myeloma (MM cell lines. The present study was undertaken to investigate a possible role of p18INK4c in increased proliferation of myeloma tumors as they progress. Results Thirteen of 40 (33% human myeloma cell lines do not express normal p18INK4c, with bi-allelic deletion of p18 in twelve, and expression of a mutated p18 fragment in one. Bi-allelic deletion of p18, which appears to be a late progression event, has a prevalence of about 2% in 261 multiple myeloma (MM tumors, but the prevalence is 6 to10% in the 50 tumors with a high expression-based proliferation index. Paradoxically, 24 of 40 (60% MM cell lines, and 30 of 50 (60% MM tumors with a high proliferation index express an increased level of p18 RNA compared to normal bone marrow plasma cells, whereas this occurs in only five of the 151 (3% MM tumors with a low proliferation index. Tumor progression is often accompanied by increased p18 expression and an increased proliferation index. Retroviral-mediated expression of exogenous p18 results in marked growth inhibition in three MM cell lines that express little or no endogenous p18, but has no effect in another MM cell line that already expresses a high level of p18. Conclusion Paradoxically, although loss of p18 appears to contribute to increased proliferation of nearly 10% of MM tumors, most MM cell lines and proliferative MM tumors have increased expression of p18. Apart from a small fraction of cell lines and tumors that have inactivated

  16. Post-Disruptive Runaway Electron Beam in COMPASS Tokamak

    OpenAIRE

    Vlainic, Milos; Mlynar, Jan; Cavalier, Jordan; Weinzettl, Vladimir; Paprok, Richard; Imrisek, Martin; Ficker, Ondrej; Noterdaeme, Jean-Marie; Team, the COMPASS

    2015-01-01

    For ITER-relevant runaway electron studies, such as suppression, mitigation, termination and/or control of runaway beam, obtaining the runaway electrons after the disruption is important. In this paper we report on the first achieved discharges with post-disruptive runaway electron beam, entitled "runaway plateau", in the COMPASS tokamak. The runaway plateau is produced by massive gas injection of argon. Almost all of the disruptions with runaway electron plateaus occurred during the plasma c...

  17. Universal versus tailored solutions for alleviating disruptive behavior in hospitals

    OpenAIRE

    Berman-Kishony, Talia; Shvarts, Shifra

    2015-01-01

    Background: Disruptive behavior among hospital staff can negatively affect quality of care. Motivated by a standard on disruptive behavior issued by The Joint Commission (LD 3.10), as well as the desire to improve patient care, minimize liability, and improve staff retention, hospitals are setting policies to prevent and resolve disruptive behaviors. However, it is unknown whether uniform conflict management tools are equally effective among different hospital settings. Methods: We surveyed r...

  18. Disruption generated secondary runaway electrons in present day tokamaks

    International Nuclear Information System (INIS)

    An analysis of the runaway electron secondary generation during disruptions in present day tokamaks (JET, JT-60U, TEXTOR) was made. It was shown that even for tokamaks with the plasma current I approx 100 kA the secondary generation may dominate the runaway production during disruptions. In the same time in tokamaks with I approx 1 MA the runaway electron secondary generation during disruptions may be suppressed

  19. Environmental endocrine disruption: an effects assessment and analysis.

    OpenAIRE

    Crisp, T M; Clegg, E D; Cooper, R. L.; Wood, W. P.; D. G. Anderson; Baetcke, K. P.; Hoffmann, J L; Morrow, M S; Rodier, D J; Schaeffer, J E; Touart, L W; Zeeman, M G; Patel, Y. M.

    1998-01-01

    This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analy...

  20. Pathological tau disrupts ongoing network activity.

    Science.gov (United States)

    Menkes-Caspi, Noa; Yamin, Hagar G; Kellner, Vered; Spires-Jones, Tara L; Cohen, Dana; Stern, Edward A

    2015-03-01

    Pathological tau leads to dementia and neurodegeneration in tauopathies, including Alzheimer's disease. It has been shown to disrupt cellular and synaptic functions, yet its effects on the function of the intact neocortical network remain unknown. Using in vivo intracellular and extracellular recordings, we measured ongoing activity of neocortical pyramidal cells during various arousal states in the rTg4510 mouse model of tauopathy, prior to significant cell death, when only a fraction of the neurons show pathological tau. In transgenic mice, membrane potential oscillations are slower during slow-wave sleep and under anesthesia. Intracellular recordings revealed that these changes are due to longer Down states and state transitions of membrane potentials. Firing rates of transgenic neurons are reduced, and firing patterns within Up states are altered, with longer latencies and inter-spike intervals. By changing the activity patterns of a subpopulation of affected neurons, pathological tau reduces the activity of the neocortical network. PMID:25704951

  1. Assessment of CRBR core disruptive accident energetics

    Energy Technology Data Exchange (ETDEWEB)

    Theofanous, T.G.; Bell, C.R.

    1984-03-01

    The results of an independent assessment of core disruptive accident energetics for the Clinch River Breeder Reactor are presented in this document. This assessment was performed for the Nuclear Regulatory Commission under the direction of the CRBR Program Office within the Office of Nuclear Reactor Regulation. It considered in detail the accident behavior for three accident initiators that are representative of three different classes of events; unprotected loss of flow, unprotected reactivity insertion, and protected loss of heat sink. The primary system's energetics accommodation capability was realistically, yet conservatively, determined in terms of core events. This accommodation capability was found to be equivalent to an isentropic work potential for expansion to one atmosphere of 2550 MJ or a ramp rate of about 200 $/s applied to a classical two-phase disassembly.

  2. Disruption of zinc homeostasis in Alzheimer's disease

    International Nuclear Information System (INIS)

    The basic hypothesis being tested is that, in Alzheimer's disease (AD), the delicate balance of brain Zn is disrupted and may play a role in the pathogenesis of neuron degeneration. Micro-PIXE measurements reveal a significant elevation of Zn in senile plaques (SP) in AD brain compared with adjacent neuropil and a significant increase in AD neuropil compared to control neuropil. The observation of elevated Zn in SP is of interest because the amyloid precursor protein contains a Zn binding site that may prevent normal cleavage leading to the generation of a toxic fragment of beta amyloid, the constituent of SP. The potential of using laser-ablation inductively coupled plasma mass spectrometry as a complimentary microprobe technique is also presented

  3. Carpal ligamentous disruptions and negative ulnar variance

    International Nuclear Information System (INIS)

    Negative ulnar variance is a condition in which the ulna is relatively shorter than the radius at the carpus. It was found in 21% of 203 normal wrists. We have observed an increased incidence (49%) of this anomaly in patients with carpal ligamentous instabilities (dorsiflexion instability, palmar flexion instability, scapholunate dissociation with rotary luxation of the scaphoid, and lunate and perilunate dislocations). While the reasons for this association have yet to be adequately delineated, the presence of a negative ulnar variant may serve as an impartial clue to the presence of ligamentous instability. Many carpal instabilities present with subtle radiographic findings requiring careful evaluation of radiographs. Patients with negative ulnar variance and histories suggestive of ligamentous instability should undergo careful radiologic evaluation to assure early diagnosis of carpal disruption. (orig.)

  4. The disruptive effect of Think Aloud

    DEFF Research Database (Denmark)

    Nielsen, Janni; Yssing, Carsten

    2004-01-01

    Thinking Aloud Thinking Aloud is the most commonly used technique used to test users´ interaction with computers. The assumption is that Think Aloud gives access to what goes on in the users´ minds. However, interfaces are multi modal and play heavily on user´s visual perception. Reflecting upon...... Think Aloud (TA), we ask the question: what happens when users are required to verbalise their visual perceptions and interactions? We argue that TA may have a disruptive effect, suggesting that other techniques be considered. With a theoretical distinction between focal and subsidiary awareness and a...... focus on the sense making process, we develop a frame for test of user´s visual interaction which rely on the coordination between hand/mouse and eye/cursor.Author Keywords: Think Aloud, visual perception, interaction, test...

  5. Collisional and Rotational Disruption of Asteroids

    CERN Document Server

    Walsh, Kevin J; Richardson, Derek C

    2009-01-01

    Asteroids are leftover pieces from the era of planet formation that help us understand conditions in the early Solar System. Unlike larger planetary bodies that were subject to global thermal modification during and subsequent to their formation, these small bodies have kept at least some unmodified primordial material from the solar nebula. However, the structural properties of asteroids have been modified considerably since their formation. Thus, we can find among them a great variety of physical configurations and dynamical histories. In fact, with only a few possible exceptions, all asteroids have been modified or completely disrupted many times during the age of the Solar System. This picture is supported by data from space mission encounters with asteroids that show much diversity of shape, bulk density, surface morphology, and other features. Moreover, the gravitational attraction of these bodies is so small that some physical processes occur in a manner far removed from our common experience on Earth....

  6. Features, Events, and Processes: Disruptive Events

    Energy Technology Data Exchange (ETDEWEB)

    J. King

    2004-03-31

    The primary purpose of this analysis is to evaluate seismic- and igneous-related features, events, and processes (FEPs). These FEPs represent areas of natural system processes that have the potential to produce disruptive events (DE) that could impact repository performance and are related to the geologic processes of tectonism, structural deformation, seismicity, and igneous activity. Collectively, they are referred to as the DE FEPs. This evaluation determines which of the DE FEPs are excluded from modeling used to support the total system performance assessment for license application (TSPA-LA). The evaluation is based on the data and results presented in supporting analysis reports, model reports, technical information, or corroborative documents that are cited in the individual FEP discussions in Section 6.2 of this analysis report.

  7. Assessment of CRBR core disruptive accident energetics

    International Nuclear Information System (INIS)

    The results of an independent assessment of core disruptive accident energetics for the Clinch River Breeder Reactor are presented in this document. This assessment was performed for the Nuclear Regulatory Commission under the direction of the CRBR Program Office within the Office of Nuclear Reactor Regulation. It considered in detail the accident behavior for three accident initiators that are representative of three different classes of events; unprotected loss of flow, unprotected reactivity insertion, and protected loss of heat sink. The primary system's energetics accommodation capability was realistically, yet conservatively, determined in terms of core events. This accommodation capability was found to be equivalent to an isentropic work potential for expansion to one atmosphere of 2550 MJ or a ramp rate of about 200 $/s applied to a classical two-phase disassembly

  8. How to Spot a Disrupted Galactic Satellite

    Science.gov (United States)

    Kohler, Susanna

    2016-03-01

    Many satellites dwarf galaxies and globular clusters are thought to be orbiting our galaxy, but detecting them can be a tricky business. In particular, satellites can be disrupted by the galactic potential and spread out into streams, making them so diffuse that were unable to spot them in photometric observations.In a recent study, a team of scientists led by John Vickers (Chinese Academy of Sciences) has cleverly worked around this difficulty by searching for groups of stars that have clustered velocities and metallicities differing from the background field.Searching Through StarsRadial velocity and metallicity of LAMOST stars near the physical location of Lamost 1. Circles are stars within 1.5 of the target location, small dots are stars within 5. [Vickers et al. 2016]The team trawled the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST) catalog, which contains spectroscopic information for 2.5 million stars. Vickers and collaborators first hunted for stars that shared an approximate physical location and had similar velocities (because the stars of a satellite will maintain similar velocities even after the satellite is disrupted). Next, they discarded any of these clumps that didnt also share a similar metallicity.Vickers and collaborators then compared the resulting set of 21 candidate streams to catalogs of known globular clusters, open clusters, and nearby galaxies. Three of the candidate clumps, clustered in a 3 area on the sky, do not correspond to any known objects. The authors postulate that these are all part of a disrupted satellite, which they dub Lamost 1.Characterizing a Former ClusterFitting the spectroscopic data for the member stars, the authors are able to estimate a number of characteristics of Lamost 1, with the best fit implying an age of 11 Gyr, a total mass of about 20,000 solar masses, and a distance from us of about 8,500 light-years.Based on the stellar motions, the authors believe that the clump is on an eccentric

  9. Features, Events, and Processes: Disruptive Events

    International Nuclear Information System (INIS)

    The primary purpose of this analysis is to evaluate seismic- and igneous-related features, events, and processes (FEPs). These FEPs represent areas of natural system processes that have the potential to produce disruptive events (DE) that could impact repository performance and are related to the geologic processes of tectonism, structural deformation, seismicity, and igneous activity. Collectively, they are referred to as the DE FEPs. This evaluation determines which of the DE FEPs are excluded from modeling used to support the total system performance assessment for license application (TSPA-LA). The evaluation is based on the data and results presented in supporting analysis reports, model reports, technical information, or corroborative documents that are cited in the individual FEP discussions in Section 6.2 of this analysis report

  10. Endocrine disrupter - estradiol - in Chesapeake Bay tributaries

    Energy Technology Data Exchange (ETDEWEB)

    Dorabawila, Nelum [University of Maryland Eastern Shore, Princess Anne, MD 21853 (United States); Gupta, Gian [University of Maryland Eastern Shore, Princess Anne, MD 21853 (United States)]. E-mail: gcgupta@umes.edu

    2005-04-11

    Exogenous chemicals that interfere with natural hormonal functions are considered endocrine disrupting chemicals (EDCs). Estradiol (17{beta}-estradiol or E2) is the most potent of all xenoestrogens. Induction of vitellogenin (VTG) production in male fish occurs at E2 concentrations as low as 1 ng l{sup -1}. E2 reaches aquatic systems mainly through sewage and animal waste disposal. Surface water samples from ponds, rivers (Wicomico, Manokin and Pocomoke), sewage treatment plants (STPs), and coastal bays (Assawoman, Monie, Chincoteague, and Tangier Sound - Chesapeake Bay) on the Eastern Shore of Maryland were analyzed for E2 using enzyme linked immuno-sorbent assay (ELISA). E2 concentrations in river waters varied between 1.9 and 6.0 ng l{sup -1}. Highest E2 concentrations in river waters were observed immediately downstream of STPs. E2 concentrations in all the coastal bays tested were 2.3-3.2 ng l{sup -1}.

  11. DISRUPTION MANAGEMENT FOR SUPPLY CHAIN COORDINATION WITH EXPONENTIAL DEMAND FUNCTION

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    The coordination problem of a supply chain comprising one supplier and one retailer under market demand disruption is studied in this article. A novel exponential demand function is adopted, and the penalty cost is introduced explicitly to capture the deviation production cost caused by the market demand disruption. The optimal strategies are obtained for different disruption scale under the centralized mode. For the decentralized mode, it is proved that the supply chain can be fully coordinated by adjusting the price discount policy appropriately when disruption occurs. Furthermore, the authors point out that similar results can be established for more general demand functions that represent different market circumstances if certain assumptions are satisfied.

  12. Disruptions in ITER and strategies for their control and mitigation

    Energy Technology Data Exchange (ETDEWEB)

    Lehnen, M., E-mail: michael.lehnen@iter.org [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Aleynikova, K.; Aleynikov, P.B.; Campbell, D.J. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Drewelow, P. [Max-Planck-Institut für Plasmaphysik, Greifswald branch, EURATOM Ass., D-17491 Greifswald (Germany); Eidietis, N.W. [General Atomics, P.O. Box 85608, San Diego, CA 92186-5608 (United States); Gasparyan, Yu. [National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Kashirskoe sh. 31, Moscow 115409 (Russian Federation); Granetz, R.S. [MIT Plasma Science and Fusion Center, Cambridge, MA 02139 (United States); Gribov, Y. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Hartmann, N. [Forschungszentrum Jülich GmbH, Institute of Energy and Climate Research—Plasma Physics, Association EURATOM-FZJ, Trilateral Euregio Cluster, 52425 Jülich (Germany); Hollmann, E.M. [University of California-San Diego, La Jolla, CA 92093 (United States); Izzo, V.A. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Jachmich, S. [Laboratory for Plasma Physics, ERM/KMS, Association EURATOM – Belgian State, B-1000 Brussels (Belgium); Kim, S.-H.; Kočan, M. [ITER Organization, Route de Vinon sur Verdon, 13115 St Paul Lez Durance (France); Koslowski, H.R. [Forschungszentrum Jülich GmbH, Institute of Energy and Climate Research—Plasma Physics, Association EURATOM-FZJ, Trilateral Euregio Cluster, 52425 Jülich (Germany); Kovalenko, D. [SRC RF TRINITI, ul. Pushkovykh, vladenie 12, Troitsk, Moscow 142190 (Russian Federation); Kruezi, U. [CCFE, Culham Science Centre, Abingdon, Oxon, OX14 3DB (United Kingdom); and others

    2015-08-15

    The thermal and electromagnetic loads related to disruptions in ITER are substantial and require careful design of tokamak components to ensure they reach the projected lifetime and to ensure that safety relevant components fulfil their function for the worst foreseen scenarios. The disruption load specifications are the basis for the design process of components like the full-W divertor, the blanket modules and the vacuum vessel and will set the boundary conditions for ITER operations. This paper will give a brief overview on the disruption loads and mitigation strategies for ITER and will discuss the physics basis which is continuously refined through the current disruption R&D programs.

  13. Disruption mitigation experiment with massive gas injection of HT-7

    International Nuclear Information System (INIS)

    Massive gas injection (MGI) is a promising method on disruption mitigation. The working principle of the fast valve for disruption mitigation was introduced. The disruption mitigation experiments by MGI on HT-7 were described. The experiment shows that the impurities radiation is improved by injecting appropriate amount of gas, and the current quench rate is slow down, so the electromagnetic load on the device is mitigated. The experiments show that the fast valve can completely satisfy the requirement of disruption mitigation on HT-7. (authors)

  14. Disruptions in ITER and strategies for their control and mitigation

    International Nuclear Information System (INIS)

    The thermal and electromagnetic loads related to disruptions in ITER are substantial and require careful design of tokamak components to ensure they reach the projected lifetime and to ensure that safety relevant components fulfil their function for the worst foreseen scenarios. The disruption load specifications are the basis for the design process of components like the full-W divertor, the blanket modules and the vacuum vessel and will set the boundary conditions for ITER operations. This paper will give a brief overview on the disruption loads and mitigation strategies for ITER and will discuss the physics basis which is continuously refined through the current disruption R&D programs

  15. A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes

    Science.gov (United States)

    Staes, Katrien; Vandesompele, Jo; Laureys, Geneviève; De Smet, Els; Berx, Geert; Speleman, Frank; van Roy, Frans

    2008-01-01

    The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17)(p36.2;q11.2) may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types. PMID:18493581

  16. A constitutional translocation t(1;17(p36.2;q11.2 in a neuroblastoma patient disrupts the human NBPF1 and ACCN1 genes.

    Directory of Open Access Journals (Sweden)

    Karl Vandepoele

    Full Text Available The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17(p36.2;q11.2 may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types.

  17. Biosensor discovery of thyroxine transport disrupting chemicals

    International Nuclear Information System (INIS)

    Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds

  18. Deletion of 7q33-q35 in a Patient with Intellectual Disability and Dysmorphic Features: Further Characterization of 7q Interstitial Deletion Syndrome

    Directory of Open Access Journals (Sweden)

    Kristen Dilzell

    2015-01-01

    Full Text Available This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome.

  19. A high-throughput method for the detection of homoeologous gene deletions in hexaploid wheat

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    Li Zhongyi

    2010-11-01

    Full Text Available Abstract Background Mutational inactivation of plant genes is an essential tool in gene function studies. Plants with inactivated or deleted genes may also be exploited for crop improvement if such mutations/deletions produce a desirable agronomical and/or quality phenotype. However, the use of mutational gene inactivation/deletion has been impeded in polyploid plant species by genetic redundancy, as polyploids contain multiple copies of the same genes (homoeologous genes encoded by each of the ancestral genomes. Similar to many other crop plants, bread wheat (Triticum aestivum L. is polyploid; specifically allohexaploid possessing three progenitor genomes designated as 'A', 'B', and 'D'. Recently modified TILLING protocols have been developed specifically for mutation detection in wheat. Whilst extremely powerful in detecting single nucleotide changes and small deletions, these methods are not suitable for detecting whole gene deletions. Therefore, high-throughput methods for screening of candidate homoeologous gene deletions are needed for application to wheat populations generated by the use of certain mutagenic agents (e.g. heavy ion irradiation that frequently generate whole-gene deletions. Results To facilitate the screening for specific homoeologous gene deletions in hexaploid wheat, we have developed a TaqMan qPCR-based method that allows high-throughput detection of deletions in homoeologous copies of any gene of interest, provided that sufficient polymorphism (as little as a single nucleotide difference amongst homoeologues exists for specific probe design. We used this method to identify deletions of individual TaPFT1 homoeologues, a wheat orthologue of the disease susceptibility and flowering regulatory gene PFT1 in Arabidopsis. This method was applied to wheat nullisomic-tetrasomic lines as well as other chromosomal deletion lines to locate the TaPFT1 gene to the long arm of chromosome 5. By screening of individual DNA samples from

  20. Genotype-phenotype correlation in 22q11.2 deletion syndrome

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    Michaelovsky Elena

    2012-12-01

    Full Text Available Abstract Background The 22q11.2 deletion syndrome (22q11.2DS is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Methods Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Results Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2% carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted. Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. Conclusions MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms. Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.