WorldWideScience

Sample records for ephx1 slow exon

  1. EPHX1 polymorphisms, COPD and asthma in 47,000 individuals and in meta-analysis

    DEFF Research Database (Denmark)

    Lee, J; Nordestgaard, B G; Dahl, Morten

    2011-01-01

    ,970 controls. The OR for spirometry-defined COPD or COPD hospitalisation did not differ from 1.0 for any of the EPHX1 genotypes or phenotypes overall, or in smokers or nonsmokers separately (p-value for trend 0.18-0.91). Likewise, EPHX1 genotypes or phenotypes did not associate with risk of asthma (p...

  2. Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses.

    Science.gov (United States)

    Chung, Jee-Eun; Lee, Kyung Eun; Chang, Byung Chul; Gwak, Hye Sun

    2018-01-30

    The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses. Copyright © 2017. Published by Elsevier B.V.

  3. Polymorphisms in xenobiotic metabolizing genes (EPHX1, NQO1 and PON1) in lymphoma susceptibility: a case control study

    International Nuclear Information System (INIS)

    Conesa-Zamora, Pablo; Vicente, Vicente; Pérez-Guillermo, Miguel; Ruiz-Cosano, Javier; Torres-Moreno, Daniel; Español, Ignacio; Gutiérrez-Meca, María D; Trujillo-Santos, Javier; Pérez-Ceballos, Elena; González-Conejero, Rocío; Corral, Javier

    2013-01-01

    The interplay between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. EPHX1, NQO1 and PON1 are three genes encoding proteins directly involved in the detoxification of potential carcinogens. We have studied the prevalence of three functional polymorphisms affecting these genes rs1051740 EPHX1, rs1800566 NQO1 and rs662 PON1 in 215 patients with lymphoma and 214 healthy controls. Genotype frequencies for EPHX and NQO1 polymorphisms did not show any correlation with disease. In contrast, the GG genotype in the PON1 polymorphism was found to be strongly associated with the disease (15.3% vs. 4.7%; OR = 3.7 CI (95%): 1.8-7.7; p < 0.001). According to the pathological diagnosis this association was related to follicular (p = 0.004) and diffuse large B-cell (p = 0.016) lymphomas. Despite the fact that further confirmation is needed, this study shows that the PON1 GG genotype in rs662 polymorphism could be a risk factor for B-cell lymphomas

  4. Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1 and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome

    Science.gov (United States)

    Pande, Mala; Amos, Christopher I.; Osterwisch, Daniel R.; Chen, Jinyun; Lynch, Patrick M.; Broaddus, Russell; Frazier, Marsha L.

    2011-01-01

    Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression, likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA = 1.78, 95% CI = 1.16–2.74, P = 0.008; and hazard ratio for TC relative to TT = 1.53, 95% CI = 1.06–2.22, P = 0.02]. Since homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome since they modify the age of colorectal cancer onset by up to 4 years. PMID:18768509

  5. Origins and Impacts of New Mammalian Exons

    Directory of Open Access Journals (Sweden)

    Jason J. Merkin

    2015-03-01

    Full Text Available Mammalian genes are composed of exons, but the evolutionary origins and functions of new internal exons are poorly understood. Here, we analyzed patterns of exon gain using deep cDNA sequencing data from five mammals and one bird, identifying thousands of species- and lineage-specific exons. Most new exons derived from unique rather than repetitive intronic sequence. Unlike exons conserved across mammals, species-specific internal exons were mostly located in 5′ UTRs and alternatively spliced. They were associated with upstream intronic deletions, increased nucleosome occupancy, and RNA polymerase II pausing. Genes containing new internal exons had increased gene expression, but only in tissues in which the exon was included. Increased expression correlated with the level of exon inclusion, promoter proximity, and signatures of cotranscriptional splicing. Altogether, these findings suggest that increased splicing at the 5′ ends of genes enhances expression and that changes in 5′ end splicing alter gene expression between tissues and between species.

  6. Slow briefs: slow food....slow architecture

    OpenAIRE

    Crotch, Joanna

    2012-01-01

    We are moving too fast…fast lives, fast cars, fast food…..and fast architecture. We are caught up in a world that allows no time to stop and think; to appreciate and enjoy all the really important things in our lives. Recent responses to this seemingly unstoppable trend are the growing movements of Slow Food and Cittaslow. Both initiatives are, within their own realms, attempting to reverse speed, homogeny, expediency and globalisation, considering the values of regionality, patience, craft, ...

  7. Identification of protein features encoded by alternative exons using Exon Ontology.

    Science.gov (United States)

    Tranchevent, Léon-Charles; Aubé, Fabien; Dulaurier, Louis; Benoit-Pilven, Clara; Rey, Amandine; Poret, Arnaud; Chautard, Emilie; Mortada, Hussein; Desmet, François-Olivier; Chakrama, Fatima Zahra; Moreno-Garcia, Maira Alejandra; Goillot, Evelyne; Janczarski, Stéphane; Mortreux, Franck; Bourgeois, Cyril F; Auboeuf, Didier

    2017-06-01

    Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological- or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named "Exon Ontology," based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information. © 2017 Tranchevent et al.; Published by Cold Spring Harbor Laboratory Press.

  8. ExonMiner: Web service for analysis of GeneChip Exon array data

    Directory of Open Access Journals (Sweden)

    Imoto Seiya

    2008-11-01

    Full Text Available Abstract Background Some splicing isoform-specific transcriptional regulations are related to disease. Therefore, detection of disease specific splice variations is the first step for finding disease specific transcriptional regulations. Affymetrix Human Exon 1.0 ST Array can measure exon-level expression profiles that are suitable to find differentially expressed exons in genome-wide scale. However, exon array produces massive datasets that are more than we can handle and analyze on personal computer. Results We have developed ExonMiner that is the first all-in-one web service for analysis of exon array data to detect transcripts that have significantly different splicing patterns in two cells, e.g. normal and cancer cells. ExonMiner can perform the following analyses: (1 data normalization, (2 statistical analysis based on two-way ANOVA, (3 finding transcripts with significantly different splice patterns, (4 efficient visualization based on heatmaps and barplots, and (5 meta-analysis to detect exon level biomarkers. We implemented ExonMiner on a supercomputer system in order to perform genome-wide analysis for more than 300,000 transcripts in exon array data, which has the potential to reveal the aberrant splice variations in cancer cells as exon level biomarkers. Conclusion ExonMiner is well suited for analysis of exon array data and does not require any installation of software except for internet browsers. What all users need to do is to access the ExonMiner URL http://ae.hgc.jp/exonminer. Users can analyze full dataset of exon array data within hours by high-level statistical analysis with sound theoretical basis that finds aberrant splice variants as biomarkers.

  9. Targeted Exon Skipping to Correct Exon Duplications in the Dystrophin Gene

    Directory of Open Access Journals (Sweden)

    Kane L Greer

    2014-01-01

    Full Text Available Duchenne muscular dystrophy is a severe muscle-wasting disease caused by mutations in the dystrophin gene that ablate functional protein expression. Although exonic deletions are the most common Duchenne muscular dystrophy lesion, duplications account for 10–15% of reported disease-causing mutations, and exon 2 is the most commonly duplicated exon. Here, we describe the in vitro evaluation of phosphorodiamidate morpholino oligomers coupled to a cell-penetrating peptide and 2′-O-methyl phosphorothioate oligonucleotides, using three distinct strategies to reframe the dystrophin transcript in patient cells carrying an exon 2 duplication. Differences in exon-skipping efficiencies in vitro were observed between oligomer analogues of the same sequence, with the phosphorodiamidate morpholino oligomer coupled to a cell-penetrating peptide proving the most effective. Differences in exon 2 excision efficiency between normal and exon 2 duplication cells, were apparent, indicating that exon context influences oligomer-induced splice switching. Skipping of a single copy of exon 2 was induced in the cells carrying an exon 2 duplication, the simplest strategy to restore the reading frame and generate a normal dystrophin transcript. In contrast, multiexon skipping of exons 2–7 to generate a Becker muscular dystrophy-like dystrophin transcript was more challenging and could only be induced efficiently with the phosphorodiamidate morpholino oligomer chemistry.

  10. Slow Antihydrogen

    International Nuclear Information System (INIS)

    Gabrielse, G.; Speck, A.; Storry, C.H.; Le Sage, D.; Guise, N.; Larochelle, P.C.; Grzonka, D.; Oelert, W.; Schepers, G.; Sefzick, T.; Pittner, H.; Herrmann, M.; Walz, J.; Haensch, T.W.; Comeau, D.; Hessels, E.A.

    2004-01-01

    Slow antihydrogen is now produced by two different production methods. In Method I, large numbers of H atoms are produced during positron-cooling of antiprotons within a nested Penning trap. In a just-demonstrated Method II, lasers control the production of antihydrogen atoms via charge exchange collisions. Field ionization detection makes it possible to probe the internal structure of the antihydrogen atoms being produced - most recently revealing atoms that are too tightly bound to be well described by the guiding center atom approximation. The speed of antihydrogen atoms has recently been measured for the first time. After the requested overview, the recent developments are surveyed

  11. Large exon size does not limit splicing in vivo.

    Science.gov (United States)

    Chen, I T; Chasin, L A

    1994-03-01

    Exon sizes in vertebrate genes are, with a few exceptions, limited to less than 300 bases. It has been proposed that this limitation may derive from the exon definition model of splice site recognition. In this model, a downstream donor site enhances splicing at the upstream acceptor site of the same exon. This enhancement may require contact between factors bound to each end of the exon; an exon size limitation would promote such contact. To test the idea that proximity was required for exon definition, we inserted random DNA fragments from Escherichia coli into a central exon in a three-exon dihydrofolate reductase minigene and tested whether the expanded exons were efficiently spliced. DNA from a plasmid library of expanded minigenes was used to transfect a CHO cell deletion mutant lacking the dhfr locus. PCR analysis of DNA isolated from the pooled stable cotransfectant populations displayed a range of DNA insert sizes from 50 to 1,500 nucleotides. A parallel analysis of the RNA from this population by reverse transcription followed by PCR showed a similar size distribution. Central exons as large as 1,400 bases could be spliced into mRNA. We also tested individual plasmid clones containing exon inserts of defined sizes. The largest exon included in mRNA was 1,200 bases in length, well above the 300-base limit implied by the survey of naturally occurring exons. We conclude that a limitation in exon size is not part of the exon definition mechanism.

  12. Exon - ASTRA | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available switchLanguage; BLAST Search Image Search Home About Archive Update History Data ...ontents Exons in variants Data file File name: astra_exon.zip File URL: ftp://ftp.biosciencedbc.jp/archive/a... About This Database Database Description Download License Update History of This Database Site Policy | Contact Us Exon - ASTRA | LSDB Archive ...

  13. FROM SLOW FOOD TO SLOW TOURISM

    Directory of Open Access Journals (Sweden)

    Bac Dorin Paul

    2014-12-01

    Full Text Available One of the effects of globalization is the faster pace of our lives. This rhythm can be noticed in all aspects of life: travel, work, shopping, etc. and it has serious negative effects. It has become common knowledge that stress and speed generate serious medical issues. Food and eating habits in the modern world have taken their toll on our health. However, some people took a stand and argued for a new kind of lifestyle. It all started in the field of gastronomy, where a new movement emerged – Slow Food, based on the ideas and philosophy of Carlo Petrini. Slow Food represents an important adversary to the concept of fast food, and is promoting local products, enjoyable meals and healthy food. The philosophy of the Slow Food movement developed in several directions: Cittaslow, slow travel and tourism, slow religion and slow money etc. The present paper will account the evolution of the concept and its development during the most recent years. We will present how the philosophy of slow food was applied in all the other fields it reached and some critical points of view. Also we will focus on the presence of the slow movement in Romania, although it is in a very early stage of development. The main objectives of the present paper are: to present the chronological and ideological evolution of the slow movement; to establish a clear separation of slow travel and slow tourism, as many mistake on for the other; to review the presence of the slow movement in Romania. Regarding the research methodology, information was gathered from relevant academic papers and books and also from interviews and discussions with local entrepreneurs. The research is mostly theoretical and empirical, as slow food and slow tourism are emerging research themes in academic circles.

  14. Movement - uncontrolled or slow

    Science.gov (United States)

    Dystonia; Involuntary slow and twisting movements; Choreoathetosis; Leg and arm movements - uncontrollable; Arm and leg movements - uncontrollable; Slow involuntary movements of large muscle groups; Athetoid movements

  15. Optimized Exon-Exon Junction Library and its Application on Rodents' Brain Transcriptome Analysis

    Directory of Open Access Journals (Sweden)

    Tong-Hai Dou

    2017-05-01

    Full Text Available ABSTRACT Background: Alternative splicing (AS, which plays an important role in gene expression and functional regulation, has been analyzed on genome-scale by various bioinformatic approaches based on RNA-seq data. Compared with the huge number of studies on mouse, the AS researches approaching the rat, whose genome is intermedia between mouse and human, were still limited. To enrich the knowledge on AS events in rodents' brain, we perfomed a comprehensive analysis on four transcriptome libraries (mouse cerebrum, mouse cerebellum, rat cerebrum, and rat cerebellum, recruiting high-throughput sequencing technology. An optimized exon-exon junction library approach was introduced to adapt the longer RNA-seq reads and to improve mapping efficiency. Results: In total, 7,106 mouse genes and 2,734 rat genes were differentially expressed between cerebrum and cerebellum, while 7,125 mouse genes and 1,795 rat genes exhibited varieties on transcript variant level. Only half of the differentially expressed exon-exon junctions could be reflected at gene expression level. Functional cluster analysis showed that 32 pathways in mouse and 9 pathways in rat were significantly enriched, and 6 of them were in both. Interestingly, some differentially expressed transcript variants did not show difference on gene expression level, such as PLCβ1 and Kcnma1. Conclusion: Our work provided a case study of a novel exon-exon junction strategy to analyze the expression of genes and isoforms, helping us understand which transcript contributes to the overall expression and further functional change.

  16. Evaluating approaches to find exon chains based on long reads.

    Science.gov (United States)

    Kuosmanen, Anna; Norri, Tuukka; Mäkinen, Veli

    2018-05-01

    Transcript prediction can be modeled as a graph problem where exons are modeled as nodes and reads spanning two or more exons are modeled as exon chains. Pacific Biosciences third-generation sequencing technology produces significantly longer reads than earlier second-generation sequencing technologies, which gives valuable information about longer exon chains in a graph. However, with the high error rates of third-generation sequencing, aligning long reads correctly around the splice sites is a challenging task. Incorrect alignments lead to spurious nodes and arcs in the graph, which in turn lead to incorrect transcript predictions. We survey several approaches to find the exon chains corresponding to long reads in a splicing graph, and experimentally study the performance of these methods using simulated data to allow for sensitivity/precision analysis. Our experiments show that short reads from second-generation sequencing can be used to significantly improve exon chain correctness either by error-correcting the long reads before splicing graph creation, or by using them to create a splicing graph on which the long-read alignments are then projected. We also study the memory and time consumption of various modules, and show that accurate exon chains lead to significantly increased transcript prediction accuracy. The simulated data and in-house scripts used for this article are available at http://www.cs.helsinki.fi/group/gsa/exon-chains/exon-chains-bib.tar.bz2.

  17. Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable - Molecular pathology of mutations in PAH exon 11

    DEFF Research Database (Denmark)

    Heintz, Caroline; Dobrowolski, Steven F.; Andersen, Henriette Skovgaard

    2012-01-01

    as a vulnerable exon and used patient derived lymphoblast cell lines and PAH minigenes to study the molecular defect that impacted pre-mRNA processing. We showed that the c.1144T>C and c.1066-3C>T mutations cause exon 11 skipping, while the c.1139C>T mutation is neutral or slightly beneficial. The c.1144T......In about 20-30% of phenylketonuria (PKU) patients, phenylalanine (Phe) levels can be controlled by cofactor 6R-tetrahydrobiopterin (BH(4)) administration. The phenylalanine hydroxylase (PAH) genotype has a predictive value concerning BH(4)-response and therefore a correct assessment of the mutation...... molecular pathology is important. Mutations that disturb the splicing of exons (e.g. interplay between splice site strength and regulatory sequences like exon splicing enhancers (ESEs)/exon splicing silencers (ESSs)) may cause different severity of PKU. In this study, we identified PAH exon 11...

  18. Naturally occuring nucleosome positioning signals in human exons and introns

    DEFF Research Database (Denmark)

    Baldi, Pierre; Brunak, Søren; Chauvin, Yves

    1996-01-01

    We describe the structural implications of a periodic pattern found in human exons and introns by hidden Markov models. We show that exons (besides the reading frame) have a specific sequential structure in the form of a pattern with triplet consensus non-T(A/T)G, and a minimal periodicity of rou...

  19. Widespread evolutionary conservation of alternatively spliced exons in caenorhabditis

    DEFF Research Database (Denmark)

    Irimia, Manuel; Rukov, Jakob L; Penny, David

    2007-01-01

    Alternative splicing (AS) contributes to increased transcriptome and proteome diversity in various eukaryotic lineages. Previous studies showed low levels of conservation of alternatively spliced (cassette) exons within mammals and within dipterans. We report a strikingly different pattern...... in Caenorhabditis nematodes-more than 92% of cassette exons from Caenorhabditis elegans are conserved in Caenorhabditis briggsae and/or Caenorhabditis remanei. High levels of conservation extend to minor-form exons (present in a minority of transcripts) and are particularly pronounced for exons showing complex...... patterns of splicing. The functionality of the vast majority of cassette exons is underscored by various other features. We suggest that differences in conservation between lineages reflect differences in levels of functionality and further suggest that these differences are due to differences in intron...

  20. Too slow, for Milton

    OpenAIRE

    Armstrong, N.

    2011-01-01

    Too slow, for Milton was written in 2011, as part of a memorial project for Milton Babbitt. The piece borrows harmonies from Babbitt's Composition for 12 Instruments (harmonies which Babbitt had in turn borrowed from Schoenberg's Ode to Napoleon), but unfolds them as part of a musical texture characterised by repetition, resonance, and a slow rate of change. As Babbitt once told me that my music was 'too slow', this seemed an appropriately obstinate form of homage.

  1. 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.

  2. Exon silencing by UAGG motifs in response to neuronal excitation.

    Directory of Open Access Journals (Sweden)

    Ping An

    2007-02-01

    Full Text Available Alternative pre-mRNA splicing plays fundamental roles in neurons by generating functional diversity in proteins associated with the communication and connectivity of the synapse. The CI cassette of the NMDA R1 receptor is one of a variety of exons that show an increase in exon skipping in response to cell excitation, but the molecular nature of this splicing responsiveness is not yet understood. Here we investigate the molecular basis for the induced changes in splicing of the CI cassette exon in primary rat cortical cultures in response to KCl-induced depolarization using an expression assay with a tight neuron-specific readout. In this system, exon silencing in response to neuronal excitation was mediated by multiple UAGG-type silencing motifs, and transfer of the motifs to a constitutive exon conferred a similar responsiveness by gain of function. Biochemical analysis of protein binding to UAGG motifs in extracts prepared from treated and mock-treated cortical cultures showed an increase in nuclear hnRNP A1-RNA binding activity in parallel with excitation. Evidence for the role of the NMDA receptor and calcium signaling in the induced splicing response was shown by the use of specific antagonists, as well as cell-permeable inhibitors of signaling pathways. Finally, a wider role for exon-skipping responsiveness is shown to involve additional exons with UAGG-related silencing motifs, and transcripts involved in synaptic functions. These results suggest that, at the post-transcriptional level, excitable exons such as the CI cassette may be involved in strategies by which neurons mount adaptive responses to hyperstimulation.

  3. Very slow neutrons

    International Nuclear Information System (INIS)

    Frank, A.

    1983-01-01

    The history is briefly presented of the research so far of very slow neutrons and their basic properties are explained. The methods are described of obtaining very slow neutrons and the problems of their preservation are discussed. The existence of very slow neutrons makes it possible to perform experiments which may deepen the knowledge of the fundamental properties of neutrons. Their wavelength approximates that of visible radiation. The possibilities and use are discussed of neutron optical systems (neutron microscope) which could be an effective instrument for the study of the detailed arrangement, especially of organic substances. (B.S.)

  4. Transformer Industry Productivity Slows.

    Science.gov (United States)

    Otto, Phyllis Flohr

    1981-01-01

    Annual productivity increases averaged 2.4 percent during 1963-79, slowing since 1972 to 1.5 percent; computer-assisted design and product standardization aided growth in output per employee-hour. (Author)

  5. First Exon Length Controls Active Chromatin Signatures and Transcription

    Directory of Open Access Journals (Sweden)

    Nicole I. Bieberstein

    2012-07-01

    Full Text Available Here, we explore the role of splicing in transcription, employing both genome-wide analysis of human ChIP-seq data and experimental manipulation of exon-intron organization in transgenic cell lines. We show that the activating histone modifications H3K4me3 and H3K9ac map specifically to first exon-intron boundaries. This is surprising, because these marks help recruit general transcription factors (GTFs to promoters. In genes with long first exons, promoter-proximal levels of H3K4me3 and H3K9ac are greatly reduced; consequently, GTFs and RNA polymerase II are low at transcription start sites (TSSs and exhibit a second, promoter-distal peak from which transcription also initiates. In contrast, short first exons lead to increased H3K4me3 and H3K9ac at promoters, higher expression levels, accuracy in TSS usage, and a lower frequency of antisense transcription. Therefore, first exon length is predictive for gene activity. Finally, splicing inhibition and intron deletion reduce H3K4me3 levels and transcriptional output. Thus, gene architecture and splicing determines transcription quantity and quality as well as chromatin signatures.

  6. Intron Retention and TE Exonization Events in ZRANB2

    Directory of Open Access Journals (Sweden)

    Sang-Je Park

    2012-01-01

    Full Text Available The Zinc finger, RAN-binding domain-containing protein 2 (ZRANB2, contains arginine/serine-rich (RS domains that mediate its function in the regulation of alternative splicing. The ZRANB2 gene contains 2 LINE elements (L3b, Plat_L3 between the 9th and 10th exons. We identified the exonization event of a LINE element (Plat_L3. Using genomic PCR, RT-PCR amplification, and sequencing of primate DNA and RNA samples, we analyzed the evolutionary features of ZRANB2 transcripts. The results indicated that 2 of the LINE elements were integrated in human and all of the tested primate samples (hominoids: 3 species; Old World monkey: 8 species; New World monkey: 6 species; prosimian: 1 species. Human, rhesus monkey, crab-eating monkey, African-green monkey, and marmoset harbor the exon derived from LINE element (Plat_L3. RT-PCR amplification revealed the long transcripts and their differential expression patterns. Intriguingly, these long transcripts were abundantly expressed in Old World monkey lineages (rhesus, crab-eating, and African-green monkeys and were expressed via intron retention (IR. Thus, the ZRANB2 gene produces 3 transcript variants in which the Cterminus varies by transposable elements (TEs exonization and IR mechanisms. Therefore, ZRANB2 is valuable for investigating the evolutionary mechanisms of TE exonization and IR during primate evolution.

  7. Modulating Calcium Signals to Boost AON Exon Skipping for DMD

    Science.gov (United States)

    2017-10-01

    for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT AON-mediated exon skipping is currently advancing as therapy for DMD...9 9. Appendices…………………………………………………………… 9 1 1. INTRODUCTION AON-AON-mediated exon skipping is currently advancing as therapy for DMD...CDMD inter-group meetings, an annual retreat, and hosting and attending seminars. While not a stated objective of this grant, trainee career

  8. SPS slow extraction septa

    CERN Multimedia

    CERN PhotoLab

    1979-01-01

    SPS long straight section (LSS) with a series of 5 septum tanks for slow extraction (view in the direction of the proton beam). There are 2 of these: in LSS2, towards the N-Area; in LSS6 towards the W-Area. See also Annual Report 1975, p.175.

  9. AGS slow extraction improvements

    International Nuclear Information System (INIS)

    Glenn, J.W.; Smith, G.A.; Sandberg, J.N.; Repeta, L.; Weisberg, H.

    1979-01-01

    Improvement of the straightness of the F5 copper septum increased the AGS slow extraction efficiency from approx. 80% to approx. 90%. Installation of an electrostatic septum at H2O, 24 betatron wavelengths upstream of F5, further improved the extraction efficiency to approx. 97%

  10. PF slow positron source

    International Nuclear Information System (INIS)

    Shirakawa, A.; Enomoto, A.; Kurihara, T.

    1993-01-01

    A new slow-positron source is under construction at the Photon Factory. Positrons are produced by bombarding a tantalum rod with high-energy electrons; they are moderated in multiple tungsten vanes. We report here the present status of this project. (author)

  11. Increased frequency of co-existing JAK2 exon-12 or MPL exon-10 mutations in patients with low JAK2(V617F) allelic burden.

    Science.gov (United States)

    Nussenzveig, Roberto H; Pham, Ha T; Perkins, Sherrie L; Prchal, Josef T; Agarwal, Archana M; Salama, Mohamed E

    2016-01-01

    The frequency of co-existing JAK2(V617F)/MPL and JAK2(V617F)/JAK2 exon-12 mutations has not been previously investigated in MPNs. Poor survival was reported in primary myelofibrosis with low JAK2(V617F) allelic burden. However, mutational status of JAK2 exon-12 or MPL were not reported in these patients. This study developed a cost-effective multiplex high resolution melt assay that screens for mutations in JAK2 gene exons-12 and -14 ((V617F)) and MPL gene exon-10. Co-existing mutations with JAK2(V617F) were detected in 2.9% (6/208; two JAK2 exon-12 and four MPL exon-10) patient specimens with known JAK2(V617F) (allelic-burden range: 0.1-96.8%). Co-existing mutations were detected in specimens with MPL exon-10 mutation should be pursued.

  12. Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    van Ommen Gert-Jan B

    2007-07-01

    Full Text Available Abstract Background Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD. Using antisense oligonucleotides (AONs targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. Following proof of concept in cultured muscle cells from patients with various deletions and point mutations, we now focus on single and multiple exon duplications. These mutations are in principle ideal targets for this approach since the specific skipping of duplicated exons would generate original, full-length transcripts. Methods Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed. Results For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62, by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons. Conclusion The correction of DMD duplications by exon skipping depends on the specific exons targeted. Its options vary from the ideal one, restoring for the first time the true, wild type dystrophin, to requiring more 'classical' skipping strategies, while the correction of multi-exon deletions may need the design of tailored approaches.

  13. Cloud-based adaptive exon prediction for DNA analysis.

    Science.gov (United States)

    Putluri, Srinivasareddy; Zia Ur Rahman, Md; Fathima, Shaik Yasmeen

    2018-02-01

    Cloud computing offers significant research and economic benefits to healthcare organisations. Cloud services provide a safe place for storing and managing large amounts of such sensitive data. Under conventional flow of gene information, gene sequence laboratories send out raw and inferred information via Internet to several sequence libraries. DNA sequencing storage costs will be minimised by use of cloud service. In this study, the authors put forward a novel genomic informatics system using Amazon Cloud Services, where genomic sequence information is stored and accessed for processing. True identification of exon regions in a DNA sequence is a key task in bioinformatics, which helps in disease identification and design drugs. Three base periodicity property of exons forms the basis of all exon identification techniques. Adaptive signal processing techniques found to be promising in comparison with several other methods. Several adaptive exon predictors (AEPs) are developed using variable normalised least mean square and its maximum normalised variants to reduce computational complexity. Finally, performance evaluation of various AEPs is done based on measures such as sensitivity, specificity and precision using various standard genomic datasets taken from National Center for Biotechnology Information genomic sequence database.

  14. Investigation of ANGPTL3 expression, exon sequence and promotor ...

    African Journals Online (AJOL)

    like proteins, has been demonstrated to affect lipid metabolism by inhibiting the activity of lipoprotein lipase (LPL). Objective: To compare the ANGPTL3 mRNA and protein expression, exon mutation and promoter district CpG island methylation ...

  15. Origin of introns by 'intronization' of exonic sequences

    DEFF Research Database (Denmark)

    Irimia, Manuel; Rukov, Jakob Lewin; Penny, David

    2008-01-01

    The mechanisms of spliceosomal intron creation have proved elusive. Here we describe a new mechanism: the recruitment of internal exonic sequences ('intronization') in Caenorhabditis species. The numbers of intronization events and introns gained by other mechanisms are similar, suggesting that i...

  16. Translational and Regulatory Challenges for Exon Skipping Therapies

    NARCIS (Netherlands)

    Aartsma-Rus, Annemieke; Ferlini, Alessandra; Goemans, Nathalie; Pasmooij, Anna M. G.; Wells, Dominic J.; Bushby, Katerine; Vroom, Elizabeth; Balabanov, Pavel

    2014-01-01

    Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and

  17. Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD)

    DEFF Research Database (Denmark)

    Brolin, Camilla; Shiraishi, Takehiko

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the dystrophin gene (DMD) that result in the absence of essential muscle protein dystrophin. Among many different approaches for DMD treatment, exon skipping, mediated by antisense oligonucleotides, is one of the most...

  18. Slow wave cyclotron maser

    International Nuclear Information System (INIS)

    Kho, T.H.; Lin, A.T.

    1988-01-01

    Cyclotron masers such as Gyrotrons and the Autoresonance Masers, are fast wave devices: the electromagnetic wave's phase velocity v rho , is greater than the electron beam velocity, v b . To be able to convert the beam kinetic energy into radiation in these devices the beam must have an initial transverse momentum, usually obtained by propagating the beam through a transverse wiggler magnet, or along a nonuniform guide magnetic field before entry into the interaction region. Either process introduces a significant amount of thermal spread in the beam which degrades the performance of the maser. However, if the wave phase velocity v rho v b , the beam kinetic energy can be converted directly into radiation without the requirement of an initial transverse beam momentum, making a slow wave cyclotron maser a potentially simpler and more compact device. The authors present the linear and nonlinear physics of the slow wave cyclotron maser and examine its potential for practical application

  19. Slow-transit Constipation.

    Science.gov (United States)

    Bharucha, Adil E.; Philips, Sidney F.

    2001-08-01

    Idiopathic slow-transit constipation is a clinical syndrome predominantly affecting women, characterized by intractable constipation and delayed colonic transit. This syndrome is attributed to disordered colonic motor function. The disorder spans a spectrum of variable severity, ranging from patients who have relatively mild delays in transit but are otherwise indistinguishable from irritable bowel syndrome to patients with colonic inertia or chronic megacolon. The diagnosis is made after excluding colonic obstruction, metabolic disorders (hypothyroidism, hypercalcemia), drug-induced constipation, and pelvic floor dysfunction (as discussed by Wald ). Most patients are treated with one or more pharmacologic agents, including dietary fiber supplementation, saline laxatives (milk of magnesia), osmotic agents (lactulose, sorbitol, and polyethylene glycol 3350), and stimulant laxatives (bisacodyl and glycerol). A subtotal colectomy is effective and occasionally is indicated for patients with medically refractory, severe slow-transit constipation, provided pelvic floor dysfunction has been excluded or treated.

  20. The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Shazia Mahamdallie

    2017-05-01

    Full Text Available Detection of deletions and duplications of whole exons (exon CNVs is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly-available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel together with Multiplex Ligation-dependent Probe Amplification (MLPA results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA under the accession number EGAS00001002428.

  1. Differential GC Content between Exons and Introns Establishes Distinct Strategies of Splice-Site Recognition

    Directory of Open Access Journals (Sweden)

    Maayan Amit

    2012-05-01

    Full Text Available During evolution segments of homeothermic genomes underwent a GC content increase. Our analyses reveal that two exon-intron architectures have evolved from an ancestral state of low GC content exons flanked by short introns with a lower GC content. One group underwent a GC content elevation that abolished the differential exon-intron GC content, with introns remaining short. The other group retained the overall low GC content as well as the differential exon-intron GC content, and is associated with longer introns. We show that differential exon-intron GC content regulates exon inclusion level in this group, in which disease-associated mutations often lead to exon skipping. This group's exons also display higher nucleosome occupancy compared to flanking introns and exons of the other group, thus “marking” them for spliceosomal recognition. Collectively, our results reveal that differential exon-intron GC content is a previously unidentified determinant of exon selection and argue that the two GC content architectures reflect the two mechanisms by which splicing signals are recognized: exon definition and intron definition.

  2. THE EXON 5, 6, 7, 8 OF P53 MUTATIONS IN ORAL SQUAMOUS CELLS CARCINOMA

    Directory of Open Access Journals (Sweden)

    Retno P Rahayu

    2012-04-01

    Full Text Available Genetic instability may underlie the etiology of multistep carcinogenesis. The altered p53 gene observed in tumors may represent the expression of such instability and may allow the accumulation of other gene alterations caused by multiple mechanism. p53 gene is the guardian of the genome, that is why we pay more attention to this gene. In this study, we evaluated the significance of p53 mutation in 55 patient with oral squamous carcinoma. Thirty among them underwent well-differentiated carcinoma, while the remaining 25 patients underwent poorly differentiated carcinoma. The mutations were detected by PCR-SSCP (Single strand Conformational Polymorphism analysis in the region between exon 5 and exon 8. The results indicated that the p53 mutation in exon 5 (40%, exon 6 (28%, exon 7 (24% and exon 8 (8% were associated with poorly differentiated carcinoma, whereas mutation in exon 5 (10%, exon 6 (30%, exon 7 (40% and exon 8 (20% were associated with well-differentiated carcinoma. These observations suggest that p53 mutation in exon 5, 6, and 7 have strong correlation with poorly differentiated in oral squamous carcinoma while well-differentiated level was related with mutation in exon 6,7 and 8.

  3. Alternative splicing of mutually exclusive exons--a review.

    Science.gov (United States)

    Pohl, Martin; Bortfeldt, Ralf H; Grützmann, Konrad; Schuster, Stefan

    2013-10-01

    Alternative splicing (AS) of pre-mRNAs in higher eukaryotes and several viruses is one major source of protein diversity. Usually, the following major subtypes of AS are distinguished: exon skipping, intron retention, and alternative 3' and 5' splice sites. Moreover, mutually exclusive exons (MXEs) represent a rare subtype. In the splicing of MXEs, two (or more) splicing events are not independent anymore, but are executed or disabled in a coordinated manner. In this review, several bioinformatics approaches for analyzing MXEs are presented and discussed. In particular, we revisit suitable definitions and nomenclatures, and bioinformatics tools for finding MXEs, adjacent and non-adjacent MXEs, clustered and grouped MXEs. Moreover, the molecular mechanisms for splicing MXEs proposed in the literature are reviewed and discussed. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Multiplex amplification of large sets of human exons.

    Science.gov (United States)

    Porreca, Gregory J; Zhang, Kun; Li, Jin Billy; Xie, Bin; Austin, Derek; Vassallo, Sara L; LeProust, Emily M; Peck, Bill J; Emig, Christopher J; Dahl, Fredrik; Gao, Yuan; Church, George M; Shendure, Jay

    2007-11-01

    A new generation of technologies is poised to reduce DNA sequencing costs by several orders of magnitude. But our ability to fully leverage the power of these technologies is crippled by the absence of suitable 'front-end' methods for isolating complex subsets of a mammalian genome at a scale that matches the throughput at which these platforms will routinely operate. We show that targeting oligonucleotides released from programmable microarrays can be used to capture and amplify approximately 10,000 human exons in a single multiplex reaction. Additionally, we show integration of this protocol with ultra-high-throughput sequencing for targeted variation discovery. Although the multiplex capture reaction is highly specific, we found that nonuniform capture is a key issue that will need to be resolved by additional optimization. We anticipate that highly multiplexed methods for targeted amplification will enable the comprehensive resequencing of human exons at a fraction of the cost of whole-genome resequencing.

  5. Multiple splicing defects in an intronic false exon.

    Science.gov (United States)

    Sun, H; Chasin, L A

    2000-09-01

    Splice site consensus sequences alone are insufficient to dictate the recognition of real constitutive splice sites within the typically large transcripts of higher eukaryotes, and large numbers of pseudoexons flanked by pseudosplice sites with good matches to the consensus sequences can be easily designated. In an attempt to identify elements that prevent pseudoexon splicing, we have systematically altered known splicing signals, as well as immediately adjacent flanking sequences, of an arbitrarily chosen pseudoexon from intron 1 of the human hprt gene. The substitution of a 5' splice site that perfectly matches the 5' consensus combined with mutation to match the CAG/G sequence of the 3' consensus failed to get this model pseudoexon included as the central exon in a dhfr minigene context. Provision of a real 3' splice site and a consensus 5' splice site and removal of an upstream inhibitory sequence were necessary and sufficient to confer splicing on the pseudoexon. This activated context also supported the splicing of a second pseudoexon sequence containing no apparent enhancer. Thus, both the 5' splice site sequence and the polypyrimidine tract of the pseudoexon are defective despite their good agreement with the consensus. On the other hand, the pseudoexon body did not exert a negative influence on splicing. The introduction into the pseudoexon of a sequence selected for binding to ASF/SF2 or its replacement with beta-globin exon 2 only partially reversed the effect of the upstream negative element and the defective polypyrimidine tract. These results support the idea that exon-bridging enhancers are not a prerequisite for constitutive exon definition and suggest that intrinsically defective splice sites and negative elements play important roles in distinguishing the real splicing signal from the vast number of false splicing signals.

  6. Translational and regulatory challenges for exon skipping therapies.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Ferlini, Alessandra; Goemans, Nathalie; Pasmooij, Anna M G; Wells, Dominic J; Bushby, Katerine; Vroom, Elizabeth; Balabanov, Pavel

    2014-10-01

    Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.

  7. Efficient use of a translation start codon in BDNF exon I.

    Science.gov (United States)

    Koppel, Indrek; Tuvikene, Jürgen; Lekk, Ingrid; Timmusk, Tõnis

    2015-09-01

    The brain-derived neurotrophic factor (BDNF) gene contains a number of 5' exons alternatively spliced with a common 3' exon. BDNF protein is synthesized from alternative transcripts as a prepro-precursor encoded by the common 3' exon IX, which has a translation start site 21 bp downstream of the splicing site. BDNF mRNAs containing exon I are an exception to this arrangement as the last three nucleotides of this exon constitute an in-frame AUG. Here, we show that this AUG is efficiently used for translation initiation in PC12 cells and cultured cortical neurons. Use of exon I-specific AUG produces higher levels of BDNF protein than use of the common translation start site, resulting from a higher translation rate. No differences in protein degradation, constitutive or regulated secretion were detected between BDNF isoforms with alternative 5' termini. As the BDNF promoter preceding exon I is known to be highly regulated by neuronal activity, our results suggest that the function of this translation start site may be efficient stimulus-dependent synthesis of BDNF protein. The brain-derived neurotrophic factor (BDNF) gene contains multiple untranslated 5' exons alternatively spliced to one common protein-coding 3' exon. However, exon I contains an in-frame ATG in a favorable translation context. Here, we show that use of this ATG is associated with more efficient protein synthesis than the commonly used ATG in exon IX. © 2015 International Society for Neurochemistry.

  8. MET amplification, expression, and exon 14 mutations in colorectal adenocarcinoma.

    Science.gov (United States)

    Zhang, Meng; Li, Guichao; Sun, Xiangjie; Ni, Shujuan; Tan, Cong; Xu, Midie; Huang, Dan; Ren, Fei; Li, Dawei; Wei, Ping; Du, Xiang

    2018-04-08

    MET amplification, expression, and splice mutations at exon 14 result in dysregulation of the MET signaling pathway. The aim of this study was to identify the relationship between MET amplification, protein or mRNA expression, and mutations in colorectal cancer (CRC). MET immunohistochemistry (IHC) was used for MET protein expression analysis and fluorescence in situ hybridization (FISH) was used for MET amplification detection. Both analyses were performed in tissue microarrays (TMA) containing 294 of colorectal adenocarcinoma tissue samples and 131 samples of adjacent normal epithelial tissue. MET mRNA expression was examined by real-time quantitative polymerase chain reaction (qRT-PCR) in 72 fresh colorectal adenocarcinoma tissue samples and adjacent normal colon tissue. PCR sequencing was performed to screen for MET exon 14 splice mutations in 59 fresh CRC tissue samples. Our results showed that MET protein expression was higher in colorectal tumor tissue than in adjacent normal intestinal epithelium. Positive MET protein expression was associated with significantly poorer overall survival (OS) and disease-free survival (DFS). Multivariate analysis revealed that positive MET protein expression was an independent risk factor for DFS, but not for OS. MET mRNA expression was upregulated in tumor tissues compared with the adjacent normal tissues. The incidence of MET amplification was 4.4%. None of the patients was positive for MET mutation. Collectively, MET was overexpressed in colorectal adenocarcinoma, and its positive protein expression predicted a poorer outcome in CRC patients. Furthermore, according to our results, MET amplification and 14 exon mutation are extremely rare events in colorectal adenocarcinoma. Copyright © 2018. Published by Elsevier Inc.

  9. Targeted exon sequencing in Usher syndrome type I.

    Science.gov (United States)

    Bujakowska, Kinga M; Consugar, Mark; Place, Emily; Harper, Shyana; Lena, Jaclyn; Taub, Daniel G; White, Joseph; Navarro-Gomez, Daniel; Weigel DiFranco, Carol; Farkas, Michael H; Gai, Xiaowu; Berson, Eliot L; Pierce, Eric A

    2014-12-02

    Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands. The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis. With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease-causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits. We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  10. Reversible optic neuropathy with OPA1 exon 5b mutation

    DEFF Research Database (Denmark)

    Cornille, K.; Milea, D.; Amati-Bonneau, P.

    2008-01-01

    A new c.740G>A (R247H) mutation in OPA1 alternate spliced exon 5b was found in a patient presenting with bilateral optic neuropathy followed by partial, spontaneous visual recovery. R247H fibroblasts from the patient and his unaffected father presented unusual highly tubular mitochondrial network......, significant increased susceptibility to apoptosis, oxidative phosphorylation uncoupling, and altered OPA1 protein profile, supporting the pathogenicity of this mutation. These results suggest that the clinical spectrum of the OPA1-associated optic neuropathies may be larger than previously described...

  11. Coaxial slow source

    International Nuclear Information System (INIS)

    Brooks, R.D.; Jarboe, T.R.

    1990-01-01

    Field reversed configurations (FRCs) are a class of compact toroid with not toroidal field. The field reversed theta pinch technique has been successfully used for formation of FRCs since their inception in 1958. In this method an initial bias field is produced. After ionization of the fill gas, the current in the coil is rapidly reversed producing the radial implosion of a current sheath. At the ends of the coil the reversed field lines rapidly tear and reconnect with the bias field lines until no more bias flux remains. At this point, vacuum reversed field accumulates around the configuration which contracts axially until an equilibrium is reached. When extrapolating the use of such a technique to reactor size plasmas two main shortcomings are found. First, the initial bias field, and hence flux in a given device, which can be reconnected to form the configuration is limited from above by destructive axial dynamics. Second, the voltages required to produce rapid current reversal in the coil are very large. Clearly, a low voltage formation technique without limitations on flux addition is desirable. The Coaxial Slow Source (CSS) device was designed to meet this need. It has two coaxial theta pinch coils. Coaxial coil geometry allows for the addition of as much magnetic flux to the annular plasma between them as can be generated inside the inner coil. Furthermore the device can be operated at charging voltages less than 10 kV and on resistive diffusion, rather than implosive time scales. The inner coil is a novel, concentric, helical design so as to allow it to be cantilevered on one end to permit translation of the plasma. Following translation off the inner coil the Annular Field Reversed Configuration would be re-formed as a true FRC. In this paper we investigate the formation process in the new parallel configuration., CSSP, in which the inner and outer coils are connected in parallel to the main capacitor bank

  12. Genomic V exons from whole genome shotgun data in reptiles.

    Science.gov (United States)

    Olivieri, D N; von Haeften, B; Sánchez-Espinel, C; Faro, J; Gambón-Deza, F

    2014-08-01

    Reptiles and mammals diverged over 300 million years ago, creating two parallel evolutionary lineages amongst terrestrial vertebrates. In reptiles, two main evolutionary lines emerged: one gave rise to Squamata, while the other gave rise to Testudines, Crocodylia, and Aves. In this study, we determined the genomic variable (V) exons from whole genome shotgun sequencing (WGS) data in reptiles corresponding to the three main immunoglobulin (IG) loci and the four main T cell receptor (TR) loci. We show that Squamata lack the TRG and TRD genes, and snakes lack the IGKV genes. In representative species of Testudines and Crocodylia, the seven major IG and TR loci are maintained. As in mammals, genes of the IG loci can be grouped into well-defined IMGT clans through a multi-species phylogenetic analysis. We show that the reptilian IGHV and IGLV genes are distributed amongst the established mammalian clans, while their IGKV genes are found within a single clan, nearly exclusive from the mammalian sequences. The reptilian and mammalian TRAV genes cluster into six common evolutionary clades (since IMGT clans have not been defined for TR). In contrast, the reptilian TRBV genes cluster into three clades, which have few mammalian members. In this locus, the V exon sequences from mammals appear to have undergone different evolutionary diversification processes that occurred outside these shared reptilian clans. These sequences can be obtained in a freely available public repository (http://vgenerepertoire.org).

  13. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.

    Science.gov (United States)

    Poulter, James A; Murillo, Gina; Brookes, Steven J; Smith, Claire E L; Parry, David A; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-10-15

    Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid. © The Author 2014. Published by Oxford University Press.

  14. Slow Tourism: Exploring the discourses

    Directory of Open Access Journals (Sweden)

    J. Guiver

    2016-05-01

    Full Text Available ‘Slow travel’ and ‘slow tourism’ are relatively new, but contested, concepts. This paper examines the meanings ascribed to them in the academic literature and websites targeted at potential tourists. It finds concurrence on aspects of savouring time at the destination and investing time to appreciate the locality, its people, history, culture and products, but detects different emphases. The academic literature stresses the benefits to the destination and global sustainability, while the websites focus on the personal benefits and ways of becoming a ‘slow tourist’. Food and drink epitomise the immersion in and absorption of the destination and the multi-dimensional tourism experience, contrasted with the superficiality of mainstream tourism. The paper discusses whether tourists practising slow tourism without using the label are slow tourists or not.

  15. Lex-SVM: exploring the potential of exon expression profiling for disease classification.

    Science.gov (United States)

    Yuan, Xiongying; Zhao, Yi; Liu, Changning; Bu, Dongbo

    2011-04-01

    Exon expression profiling technologies, including exon arrays and RNA-Seq, measure the abundance of every exon in a gene. Compared with gene expression profiling technologies like 3' array, exon expression profiling technologies could detect alterations in both transcription and alternative splicing, therefore they are expected to be more sensitive in diagnosis. However, exon expression profiling also brings higher dimension, more redundancy, and significant correlation among features. Ignoring the correlation structure among exons of a gene, a popular classification method like L1-SVM selects exons individually from each gene and thus is vulnerable to noise. To overcome this limitation, we present in this paper a new variant of SVM named Lex-SVM to incorporate correlation structure among exons and known splicing patterns to promote classification performance. Specifically, we construct a new norm, ex-norm, including our prior knowledge on exon correlation structure to regularize the coefficients of a linear SVM. Lex-SVM can be solved efficiently using standard linear programming techniques. The advantage of Lex-SVM is that it can select features group-wisely, force features in a subgroup to take equal weihts and exclude the features that contradict the majority in the subgroup. Experimental results suggest that on exon expression profile, Lex-SVM is more accurate than existing methods. Lex-SVM also generates a more compact model and selects genes more consistently in cross-validation. Unlike L1-SVM selecting only one exon in a gene, Lex-SVM assigns equal weights to as many exons in a gene as possible, lending itself easier for further interpretation.

  16. Biased exonization of transposed elements in duplicated genes: A lesson from the TIF-IA gene

    Directory of Open Access Journals (Sweden)

    Shomron Noam

    2007-11-01

    Full Text Available Abstract Background Gene duplication and exonization of intronic transposed elements are two mechanisms that enhance genomic diversity. We examined whether there is less selection against exonization of transposed elements in duplicated genes than in single-copy genes. Results Genome-wide analysis of exonization of transposed elements revealed a higher rate of exonization within duplicated genes relative to single-copy genes. The gene for TIF-IA, an RNA polymerase I transcription initiation factor, underwent a humanoid-specific triplication, all three copies of the gene are active transcriptionally, although only one copy retains the ability to generate the TIF-IA protein. Prior to TIF-IA triplication, an Alu element was inserted into the first intron. In one of the non-protein coding copies, this Alu is exonized. We identified a single point mutation leading to exonization in one of the gene duplicates. When this mutation was introduced into the TIF-IA coding copy, exonization was activated and the level of the protein-coding mRNA was reduced substantially. A very low level of exonization was detected in normal human cells. However, this exonization was abundant in most leukemia cell lines evaluated, although the genomic sequence is unchanged in these cancerous cells compared to normal cells. Conclusion The definition of the Alu element within the TIF-IA gene as an exon is restricted to certain types of cancers; the element is not exonized in normal human cells. These results further our understanding of the delicate interplay between gene duplication and alternative splicing and of the molecular evolutionary mechanisms leading to genetic innovations. This implies the existence of purifying selection against exonization in single copy genes, with duplicate genes free from such constrains.

  17. Characterization of novel RS1 exonic deletions in juvenile X-linked retinoschisis.

    Science.gov (United States)

    D'Souza, Leera; Cukras, Catherine; Antolik, Christian; Craig, Candice; Lee, Ji-Yun; He, Hong; Li, Shibo; Smaoui, Nizar; Hejtmancik, James F; Sieving, Paul A; Wang, Xinjing

    2013-01-01

    X-linked juvenile retinoschisis (XLRS) is a vitreoretinal dystrophy characterized by schisis (splitting) of the inner layers of the neuroretina. Mutations within the retinoschisis (RS1) gene are responsible for this disease. The mutation spectrum consists of amino acid substitutions, splice site variations, small indels, and larger genomic deletions. Clinically, genomic deletions are rarely reported. Here, we characterize two novel full exonic deletions: one encompassing exon 1 and the other spanning exons 4-5 of the RS1 gene. We also report the clinical findings in these patients with XLRS with two different exonic deletions. Unrelated XLRS men and boys and their mothers (if available) were enrolled for molecular genetics evaluation. The patients also underwent ophthalmologic examination and in some cases electroretinogram (ERG) recording. All the exons and the flanking intronic regions of the RS1 gene were analyzed with direct sequencing. Two patients with exonic deletions were further evaluated with array comparative genomic hybridization to define the scope of the genomic aberrations. After the deleted genomic region was identified, primer walking followed by direct sequencing was used to determine the exact breakpoints. Two novel exonic deletions of the RS1 gene were identified: one including exon 1 and the other spanning exons 4 and 5. The exon 1 deletion extends from the 5' region of the RS1 gene (including the promoter) through intron 1 (c.(-35)-1723_c.51+2664del4472). The exon 4-5 deletion spans introns 3 to intron 5 (c.185-1020_c.522+1844del5764). Here we report two novel exonic deletions within the RS1 gene locus. We have also described the clinical presentations and hypothesized the genomic mechanisms underlying these schisis phenotypes.

  18. Exonic variants associated with development of aspirin exacerbated respiratory diseases.

    Directory of Open Access Journals (Sweden)

    Seung-Woo Shin

    Full Text Available Aspirin-exacerbated respiratory disease (AERD is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA, and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1 were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC of the receiver operating characteristic (ROC curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10-8 in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954 showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21, with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be "probably damaging" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

  19. Exon microarray analysis of human dorsolateral prefrontal cortex in alcoholism.

    Science.gov (United States)

    Manzardo, Ann M; Gunewardena, Sumedha; Wang, Kun; Butler, Merlin G

    2014-06-01

    Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN), and signaling (e.g., RASGRP3, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease and development including cellular assembly and organization impacting on psychological disorders. Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation, and signaling that targets white matter of the brain. Copyright © 2014 by the Research Society on Alcoholism.

  20. The effects of multiple features of alternatively spliced exons on the KA/KS ratio test

    Directory of Open Access Journals (Sweden)

    Chen Feng-Chi

    2006-05-01

    Full Text Available Abstract Background The evolution of alternatively spliced exons (ASEs is of primary interest because these exons are suggested to be a major source of functional diversity of proteins. Many exon features have been suggested to affect the evolution of ASEs. However, previous studies have relied on the KA/KS ratio test without taking into consideration information sufficiency (i.e., exon length > 75 bp, cross-species divergence > 5% of the studied exons, leading to potentially biased interpretations. Furthermore, which exon feature dominates the results of the KA/KS ratio test and whether multiple exon features have additive effects have remained unexplored. Results In this study, we collect two different datasets for analysis – the ASE dataset (which includes lineage-specific ASEs and conserved ASEs and the ACE dataset (which includes only conserved ASEs. We first show that information sufficiency can significantly affect the interpretation of relationship between exons features and the KA/KS ratio test results. After discarding exons with insufficient information, we use a Boolean method to analyze the relationship between test results and four exon features (namely length, protein domain overlapping, inclusion level, and exonic splicing enhancer (ESE frequency for the ASE dataset. We demonstrate that length and protein domain overlapping are dominant factors, and they have similar impacts on test results of ASEs. In addition, despite the weak impacts of inclusion level and ESE motif frequency when considered individually, combination of these two factors still have minor additive effects on test results. However, the ACE dataset shows a slightly different result in that inclusion level has a marginally significant effect on test results. Lineage-specific ASEs may have contributed to the difference. Overall, in both ASEs and ACEs, protein domain overlapping is the most dominant exon feature while ESE frequency is the weakest one in affecting

  1. Computer analysis of protein functional sites projection on exon structure of genes in Metazoa.

    Science.gov (United States)

    Medvedeva, Irina V; Demenkov, Pavel S; Ivanisenko, Vladimir A

    2015-01-01

    Study of the relationship between the structural and functional organization of proteins and their coding genes is necessary for an understanding of the evolution of molecular systems and can provide new knowledge for many applications for designing proteins with improved medical and biological properties. It is well known that the functional properties of proteins are determined by their functional sites. Functional sites are usually represented by a small number of amino acid residues that are distantly located from each other in the amino acid sequence. They are highly conserved within their functional group and vary significantly in structure between such groups. According to this facts analysis of the general properties of the structural organization of the functional sites at the protein level and, at the level of exon-intron structure of the coding gene is still an actual problem. One approach to this analysis is the projection of amino acid residue positions of the functional sites along with the exon boundaries to the gene structure. In this paper, we examined the discontinuity of the functional sites in the exon-intron structure of genes and the distribution of lengths and phases of the functional site encoding exons in vertebrate genes. We have shown that the DNA fragments coding the functional sites were in the same exons, or in close exons. The observed tendency to cluster the exons that code functional sites which could be considered as the unit of protein evolution. We studied the characteristics of the structure of the exon boundaries that code, and do not code, functional sites in 11 Metazoa species. This is accompanied by a reduced frequency of intercodon gaps (phase 0) in exons encoding the amino acid residue functional site, which may be evidence of the existence of evolutionary limitations to the exon shuffling. These results characterize the features of the coding exon-intron structure that affect the functionality of the encoded protein and

  2. EXONSAMPLER: a computer program for genome-wide and candidate gene exon sampling for targeted next-generation sequencing.

    Science.gov (United States)

    Cosart, Ted; Beja-Pereira, Albano; Luikart, Gordon

    2014-11-01

    The computer program EXONSAMPLER automates the sampling of thousands of exon sequences from publicly available reference genome sequences and gene annotation databases. It was designed to provide exon sequences for the efficient, next-generation gene sequencing method called exon capture. The exon sequences can be sampled by a list of gene name abbreviations (e.g. IFNG, TLR1), or by sampling exons from genes spaced evenly across chromosomes. It provides a list of genomic coordinates (a bed file), as well as a set of sequences in fasta format. User-adjustable parameters for collecting exon sequences include a minimum and maximum acceptable exon length, maximum number of exonic base pairs (bp) to sample per gene, and maximum total bp for the entire collection. It allows for partial sampling of very large exons. It can preferentially sample upstream (5 prime) exons, downstream (3 prime) exons, both external exons, or all internal exons. It is written in the Python programming language using its free libraries. We describe the use of EXONSAMPLER to collect exon sequences from the domestic cow (Bos taurus) genome for the design of an exon-capture microarray to sequence exons from related species, including the zebu cow and wild bison. We collected ~10% of the exome (~3 million bp), including 155 candidate genes, and ~16,000 exons evenly spaced genomewide. We prioritized the collection of 5 prime exons to facilitate discovery and genotyping of SNPs near upstream gene regulatory DNA sequences, which control gene expression and are often under natural selection. © 2014 John Wiley & Sons Ltd.

  3. Slow light in moving media

    Science.gov (United States)

    Leonhardt, U.; Piwnicki, P.

    2001-06-01

    We review the theory of light propagation in moving media with extremely low group velocity. We intend to clarify the most elementary features of monochromatic slow light in a moving medium and, whenever possible, to give an instructive simplified picture.

  4. Birth control - slow release methods

    Science.gov (United States)

    Contraception - slow-release hormonal methods; Progestin implants; Progestin injections; Skin patch; Vaginal ring ... might want to consider a different birth control method. SKIN PATCH The skin patch is placed on ...

  5. Slow rupture of frictional interfaces

    OpenAIRE

    Sinai, Yohai Bar; Brener, Efim A.; Bouchbinder, Eran

    2011-01-01

    The failure of frictional interfaces and the spatiotemporal structures that accompany it are central to a wide range of geophysical, physical and engineering systems. Recent geophysical and laboratory observations indicated that interfacial failure can be mediated by slow slip rupture phenomena which are distinct from ordinary, earthquake-like, fast rupture. These discoveries have influenced the way we think about frictional motion, yet the nature and properties of slow rupture are not comple...

  6. The role of exon shuffling in shaping protein-protein interaction networks

    Directory of Open Access Journals (Sweden)

    França Gustavo S

    2010-12-01

    Full Text Available Abstract Background Physical protein-protein interaction (PPI is a critical phenomenon for the function of most proteins in living organisms and a significant fraction of PPIs are the result of domain-domain interactions. Exon shuffling, intron-mediated recombination of exons from existing genes, is known to have been a major mechanism of domain shuffling in metazoans. Thus, we hypothesized that exon shuffling could have a significant influence in shaping the topology of PPI networks. Results We tested our hypothesis by compiling exon shuffling and PPI data from six eukaryotic species: Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Cryptococcus neoformans and Arabidopsis thaliana. For all four metazoan species, genes enriched in exon shuffling events presented on average higher vertex degree (number of interacting partners in PPI networks. Furthermore, we verified that a set of protein domains that are simultaneously promiscuous (known to interact to multiple types of other domains, self-interacting (able to interact with another copy of themselves and abundant in the genomes presents a stronger signal for exon shuffling. Conclusions Exon shuffling appears to have been a recurrent mechanism for the emergence of new PPIs along metazoan evolution. In metazoan genomes, exon shuffling also promoted the expansion of some protein domains. We speculate that their promiscuous and self-interacting properties may have been decisive for that expansion.

  7. The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons.

    Science.gov (United States)

    Finta, C; Zaphiropoulos, P G

    2000-12-30

    Using a bacterial artificial chromosome (BAC) clone, we have mapped the human cytochrome P450 3A (CYP3A) locus containing the genes encoding for CYP3A4, CYP3A5 and CYP3A7. The genes lie in a head-to-tail orientation in the order of 3A4, 3A7 and 3A5. In both intergenic regions (3A4-3A7 and 3A7-3A5), we have detected several additional cytochrome P450 3A exons, forming two CYP3A pseudogenes. These pseudogenes have the same orientation as the CYP3A genes. To our surprise, a 3A7 mRNA species has been detected in which the exons 2 and 13 of one of the pseudogenes (the one that is downstream of 3A7) are spliced after the 3A7 terminal exon. This results in an mRNA molecule that consists of the 13 3A7 exons and two additional exons at the 3' end. The additional two exons originating from the pseudogene are in an altered reading frame and consequently have the capability to code a completely different amino acid sequence than the canonical CYP3A exons 2 and 13. These findings may represent a generalized evolutionary process with genes having the potential to capture neighboring sequences and use them as functional exons.

  8. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene.

    Science.gov (United States)

    Vaughn, Cecily P; Baker, Christine L; Samowitz, Wade S; Swensen, Jeffrey J

    2013-01-01

    Lynch syndrome is characterized by mutations in one of four mismatch repair genes, MLH1, MSH2, MSH6, or PMS2. Clinical mutation analysis of these genes includes sequencing of exonic regions and deletion/duplication analysis. However, detection of deletions and duplications in PMS2 has previously been confined to Exons 1-11 due to gene conversion between PMS2 and the pseudogene PMS2CL in the remaining 3' exons (Exons 12-15). We have recently described an MLPA-based method that permits detection of deletions of PMS2 Exons 12-15; however, the frequency of such deletions has not yet been determined. To address this question, we tested for 3' deletions in 58 samples that were reported to be negative for PMS2 mutations using previously available methods. All samples were from individuals whose tumors exhibited loss of PMS2 immunohistochemical staining without concomitant loss of MLH1 immunostaining. We identified seven samples in this cohort with deletions in the 3' region of PMS2, including three previously reported samples with deletions of Exons 13-15 (two samples) and Exons 14-15. Also detected were deletions of Exons 12-15, Exon 13, and Exon 14 (two samples). Breakpoint analysis of the intragenic deletions suggests they occurred through Alu-mediated recombination. Our results indicate that ∼12% of samples suspected of harboring a PMS2 mutation based on immunohistochemical staining, for which mutations have not yet been identified, would benefit from testing using the new methodology. Copyright © 2012 Wiley Periodicals, Inc.

  9. Functional importance of different patterns of correlation between adjacent cassette exons in human and mouse.

    Science.gov (United States)

    Peng, Tao; Xue, Chenghai; Bi, Jianning; Li, Tingting; Wang, Xiaowo; Zhang, Xuegong; Li, Yanda

    2008-04-26

    Alternative splicing expands transcriptome diversity and plays an important role in regulation of gene expression. Previous studies focus on the regulation of a single cassette exon, but recent experiments indicate that multiple cassette exons within a gene may interact with each other. This interaction can increase the potential to generate various transcripts and adds an extra layer of complexity to gene regulation. Several cases of exon interaction have been discovered. However, the extent to which the cassette exons coordinate with each other remains unknown. Based on EST data, we employed a metric of correlation coefficients to describe the interaction between two adjacent cassette exons and then categorized these exon pairs into three different groups by their interaction (correlation) patterns. Sequence analysis demonstrates that strongly-correlated groups are more conserved and contain a higher proportion of pairs with reading frame preservation in a combinatorial manner. Multiple genome comparison further indicates that different groups of correlated pairs have different evolutionary courses: (1) The vast majority of positively-correlated pairs are old, (2) most of the weakly-correlated pairs are relatively young, and (3) negatively-correlated pairs are a mixture of old and young events. We performed a large-scale analysis of interactions between adjacent cassette exons. Compared with weakly-correlated pairs, the strongly-correlated pairs, including both the positively and negatively correlated ones, show more evidence that they are under delicate splicing control and tend to be functionally important. Additionally, the positively-correlated pairs bear strong resemblance to constitutive exons, which suggests that they may evolve from ancient constitutive exons, while negatively and weakly correlated pairs are more likely to contain newly emerging exons.

  10. The Potential of/for 'Slow': Slow Tourists and Slow Destinations

    Directory of Open Access Journals (Sweden)

    J. Guiver

    2016-05-01

    Full Text Available Slow tourism practices are nothing new; in fact, they were once the norm and still are for millions of people whose annual holiday is spent camping, staying in caravans, rented accommodation, with friends and relations or perhaps in a second home, who immerse themselves in their holiday environment, eat local food, drink local wine and walk or cycle around the area. So why a special edition about slow tourism? Like many aspects of life once considered normal (such as organic farming or free-range eggs, the emergence of new practices has highlighted differences and prompted a re-evaluation of once accepted practices and values. In this way, the concept of ‘slow tourism’ has recently appeared as a type of tourism that contrasts with many contemporary mainstream tourism practices. It has also been associated with similar trends already ‘branded’ slow: slow food and cittaslow (slow towns and concepts such as mindfulness, savouring and well-being.

  11. Slow, stopped and stored light

    International Nuclear Information System (INIS)

    Welch, G.; Scully, M.

    2005-01-01

    Light that can been slowed to walking pace could have applications in telecommunications, optical storage and quantum computing. Whether we use it to estimate how far away a thunderstorm is, or simply take it for granted that we can have a conversation with someone on the other side of the world, we all know that light travels extremely fast. Indeed, special relativity teaches us that nothing in the universe can ever move faster than the speed of light in a vacuum: 299 792 458 ms sup - sup 1. However, there is no such limitation on how slowly light can travel. For the last few years, researchers have been routinely slowing light to just a few metres per second, and have recently even stopped it dead in its tracks so that it can be stored for future use. Slow-light has considerable popular appeal, deriving perhaps from the importance of the speed of light in relativity and cosmology. If everyday objects such as cars or people can travel faster than 'slow' light, for example, then it might appear that relativistic effects could be observed at very low speeds. Although this is not the case, slow light nonetheless promises to play an important role in optical technology because it allows light to be delayed for any period of time desired. This could lead to all-optical routers that would increase the bandwidth of the Internet, and applications in optical data storage, quantum information and even radar. (U.K.)

  12. Slow rupture of frictional interfaces

    Science.gov (United States)

    Bar Sinai, Yohai; Brener, Efim A.; Bouchbinder, Eran

    2012-02-01

    The failure of frictional interfaces and the spatiotemporal structures that accompany it are central to a wide range of geophysical, physical and engineering systems. Recent geophysical and laboratory observations indicated that interfacial failure can be mediated by slow slip rupture phenomena which are distinct from ordinary, earthquake-like, fast rupture. These discoveries have influenced the way we think about frictional motion, yet the nature and properties of slow rupture are not completely understood. We show that slow rupture is an intrinsic and robust property of simple non-monotonic rate-and-state friction laws. It is associated with a new velocity scale cmin, determined by the friction law, below which steady state rupture cannot propagate. We further show that rupture can occur in a continuum of states, spanning a wide range of velocities from cmin to elastic wave-speeds, and predict different properties for slow rupture and ordinary fast rupture. Our results are qualitatively consistent with recent high-resolution laboratory experiments and may provide a theoretical framework for understanding slow rupture phenomena along frictional interfaces.

  13. Slow Images and Entangled Photons

    International Nuclear Information System (INIS)

    Swordy, Simon

    2007-01-01

    I will discuss some recent experiments using slow light and entangled photons. We recently showed that it was possible to map a two dimensional image onto very low light level signals, slow them down in a hot atomic vapor while preserving the amplitude and phase of the images. If time remains, I will discuss some of our recent work with time-energy entangled photons for quantum cryptography. We were able to show that we could have a measurable state space of over 1000 states for a single pair of entangled photons in fiber.

  14. Pulsar slow-down epochs

    International Nuclear Information System (INIS)

    Heintzmann, H.; Novello, M.

    1981-01-01

    The relative importance of magnetospheric currents and low frequency waves for pulsar braking is assessed and a model is developed which tries to account for the available pulsar timing data under the unifying aspect that all pulsars have equal masses and magnetic moments and are born as rapid rotators. Four epochs of slow-down are distinguished which are dominated by different braking mechanisms. According to the model no direct relationship exists between 'slow-down age' and true age of a pulsar and leads to a pulsar birth-rate of one event per hundred years. (Author) [pt

  15. Functional understanding of the diverse exon-intron structures of human GPCR genes.

    Science.gov (United States)

    Hammond, Dorothy A; Olman, Victor; Xu, Ying

    2014-02-01

    The GPCR genes have a variety of exon-intron structures even though their proteins are all structurally homologous. We have examined all human GPCR genes with at least two functional protein isoforms, totaling 199, aiming to gain an understanding of what may have contributed to the large diversity of the exon-intron structures of the GPCR genes. The 199 genes have a total of 808 known protein splicing isoforms with experimentally verified functions. Our analysis reveals that 1301 (80.6%) adjacent exon-exon pairs out of the total of 1,613 in the 199 genes have either exactly one exon skipped or the intron in-between retained in at least one of the 808 protein splicing isoforms. This observation has a statistical significance p-value of 2.051762 * e(-09), assuming that the observed splicing isoforms are independent of the exon-intron structures. Our interpretation of this observation is that the exon boundaries of the GPCR genes are not randomly determined; instead they may be selected to facilitate specific alternative splicing for functional purposes.

  16. Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Echigoya, Yusuke; Lim, Kenji Rowel Q; Trieu, Nhu; Bao, Bo; Miskew Nichols, Bailey; Vila, Maria Candida; Novak, James S; Hara, Yuko; Lee, Joshua; Touznik, Aleksander; Mamchaoui, Kamel; Aoki, Yoshitsugu; Takeda, Shin'ichi; Nagaraju, Kanneboyina; Mouly, Vincent; Maruyama, Rika; Duddy, William; Yokota, Toshifumi

    2017-11-01

    Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping. Eteplirsen remains controversial with insufficient evidence of its therapeutic effect in patients. We recently developed an in silico tool to design antisense morpholino sequences for exon skipping. Here, we designed morpholino AOs targeting DMD exon 51 using the in silico tool and quantitatively evaluated the effects in immortalized DMD muscle cells in vitro. To our surprise, most of the newly designed morpholinos induced exon 51 skipping more efficiently compared with the eteplirsen sequence. The efficacy of exon 51 skipping and rescue of dystrophin protein expression were increased by up to more than 12-fold and 7-fold, respectively, compared with the eteplirsen sequence. Significant in vivo efficacy of the most effective morpholino, determined in vitro, was confirmed in mice carrying the human DMD gene. These findings underscore the importance of AO sequence optimization for exon skipping. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  17. Clinical and molecular consequences of exon 78 deletion in DMD gene.

    Science.gov (United States)

    Traverso, Monica; Assereto, Stefania; Baratto, Serena; Iacomino, Michele; Pedemonte, Marina; Diana, Maria Cristina; Ferretti, Marta; Broda, Paolo; Minetti, Carlo; Gazzerro, Elisabetta; Madia, Francesca; Bruno, Claudio; Zara, Federico; Fiorillo, Chiara

    2018-03-19

    We present a 13-year-old patient with persistent increase of serum Creatine Kinase (CK) and myalgia after exertion. Skeletal muscle biopsy showed marked reduction of dystrophin expression leading to genetic analysis of DMD gene by MLPA, which detected a single deletion of exon 78. To the best of our knowledge, DMD exon 78 deletion has never been described in literature and, according to prediction, it should lead to loss of reading frame in the dystrophin gene. To further assess the actual effect of exon 78 deletion, we analysed cDNA from muscle mRNA. This analysis confirmed the absence of 32 bp of exon 78. Exclusion of exon 78 changes the open reading frame of exon 79 and generate a downstream stop codon, producing a dystrophin protein of 3703 amino acids instead of 3685 amino acids. Albeit loss of reading frame usually leads to protein degradation and severe phenotype, in this case, we demonstrated that deletion of DMD exon 78 can be associated with a functional protein able to bind DGC complex and a very mild phenotype. This study adds a novel deletion in DMD gene in human and helps to define the compliance between maintaining/disrupting the reading frame and clinical form of the disease.

  18. Antisense Oligonucleotide-mediated Exon Skipping as a Systemic Therapeutic Approach for Recessive Dystrophic Epidermolysis Bullosa.

    Science.gov (United States)

    Bremer, Jeroen; Bornert, Olivier; Nyström, Alexander; Gostynski, Antoni; Jonkman, Marcel F; Aartsma-Rus, Annemieke; van den Akker, Peter C; Pasmooij, Anna Mg

    2016-10-18

    The "generalized severe" form of recessive dystrophic epidermolysis bullosa (RDEB-gen sev) is caused by bi-allelic null mutations in COL7A1, encoding type VII collagen. The absence of type VII collagen leads to blistering of the skin and mucous membranes upon the slightest trauma. Because most patients carry exonic point mutations or small insertions/deletions, most exons of COL7A1 are in-frame, and low levels of type VII collagen already drastically improve the disease phenotype, this gene seems a perfect candidate for antisense oligonucleotide (AON)-mediated exon skipping. In this study, we examined the feasibility of AON-mediated exon skipping in vitro in primary cultured keratinocytes and fibroblasts, and systemically in vivo using a human skin-graft mouse model. We show that treatment with AONs designed against exon 105 leads to in-frame exon 105 skipping at the RNA level and restores type VII collagen protein production in vitro. Moreover, we demonstrate that systemic delivery in vivo induces de novo expression of type VII collagen in skin grafts generated from patient cells. Our data demonstrate strong proof-of-concept for AON-mediated exon skipping as a systemic therapeutic strategy for RDEB.

  19. Tracking the evolution of alternatively spliced exons within the Dscam family

    Directory of Open Access Journals (Sweden)

    Vision Todd J

    2006-02-01

    Full Text Available Abstract Background The Dscam gene in the fruit fly, Drosophila melanogaster, contains twenty-four exons, four of which are composed of tandem arrays that each undergo mutually exclusive alternative splicing (4, 6, 9 and 17, potentially generating 38,016 protein isoforms. This degree of transcript diversity has not been found in mammalian homologs of Dscam. We examined the molecular evolution of exons within this gene family to locate the point of divergence for this alternative splicing pattern. Results Using the fruit fly Dscam exons 4, 6, 9 and 17 as seed sequences, we iteratively searched sixteen genomes for homologs, and then performed phylogenetic analyses of the resulting sequences to examine their evolutionary history. We found homologs in the nematode, arthropod and vertebrate genomes, including homologs in several vertebrates where Dscam had not been previously annotated. Among these, only the arthropods contain homologs arranged in tandem arrays indicative of mutually exclusive splicing. We found no homologs to these exons within the Arabidopsis, yeast, tunicate or sea urchin genomes but homologs to several constitutive exons from fly Dscam were present within tunicate and sea urchin. Comparing the rate of turnover within the tandem arrays of the insect taxa (fruit fly, mosquito and honeybee, we found the variants within exons 4 and 17 are well conserved in number and spatial arrangement despite 248–283 million years of divergence. In contrast, the variants within exons 6 and 9 have undergone considerable turnover since these taxa diverged, as indicated by deeply branching taxon-specific lineages. Conclusion Our results suggest that at least one Dscam exon array may be an ancient duplication that predates the divergence of deuterostomes from protostomes but that there is no evidence for the presence of arrays in the common ancestor of vertebrates. The different patterns of conservation and turnover among the Dscam exon arrays

  20. Changes in exon–intron structure during vertebrate evolution affect the splicing pattern of exons

    Science.gov (United States)

    Gelfman, Sahar; Burstein, David; Penn, Osnat; Savchenko, Anna; Amit, Maayan; Schwartz, Schraga; Pupko, Tal; Ast, Gil

    2012-01-01

    Exon–intron architecture is one of the major features directing the splicing machinery to the short exons that are located within long flanking introns. However, the evolutionary dynamics of exon–intron architecture and its impact on splicing is largely unknown. Using a comparative genomic approach, we analyzed 17 vertebrate genomes and reconstructed the ancestral motifs of both 3′ and 5′ splice sites, as also the ancestral length of exons and introns. Our analyses suggest that vertebrate introns increased in length from the shortest ancestral introns to the longest primate introns. An evolutionary analysis of splice sites revealed that weak splice sites act as a restrictive force keeping introns short. In contrast, strong splice sites allow recognition of exons flanked by long introns. Reconstruction of the ancestral state suggests these phenomena were not prevalent in the vertebrate ancestor, but appeared during vertebrate evolution. By calculating evolutionary rate shifts in exons, we identified cis-acting regulatory sequences that became fixed during the transition from early vertebrates to mammals. Experimental validations performed on a selection of these hexamers confirmed their regulatory function. We additionally revealed many features of exons that can discriminate alternative from constitutive exons. These features were integrated into a machine-learning approach to predict whether an exon is alternative. Our algorithm obtains very high predictive power (AUC of 0.91), and using these predictions we have identified and successfully validated novel alternatively spliced exons. Overall, we provide novel insights regarding the evolutionary constraints acting upon exons and their recognition by the splicing machinery. PMID:21974994

  1. Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution.

    Directory of Open Access Journals (Sweden)

    Pawandeep Dhami

    2010-08-01

    Full Text Available It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II occupancy show preferential association with exons ("exon-intron marking", linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.

  2. The proximal first exon architecture of the murine ghrelin gene is highly similar to its human orthologue

    Directory of Open Access Journals (Sweden)

    Seim Inge

    2009-05-01

    Full Text Available Abstract Background The murine ghrelin gene (Ghrl, originally sequenced from stomach tissue, contains five exons and a single transcription start site in a short, 19 bp first exon (exon 0. We recently isolated several novel first exons of the human ghrelin gene and found evidence of a complex transcriptional repertoire. In this report, we examined the 5' exons of the murine ghrelin orthologue in a range of tissues using 5' RACE. Findings 5' RACE revealed two transcription start sites (TSSs in exon 0 and four TSSs in intron 0, which correspond to 5' extensions of exon 1. Using quantitative, real-time RT-PCR (qRT-PCR, we demonstrated that extended exon 1 containing Ghrl transcripts are largely confined to the spleen, adrenal gland, stomach, and skin. Conclusion We demonstrate that multiple transcription start sites are present in exon 0 and an extended exon 1 of the murine ghrelin gene, similar to the proximal first exon organisation of its human orthologue. The identification of several transcription start sites in intron 0 of mouse ghrelin (resulting in an extension of exon 1 raises the possibility that developmental-, cell- and tissue-specific Ghrl mRNA species are created by employing alternative promoters and further studies of the murine ghrelin gene are warranted.

  3. A slowing-down problem

    Energy Technology Data Exchange (ETDEWEB)

    Carlvik, I; Pershagen, B

    1958-06-15

    An infinitely long circular cylinder of radius a is surrounded by an infinite moderator. Both media are non-capturing. The cylinder emits neutrons of age zero with a constant source density of S. We assume that the ratios of the slowing-down powers and of the diffusion constants are independent of the neutron energy. The slowing-down density is calculated for two cases, a) when the slowing-down power of the cylinder medium is very small, and b) when the cylinder medium is identical with the moderator. The ratios of the slowing-down density at the age {tau} and the source density in the two cases are called {psi}{sub V}, and {psi}{sub M} respectively. {psi}{sub V} and {psi}{sub M} are functions of y=a{sup 2}/4{tau}. These two functions ({psi}{sub V} and {psi}{sub M}) are calculated and tabulated for y = 0-0.25.

  4. Numerical modeling of slow shocks

    International Nuclear Information System (INIS)

    Winske, D.

    1987-01-01

    This paper reviews previous attempt and the present status of efforts to understand the structure of slow shocks by means of time dependent numerical calculations. Studies carried out using MHD or hybrid-kinetic codes have demonstrated qualitative agreement with theory. A number of unresolved issues related to hybrid simulations of the internal shock structure are discussed in some detail. 43 refs., 8 figs

  5. Evolution of the Exon-Intron Structure in Ciliate Genomes.

    Directory of Open Access Journals (Sweden)

    Vladyslav S Bondarenko

    Full Text Available A typical eukaryotic gene is comprised of alternating stretches of regions, exons and introns, retained in and spliced out a mature mRNA, respectively. Although the length of introns may vary substantially among organisms, a large fraction of genes contains short introns in many species. Notably, some Ciliates (Paramecium and Nyctotherus possess only ultra-short introns, around 25 bp long. In Paramecium, ultra-short introns with length divisible by three (3n are under strong evolutionary pressure and have a high frequency of in-frame stop codons, which, in the case of intron retention, cause premature termination of mRNA translation and consequent degradation of the mis-spliced mRNA by the nonsense-mediated decay mechanism. Here, we analyzed introns in five genera of Ciliates, Paramecium, Tetrahymena, Ichthyophthirius, Oxytricha, and Stylonychia. Introns can be classified into two length classes in Tetrahymena and Ichthyophthirius (with means 48 bp, 69 bp, and 55 bp, 64 bp, respectively, but, surprisingly, comprise three distinct length classes in Oxytricha and Stylonychia (with means 33-35 bp, 47-51 bp, and 78-80 bp. In most ranges of the intron lengths, 3n introns are underrepresented and have a high frequency of in-frame stop codons in all studied species. Introns of Paramecium, Tetrahymena, and Ichthyophthirius are preferentially located at the 5' and 3' ends of genes, whereas introns of Oxytricha and Stylonychia are strongly skewed towards the 5' end. Analysis of evolutionary conservation shows that, in each studied genome, a significant fraction of intron positions is conserved between the orthologs, but intron lengths are not correlated between the species. In summary, our study provides a detailed characterization of introns in several genera of Ciliates and highlights some of their distinctive properties, which, together, indicate that splicing spellchecking is a universal and evolutionarily conserved process in the biogenesis of short

  6. The unappreciated slowness of conventional tourism

    Directory of Open Access Journals (Sweden)

    G.R. Larsen

    2016-05-01

    Full Text Available Most tourists are not consciously engaging in ‘slow travel’, but a number of travel behaviours displayed by conventional tourists can be interpreted as slow travel behaviour. Based on Danish tourists’ engagement with the distances they travel across to reach their holiday destination, this paper explores unintended slow travel behaviours displayed by these tourists. None of the tourists participating in this research were consciously doing ‘slow travel’, and yet some of their most valued holiday memories are linked to slow travel behaviours. Based on the analysis of these unintended slow travel behaviours, this paper will discuss the potential this insight might hold for promotion of slow travel. If unappreciated and unintentional slow travel behaviours could be utilised in the deliberate effort of encouraging more people to travel slow, ‘slow travel’ will be in a better position to become integrated into conventional travel behaviour.

  7. Analysis of KIT expression and KIT exon 11 mutations in canine oral malignant melanomas.

    Science.gov (United States)

    Murakami, A; Mori, T; Sakai, H; Murakami, M; Yanai, T; Hoshino, Y; Maruo, K

    2011-09-01

    KIT, a transmembrane receptor tyrosine kinase, is one of the specific targets for anti-cancer therapy. In humans, its expression and mutations have been identified in malignant melanomas and therapies using molecular-targeted agents have been promising in these tumours. As human malignant melanoma, canine malignant melanoma is a fatal disease with metastases and the poor response has been observed with all standard protocols. In our study, KIT expression and exon 11 mutations in dogs with histologically confirmed malignant oral melanomas were evaluated. Although 20 of 39 cases were positive for KIT protein, there was no significant difference between KIT expression and overall survival. Moreover, polymerase chain reaction amplification and sequencing of KIT exon 11 in 17 samples did not detect any mutations and proved disappointing. For several reasons, however, KIT expression and mutations of various exons including exon 11 should be investigated in more cases. © 2011 Blackwell Publishing Ltd.

  8. Plant Proteins Are Smaller Because They Are Encoded by Fewer Exons than Animal Proteins.

    Science.gov (United States)

    Ramírez-Sánchez, Obed; Pérez-Rodríguez, Paulino; Delaye, Luis; Tiessen, Axel

    2016-12-01

    Protein size is an important biochemical feature since longer proteins can harbor more domains and therefore can display more biological functionalities than shorter proteins. We found remarkable differences in protein length, exon structure, and domain count among different phylogenetic lineages. While eukaryotic proteins have an average size of 472 amino acid residues (aa), average protein sizes in plant genomes are smaller than those of animals and fungi. Proteins unique to plants are ∼81aa shorter than plant proteins conserved among other eukaryotic lineages. The smaller average size of plant proteins could neither be explained by endosymbiosis nor subcellular compartmentation nor exon size, but rather due to exon number. Metazoan proteins are encoded on average by ∼10 exons of small size [∼176 nucleotides (nt)]. Streptophyta have on average only ∼5.7 exons of medium size (∼230nt). Multicellular species code for large proteins by increasing the exon number, while most unicellular organisms employ rather larger exons (>400nt). Among subcellular compartments, membrane proteins are the largest (∼520aa), whereas the smallest proteins correspond to the gene ontology group of ribosome (∼240aa). Plant genes are encoded by half the number of exons and also contain fewer domains than animal proteins on average. Interestingly, endosymbiotic proteins that migrated to the plant nucleus became larger than their cyanobacterial orthologs. We thus conclude that plants have proteins larger than bacteria but smaller than animals or fungi. Compared to the average of eukaryotic species, plants have ∼34% more but ∼20% smaller proteins. This suggests that photosynthetic organisms are unique and deserve therefore special attention with regard to the evolutionary forces acting on their genomes and proteomes. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

  9. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy

    DEFF Research Database (Denmark)

    Holmström, M O; Martinenaite, E; Ahmad, S M

    2017-01-01

    The calreticulin (CALR) exon 9 mutations are found in ∼30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically re...... CALR exon 9 mutations.Leukemia advance online publication, 15 August 2017; doi:10.1038/leu.2017.214....

  10. DNA amplification of a further exon of Duchenne muscular dystrophy locus increase possibilities for deletion screening

    Energy Technology Data Exchange (ETDEWEB)

    Speer, A.; Rosenthal, A.; Billwitz, H.; Hanke, R.; Forrest, S.M; Love, D.; Davies, K.E.; Coutelle, C. (John Radcliffe Hospital, Oxford (England))

    1989-06-26

    The data of Chamberlain et al allow the detection of 76% of deletions in the region Cf56A/Cf23a identified by hybridization in their patients. The authors have generated two oligonucleotides allowing the amplification of a further exon which is included in the 3.4 kb hybridization of fragment of Cf56a. This exon is deleted in about 10% of their patients.

  11. Plant Proteins Are Smaller Because They Are Encoded by Fewer Exons than Animal Proteins

    Directory of Open Access Journals (Sweden)

    Obed Ramírez-Sánchez

    2016-12-01

    Full Text Available Protein size is an important biochemical feature since longer proteins can harbor more domains and therefore can display more biological functionalities than shorter proteins. We found remarkable differences in protein length, exon structure, and domain count among different phylogenetic lineages. While eukaryotic proteins have an average size of 472 amino acid residues (aa, average protein sizes in plant genomes are smaller than those of animals and fungi. Proteins unique to plants are ∼81 aa shorter than plant proteins conserved among other eukaryotic lineages. The smaller average size of plant proteins could neither be explained by endosymbiosis nor subcellular compartmentation nor exon size, but rather due to exon number. Metazoan proteins are encoded on average by ∼10 exons of small size [∼176 nucleotides (nt]. Streptophyta have on average only ∼5.7 exons of medium size (∼230 nt. Multicellular species code for large proteins by increasing the exon number, while most unicellular organisms employ rather larger exons (>400 nt. Among subcellular compartments, membrane proteins are the largest (∼520 aa, whereas the smallest proteins correspond to the gene ontology group of ribosome (∼240 aa. Plant genes are encoded by half the number of exons and also contain fewer domains than animal proteins on average. Interestingly, endosymbiotic proteins that migrated to the plant nucleus became larger than their cyanobacterial orthologs. We thus conclude that plants have proteins larger than bacteria but smaller than animals or fungi. Compared to the average of eukaryotic species, plants have ∼34% more but ∼20% smaller proteins. This suggests that photosynthetic organisms are unique and deserve therefore special attention with regard to the evolutionary forces acting on their genomes and proteomes.

  12. Screening for mutations in two exons of FANCG gene in Pakistani population.

    Science.gov (United States)

    Aymun, Ujala; Iram, Saima; Aftab, Iram; Khaliq, Saba; Nadir, Ali; Nisar, Ahmed; Mohsin, Shahida

    2017-06-01

    Fanconi anemia is a rare autosomal recessive disorder of genetic instability. It is both molecularly and clinically, a heterogeneous disorder. Its incidence is 1 in 129,000 births and relatively high in some ethnic groups. Sixteen genes have been identified among them mutations in FANCG gene are most common after FANCA and FANCC gene mutations. To study mutations in exon 3 and 4 of FANCG gene in Pakistani population. Thirty five patients with positive Diepoxybutane test were included in the study. DNA was extracted and amplified for exons 3 and 4. Thereafter Sequencing was done and analyzed for the presence of mutations. No mutation was detected in exon 3 whereas a carrier of known mutation c.307+1 G>T was found in exon 4 of the FANCG gene. Absence of any mutation in exon 3 and only one heterozygous mutation in exon 4 of FANCG gene points to a different spectrum of FA gene pool in Pakistan that needs extensive research in this area.

  13. Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Zhiqiang; Su, Lijing; Pei, Jimin; Grishin, Nick V.; Zhang, Hong (UTSMC)

    2017-08-01

    In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC. Unique to Exon19:CIPC, three highly conserved polar residues, Asn341 of CIPC and Gln544 of the two Exon19 helices, are located at the mid-section of the coiled-coil bundle interior and form hydrogen bonds with each other. Combining results from protein database search, sequence analysis, and mutagenesis studies, we discovered for the first time that CLOCK Exon19:CIPC interaction is a conserved transcription regulatory mechanism among mammals, fish, flies, and other invertebrates.

  14. A Primer to Slow Light

    OpenAIRE

    Leonhardt, U.

    2001-01-01

    Laboratory-based optical analogs of astronomical objects such as black holes rely on the creation of light with an extremely low or even vanishing group velocity (slow light). These brief notes represent a pedagogical attempt towards elucidating this extraordinary form of light. This paper is a contribution to the book Artificial Black Holes edited by Mario Novello, Matt Visser and Grigori Volovik. The paper is intended as a primer, an introduction to the subject for non-experts, not as a det...

  15. Capillary waves in slow motion

    International Nuclear Information System (INIS)

    Seydel, Tilo; Tolan, Metin; Press, Werner; Madsen, Anders; Gruebel, Gerhard

    2001-01-01

    Capillary wave dynamics on glycerol surfaces has been investigated by means of x-ray photon correlation spectroscopy performed at grazing angles. The measurements show that thermally activated capillary wave motion is slowed down exponentially when the sample is cooled below 273 K. This finding directly reflects the freezing of the surface waves. The wave-number dependence of the measured time constants is in quantitative agreement with theoretical predictions for overdamped capillary waves

  16. The fast slow TDPAC spectrometer

    International Nuclear Information System (INIS)

    Cekic, B.; Koicki, S.; Manasijevic, M.; Ivanovic, N.; Koteski, V.; Milosevic, Z.; Radisavljevic, I.; Cavor, J.; Novakovic, N.; Marjanovic, D.

    2001-01-01

    A 2-BaF 2 detector - fast slow time spectrometer for time differential perturbed angular correlations (TDPAC) experiments is described. This apparatus has been developed in the Group for Hyperfine Interactions in the Institute for Nuclear Sciences in VINCA. The excellent time resolution combined with high efficiency offered by these detectors enables one high counting rate performance and is operating in the wide temperature range 78-1200 K. (author)

  17. Hidden slow pulsars in binaries

    Science.gov (United States)

    Tavani, Marco; Brookshaw, Leigh

    1993-01-01

    The recent discovery of the binary containing the slow pulsar PSR 1718-19 orbiting around a low-mass companion star adds new light on the characteristics of binary pulsars. The properties of the radio eclipses of PSR 1718-19 are the most striking observational characteristics of this system. The surface of the companion star produces a mass outflow which leaves only a small 'window' in orbital phase for the detection of PSR 1718-19 around 400 MHz. At this observing frequency, PSR 1718-19 is clearly observable only for about 1 hr out of the total 6.2 hr orbital period. The aim of this Letter is twofold: (1) to model the hydrodynamical behavior of the eclipsing material from the companion star of PSR 1718-19 and (2) to argue that a population of binary slow pulsars might have escaped detection in pulsar surveys carried out at 400 MHz. The possible existence of a population of partially or totally hidden slow pulsars in binaries will have a strong impact on current theories of binary evolution of neutron stars.

  18. Inactivating Mutation screening of Exon 6 and Exon 10E of FSHR gene in women with Polycystic Ovarian Syndrome in Vellore population

    Science.gov (United States)

    Sekar, Nishu; Sapre, Madhura; Kale, Vaikhari; Prabhu, Yogamaya D.; Renu, Kaviyarasi; Ramgir, Shalaka S.; Abilash, V. G.

    2017-11-01

    Polycystic Ovarian syndrome (PCOS) is a major cause of infertility in females of reproducing age and is typified by oligo-anovulation, hyperandrogenism, hirsutism and polycystic ovaries. FSHR gene located on chromosome 2 p21 is responsible for the normal follicular development and any deletion or mutation in the gene affects the interaction of FSH with its receptor. Thus, it becomes the candidate gene for PCOS study. Inactivating mutation in FSHR gene limits the receptor’s function by creating a complete block, changing the receptor-ligand complex or the basic hormone signal transduction.To screen the inactivating mutations in Exon 6 and Exon 10E of FSHR gene in women diagnosed with PCOS.PCR-RFLP analysis indicated that there were no inactivating mutations found in Exon 6 and Exon 10E. Variations in hormone levels were seen amongst the PCOS patients. There were no inactivating mutations found in FSHR gene of the women diagnosed with PCOS according to the Rotterdam criteria in Vellore population.

  19. Canine and human gastrointestinal stromal tumors display similar mutations in c-KIT exon 11

    International Nuclear Information System (INIS)

    Gregory-Bryson, Emmalena; Bartlett, Elizabeth; Kiupel, Matti; Hayes, Schantel; Yuzbasiyan-Gurkan, Vilma

    2010-01-01

    Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs. Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin-embedded samples. Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA. The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further

  20. Exon-primed intron-crossing (EPIC markers for non-model teleost fishes

    Directory of Open Access Journals (Sweden)

    Riethoven Jean-Jack M

    2010-03-01

    Full Text Available Abstract Background Exon-primed intron-crossing (EPIC markers have three advantages over anonymous genomic sequences in studying evolution of natural populations. First, the universal primers designed in exon regions can be applied across a broad taxonomic range. Second, the homology of EPIC-amplified sequences can be easily determined by comparing either their exon or intron portion depending on the genetic distance between the taxa. Third, having both the exon and intron fragments could help in examining genetic variation at the intraspecific and interspecific level simultaneously, particularly helpful when studying species complex. However, the paucity of EPIC markers has hindered multilocus studies using nuclear gene sequences, particularly in teleost fishes. Results We introduce a bioinformatics pipeline for developing EPIC markers by comparing the whole genome sequences between two or more species. By applying this approach on five teleost fishes whose genomes were available in the Ensembl database http://www.ensembl.org, we identified 210 EPIC markers that have single-copy and conserved exon regions with identity greater than 85% among the five teleost fishes. We tested 12 randomly chosen EPIC markers in nine teleost species having a wide phylogenetic range. The success rate of amplifying and sequencing those markers varied from 44% to 100% in different species. We analyzed the exon sequences of the 12 EPIC markers from 13 teleosts. The resulting phylogeny contains many traditionally well-supported clades, indicating the usefulness of the exon portion of EPIC markers in reconstructing species phylogeny, in addition to the value of the intron portion of EPIC markers in interrogating the population history. Conclusions This study illustrated an effective approach to develop EPIC markers in a taxonomic group, where two or more genome sequences are available. The markers identified could be amplified across a broad taxonomic range of teleost

  1. Slow electrons kill the ozone

    International Nuclear Information System (INIS)

    Maerk, T.

    2001-01-01

    A new method and apparatus (Trochoidal electron monochromator) to study the interactions of electrons with atoms, molecules and clusters was developed. Two applications are briefly reported: a) the ozone destruction in the atmosphere is caused by different reasons, a new mechanism is proposed, that slow thermal electrons are self added to the ozone molecule (O 3 ) with a high frequency, then O 3 is destroyed ( O 3 + e - → O - + O 2 ); b) another application is the study of the binding energy of the football molecule C60. (nevyjel)

  2. The CUORE slow monitoring systems

    Science.gov (United States)

    Gladstone, L.; Biare, D.; Cappelli, L.; Cushman, J. S.; Del Corso, F.; Fujikawa, B. K.; Hickerson, K. P.; Moggi, N.; Pagliarone, C. E.; Schmidt, B.; Wagaarachchi, S. L.; Welliver, B.; Winslow, L. A.

    2017-09-01

    CUORE is a cryogenic experiment searching primarily for neutrinoless double decay in 130Te. It will begin data-taking operations in 2016. To monitor the cryostat and detector during commissioning and data taking, we have designed and developed Slow Monitoring systems. In addition to real-time systems using LabVIEW, we have an alarm, analysis, and archiving website that uses MongoDB, AngularJS, and Bootstrap software. These modern, state of the art software packages make the monitoring system transparent, easily maintainable, and accessible on many platforms including mobile devices.

  3. Blowup for flat slow manifolds

    DEFF Research Database (Denmark)

    Kristiansen, Kristian Uldall

    2017-01-01

    In this paper, we present a way of extending the blowup method, in the formulation of Krupa and Szmolyan, to flat slow manifolds that lose hyperbolicity beyond any algebraic order. Although these manifolds have infinite co-dimensions, they do appear naturally in certain settings; for example, in (a......) the regularization of piecewise smooth systems by tanh, (b) a particular aircraft landing dynamics model, and finally (c) in a model of earthquake faulting. We demonstrate the approach using a simple model system and the examples (a) and (b)....

  4. Blowup for flat slow manifolds

    Science.gov (United States)

    Kristiansen, K. U.

    2017-05-01

    In this paper, we present a way of extending the blowup method, in the formulation of Krupa and Szmolyan, to flat slow manifolds that lose hyperbolicity beyond any algebraic order. Although these manifolds have infinite co-dimensions, they do appear naturally in certain settings; for example, in (a) the regularization of piecewise smooth systems by \\tanh , (b) a particular aircraft landing dynamics model, and finally (c) in a model of earthquake faulting. We demonstrate the approach using a simple model system and the examples (a) and (b).

  5. Connecting slow earthquakes to huge earthquakes

    OpenAIRE

    Obara, Kazushige; Kato, Aitaro

    2016-01-01

    Slow earthquakes are characterized by a wide spectrum of fault slip behaviors and seismic radiation patterns that differ from those of traditional earthquakes. However, slow earthquakes and huge megathrust earthquakes can have common slip mechanisms and are located in neighboring regions of the seismogenic zone. The frequent occurrence of slow earthquakes may help to reveal the physics underlying megathrust events as useful analogs. Slow earthquakes may function as stress meters because of th...

  6. Integrated Photonics Enabled by Slow Light

    DEFF Research Database (Denmark)

    Mørk, Jesper; Chen, Yuntian; Ek, Sara

    2012-01-01

    In this talk we will discuss the physics of slow light in semiconductor materials and in particular the possibilities offered for integrated photonics. This includes ultra-compact slow light enabled optical amplifiers, lasers and pulse sources.......In this talk we will discuss the physics of slow light in semiconductor materials and in particular the possibilities offered for integrated photonics. This includes ultra-compact slow light enabled optical amplifiers, lasers and pulse sources....

  7. Slowing down bubbles with sound

    Science.gov (United States)

    Poulain, Cedric; Dangla, Remie; Guinard, Marion

    2009-11-01

    We present experimental evidence that a bubble moving in a fluid in which a well-chosen acoustic noise is superimposed can be significantly slowed down even for moderate acoustic pressure. Through mean velocity measurements, we show that a condition for this effect to occur is for the acoustic noise spectrum to match or overlap the bubble's fundamental resonant mode. We render the bubble's oscillations and translational movements using high speed video. We show that radial oscillations (Rayleigh-Plesset type) have no effect on the mean velocity, while above a critical pressure, a parametric type instability (Faraday waves) is triggered and gives rise to nonlinear surface oscillations. We evidence that these surface waves are subharmonic and responsible for the bubble's drag increase. When the acoustic intensity is increased, Faraday modes interact and the strongly nonlinear oscillations behave randomly, leading to a random behavior of the bubble's trajectory and consequently to a higher slow down. Our observations may suggest new strategies for bubbly flow control, or two-phase microfluidic devices. It might also be applicable to other elastic objects, such as globules, cells or vesicles, for medical applications such as elasticity-based sorting.

  8. Intrasplicing coordinates alternative first exons with alternative splicing in the protein 4.1R gene

    Energy Technology Data Exchange (ETDEWEB)

    Conboy, John G.; Parra, Marilyn K.; Tan, Jeff S.; Mohandas, Narla; Conboy, John G.

    2008-11-07

    In the protein 4.1R gene, alternative first exons splice differentially to alternative 3' splice sites far downstream in exon 2'/2 (E2'/2). We describe a novel intrasplicing mechanism by which exon 1A (E1A) splices exclusively to the distal E2'/2 acceptor via two nested splicing reactions regulated by novel properties of exon 1B (E1B). E1B behaves as an exon in the first step, using its consensus 5' donor to splice to the proximal E2'/2 acceptor. A long region of downstream intron is excised, juxtaposing E1B with E2'/2 to generate a new composite acceptor containing the E1B branchpoint/pyrimidine tract and E2 distal 3' AG-dinucleotide. Next, the upstream E1A splices over E1B to this distal acceptor, excising the remaining intron plus E1B and E2' to form mature E1A/E2 product. We mapped branch points for both intrasplicing reactions and demonstrated that mutation of the E1B 5' splice site or branchpoint abrogates intrasplicing. In the 4.1R gene, intrasplicing ultimately determines N-terminal protein structure and function. More generally, intrasplicing represents a new mechanism whereby alternative promoters can be coordinated with downstream alternative splicing.

  9. Some mutations of exon-7 in cytochrome P450 gene 3A4 and their effect on 6beta-hydroxylation of cortisol.

    Science.gov (United States)

    Shchepotina, E G; Vavilin, V A; Goreva, O B; Lyakhovich, V V

    2006-06-01

    Analysis of variants of exon 7 sequences in cytochrome P450 gene 3A4 in a sample of Caucasoid persons was carried out. The effect of these variants on activity of CYP3A was assessed by the level of cortisol 6beta-hydroxylation. Alleles CYP3A4*5 and *17 were not detected: probably, these mutations are rare and consequently they have little effect on the character of polymorphic distribution of CYP3A4 activity in this population. The incidence of CYP3A4*2 was 5.26%. The 6betaOH-cortisol/cortisol ratio in an individual with CYP3A4*2/*2 genotype was 7.408, which corresponded to "slow metabolizer" phenotype in this sample.

  10. Modulation of splicing of the preceding intron by antisense oligonucleotide complementary to intra-exon sequence deleted in dystrophin Kobe

    Energy Technology Data Exchange (ETDEWEB)

    Takeshima, Y.; Matuso, M.; Sakamoto, H.; Nishio, H. [Kobe Univ. School of Medicine and Science (Japan)

    1994-09-01

    Molecular analysis of dystrophin Kobe showed that exon 19 of the dystrophin gene bearing a 52 bp deletion was skipped during splicing, although the known consensus sequences at the 5{prime} and 3{prime} splice site of exon 19 were maintained. These data suggest that the deleted sequence of exon 19 may function as a cis-acting factor for exact splicing for the upstream intron. To investigate this potential role, an in vitro splicing system using dystrophin precursors was established. A two-exon precursor containing exon 18, truncated intron 18, and exon 19 was accurately spliced. However, splicing of intron 18 was dramatically inhibited when wild exon 19 was replaced with mutated exon 19. Even though the length of exon 19 was restored to normal by replacing the deleted sequence with other sequence, splicing of intron 18 was not fully reactivated. Characteristically, splicing of intron 18 was inactivated more markedly when the replaced sequence contained less polypurine stretches. These data suggested that modification of the exon sequence would result in a splicing abnormality. Antisense 31 mer 2`-O-methyl ribonucleotide was targeted against 5{prime} end of deleted region of exon 19 to modulate splicing of the mRNA precursor. Splicing of intron 18 was inhibited in a dose- and time-dependent manner. This is the first in vitro evidence to show splicing of dystrophin pre-mRNA can be managed by antisense oligonucleotides. These experiments represent an approach in which antisense oligonucleotides are used to restore the function of a defective dystrophin gene in Duchenne muscular dystrophy by inducing skipping of certain exons during splicing.

  11. A fast-slow logic system

    International Nuclear Information System (INIS)

    Kawashima, Hideo.

    1977-01-01

    A fast-slow logic system has been made for use in multi-detector experiments in nuclear physics such as particle-gamma and particle-particle coincidence experiments. The system consists of a fast logic system and a slow logic system. The fast logic system has a function of fast coincidences and provides timing signals for the slow logic system. The slow logic system has a function of slow coincidences and a routing control of input analog signals to the ADCs. (auth.)

  12. Molecular evolution of the leptin exon 3 in some species of the family Canidae

    Directory of Open Access Journals (Sweden)

    Switonski Marek

    2003-09-01

    Full Text Available Abstract The structure of the leptin gene seems to be well conserved. The polymorphism of this gene in four species belonging to the Canidae family (the dog (Canis familiaris – 16 different breeds, the Chinese racoon dog (Nyctereutes procyonoides procyonoides, the red fox (Vulpes vulpes and the arctic fox (Alopex lagopus were studied with the use of single strand conformation polymorphism (SSCP, restriction fragment length polymorphism (RFLP and DNA sequencing techniques. For exon 2, all species presented the same SSCP pattern, while in exon 3 some differences were found. DNA sequencing of exon 3 revealed the presence of six nucleotide substitutions, differentiating the studied species. Three of them cause amino acid substitutions as well. For all dog breeds studied, SSCP patterns were identical.

  13. Exonal deletion of SLC24A4 causes hypomaturation amelogenesis imperfecta.

    Science.gov (United States)

    Seymen, F; Lee, K-E; Tran Le, C G; Yildirim, M; Gencay, K; Lee, Z H; Kim, J-W

    2014-04-01

    Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.

  14. Traditional Procurement is too Slow

    Directory of Open Access Journals (Sweden)

    Ann Kong

    2012-11-01

    Full Text Available This paper reports on an exploratory interview survey of construction project participants aimed at identifying the reasons for the decrease in use of the traditional, lump-sum, procurement system in Malaysia. The results show that most people believe it is too slow. This appears to be in part due to the contiguous nature of the various phase and stages of the process and especially the separation of the design and construction phases. The delays caused by disputes between the various parties are also seen as a contributory factor - the most prominent cause being the frequency of variations, with design and scope changes being a particular source of discontent. It is concluded that an up scaling of the whole of the time related reward/penalty system may be the most appropriate measure for the practice in future.

  15. Slow pyrolysis of pistachio shell

    Energy Technology Data Exchange (ETDEWEB)

    Apaydin-Varol, Esin; Putun, Ersan; Putun, Ayse E [Anadolu University, Eskisehir (Turkey). Department of Chemical Engineering

    2007-08-15

    In this study, pistachio shell is taken as the biomass sample to investigate the effects of pyrolysis temperature on the product yields and composition when slow pyrolysis is applied in a fixed-bed reactor at atmospheric pressure to the temperatures of 300, 400, 500, 550, 700{sup o}C. The maximum liquid yield was attained at about 500-550{sup o}C with a yield of 20.5%. The liquid product obtained under this optimum temperature and solid products obtained at all temperatures were characterized. As well as proximate and elemental analysis for the products were the basic steps for characterization, column chromatography, FT-IR, GC/MS and SEM were used for further characterization. The results showed that liquid and solid products from pistachio shells show similarities with high value conventional fuels. 31 refs., 9 figs., 1 tab.

  16. The TTI slowness surface approximation

    KAUST Repository

    Stovas, A.

    2011-01-01

    The relation between the vertical and horizontal slownesses, better known as the dispersion relation, for a transversely isotropic media with titled symmetry axis {left parenthesis, less than bracket}TTI{right parenthesis, greater than bracket} requires solving a quartic polynomial, which does not admit a practical explicit solution to be used, for example, in downward continuation. Using a combination of perturbation theory with respect to the anelliptic parameter and Shanks transform to improve the accuracy of the expansion, we develop an explicit formula for the dispersion relation that is highly accurate for all practical purposes. It also reveals some insights into the anisotropy parameter dependency of the dispersion relation including the low impact that the anelliptic parameter has on the vertical placement of reflectors for small tilt in the symmetry angle. © 2011 Society of Exploration Geophysicists.

  17. Characterization of major histocompatibility complex (MHC DRB exon 2 and DRA exon 3 fragments in a primary terrestrial rabies vector (Procyon lotor.

    Directory of Open Access Journals (Sweden)

    Sarrah Castillo

    Full Text Available The major histocompatibility complex (MHC presents a unique system to explore links between genetic diversity and pathogens, as diversity within MHC is maintained in part by pathogen driven selection. While the majority of wildlife MHC studies have investigated species that are of conservation concern, here we characterize MHC variation in a common and broadly distributed species, the North American raccoon (Procyon lotor. Raccoons host an array of broadly distributed wildlife diseases (e.g., canine distemper, parvovirus and raccoon rabies virus and present important human health risks as they persist in high densities and in close proximity to humans and livestock. To further explore how genetic variation influences the spread and maintenance of disease in raccoons we characterized a fragment of MHC class II DRA exon 3 (250 bp and DRB exon 2 (228 bp. MHC DRA was found to be functionally monomorphic in the 32 individuals screened; whereas DRB exon 2 revealed 66 unique alleles among the 246 individuals screened. Between two and four alleles were observed in each individual suggesting we were amplifying a duplicated DRB locus. Nucleotide differences between DRB alleles ranged from 1 to 36 bp (0.4-15.8% divergence and translated into 1 to 21 (1.3-27.6% divergence amino acid differences. We detected a significant excess of nonsynonymous substitutions at the peptide binding region (P = 0.005, indicating that DRB exon 2 in raccoons has been influenced by positive selection. These data will form the basis of continued analyses into the spatial and temporal relationship of the raccoon rabies virus and the immunogenetic response in its primary host.

  18. High resolution melting for mutation scanning of TP53 exons 5–8

    International Nuclear Information System (INIS)

    Krypuy, Michael; Dobrovic, Alexander; Ahmed, Ahmed Ashour; Etemadmoghadam, Dariush; Hyland, Sarah J; Australian Ovarian Cancer Study Group; Fazio, Anna de; Fox, Stephen B; Brenton, James D; Bowtell, David D

    2007-01-01

    p53 is commonly inactivated by mutations in the DNA-binding domain in a wide range of cancers. As mutant p53 often influences response to therapy, effective and rapid methods to scan for mutations in TP53 are likely to be of clinical value. We therefore evaluated the use of high resolution melting (HRM) as a rapid mutation scanning tool for TP53 in tumour samples. We designed PCR amplicons for HRM mutation scanning of TP53 exons 5 to 8 and tested them with DNA from cell lines hemizygous or homozygous for known mutations. We assessed the sensitivity of each PCR amplicon using dilutions of cell line DNA in normal wild-type DNA. We then performed a blinded assessment on ovarian tumour DNA samples that had been previously sequenced for mutations in TP53 to assess the sensitivity and positive predictive value of the HRM technique. We also performed HRM analysis on breast tumour DNA samples with unknown TP53 mutation status. One cell line mutation was not readily observed when exon 5 was amplified. As exon 5 contained multiple melting domains, we divided the exon into two amplicons for further screening. Sequence changes were also introduced into some of the primers to improve the melting characteristics of the amplicon. Aberrant HRM curves indicative of TP53 mutations were observed for each of the samples in the ovarian tumour DNA panel. Comparison of the HRM results with the sequencing results revealed that each mutation was detected by HRM in the correct exon. For the breast tumour panel, we detected seven aberrant melt profiles by HRM and subsequent sequencing confirmed the presence of these and no other mutations in the predicted exons. HRM is an effective technique for simple and rapid scanning of TP53 mutations that can markedly reduce the amount of sequencing required in mutational studies of TP53

  19. Multi-exon deletions of the FBN1 gene in Marfan syndrome

    Directory of Open Access Journals (Sweden)

    Schrijver Iris

    2001-10-01

    Full Text Available Abstract Background Mutations in the fibrillin -1 gene (FBN1 cause Marfan syndrome (MFS, an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene include only one family with a genomic multi-exon deletion. Methods We used long-range RT-PCR for mutation detection and long-range genomic PCR and DNA sequencing for identification of deletion breakpoints, allele-specific transcript analyses to determine stability of the mutant RNA, and pulse-chase studies to quantitate fibrillin synthesis and extracellular matrix deposition in cultured fibroblasts. Southern blots of genomic DNA were probed with three overlapping fragments covering the FBN1 coding exons Results Two novel multi-exon FBN1 deletions were discovered. Identical nucleotide pentamers were found at or near the intronic breakpoints. In a Case with classic MFS, an in-frame deletion of exons 42 and 43 removed the C-terminal 24 amino acids of the 5th LTBP (8-cysteine domain and the adjacent 25th calcium-binding EGF-like (6-cysteine domain. The mutant mRNA was stable, but fibrillin synthesis and matrix deposition were significantly reduced. A Case with severe childhood-onset MFS has a de novo deletion of exons 44–46 that removed three EGF-like domains. Fibrillin protein synthesis was normal, but matrix deposition was strikingly reduced. No genomic rearrangements were detected by Southern analysis of 18 unrelated MFS samples negative for FBN1 mutation screening. Conclusions Two novel deletion cases expand knowledge of mutational mechanisms and genotype/phenotype correlations of fibrillinopathies. Deletions or mutations affecting an LTBP domain may result in unstable mutant protein cleavage products that interfere with microfibril assembly.

  20. Neonatal Marfan syndrome caused by an exon 25 mutation of the fibrillin-1 gene.

    Science.gov (United States)

    Elçioglu, N H; Akalin, F; Elçioglu, M; Comeglio, P; Child, A H

    2004-01-01

    Neonatal Marfan syndrome caused by an exon 25 mutation of the Fibrillin-1 gene: We describe a male infant with severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, microretrognathia, crumpled ears, rockerbottom feet, loose redundant skin, and lens dislocations. Cardiac valve insufficiency and aortic dilatation resulted in cardiac failure, decompensated with digitalisation and death occurred at the age of 4 months. This case represents the severe end of the clinical spectrum of Marfan syndrome, namely neonatal Marfan syndrome. Molecular diagnostic analyses confirmed a de novo exon 25 mutation in the FBN1 gene.

  1. Antisense PMO found in dystrophic dog model was effective in cells from exon 7-deleted DMD patient.

    Directory of Open Access Journals (Sweden)

    Takashi Saito

    Full Text Available BACKGROUND: Antisense oligonucleotide-induced exon skipping is a promising approach for treatment of Duchenne muscular dystrophy (DMD. We have systemically administered an antisense phosphorodiamidate morpholino oligomer (PMO targeting dystrophin exons 6 and 8 to a dog with canine X-linked muscular dystrophy in Japan (CXMD(J lacking exon 7 and achieved recovery of dystrophin in skeletal muscle. To date, however, antisense chemical compounds used in DMD animal models have not been directly applied to a DMD patient having the same type of exon deletion. We recently identified a DMD patient with an exon 7 deletion and tried direct translation of the antisense PMO used in dog models to the DMD patient's cells. METHODOLOGY/PRINCIPAL FINDINGS: We converted fibroblasts of CXMD(J and the DMD patient to myotubes by FACS-aided MyoD transduction. Antisense PMOs targeting identical regions of dog and human dystrophin exons 6 and 8 were designed. These antisense PMOs were mixed and administered as a cocktail to either dog or human cells in vitro. In the CXMD(J and human DMD cells, we observed a similar efficacy of skipping of exons 6 and 8 and a similar extent of dystrophin protein recovery. The accompanying skipping of exon 9, which did not alter the reading frame, was different between cells of these two species. CONCLUSION/SIGNIFICANCE: Antisense PMOs, the effectiveness of which has been demonstrated in a dog model, achieved multi-exon skipping of dystrophin gene on the FACS-aided MyoD-transduced fibroblasts from an exon 7-deleted DMD patient, suggesting the feasibility of systemic multi-exon skipping in humans.

  2. Plant domestication slows pest evolution.

    Science.gov (United States)

    Turcotte, Martin M; Lochab, Amaneet K; Turley, Nash E; Johnson, Marc T J

    2015-09-01

    Agricultural practices such as breeding resistant varieties and pesticide use can cause rapid evolution of pest species, but it remains unknown how plant domestication itself impacts pest contemporary evolution. Using experimental evolution on a comparative phylogenetic scale, we compared the evolutionary dynamics of a globally important economic pest - the green peach aphid (Myzus persicae) - growing on 34 plant taxa, represented by 17 crop species and their wild relatives. Domestication slowed aphid evolution by 13.5%, maintained 10.4% greater aphid genotypic diversity and 5.6% higher genotypic richness. The direction of evolution (i.e. which genotypes increased in frequency) differed among independent domestication events but was correlated with specific plant traits. Individual-based simulation models suggested that domestication affects aphid evolution directly by reducing the strength of selection and indirectly by increasing aphid density and thus weakening genetic drift. Our results suggest that phenotypic changes during domestication can alter pest evolutionary dynamics. © 2015 John Wiley & Sons Ltd/CNRS.

  3. Genetic variation at Exon2 of TLR4 gene and its association with ...

    African Journals Online (AJOL)

    This study was conducted to analyze the polymorphisms of chicken Toll-like receptors 4(TLR4) gene and aimed to provide a theoretical foundation for a further research on correlation between chicken TLR4 gene and disease resistance. Genetic variations at exon 2 of TLR4 gene in 14 chicken breeds and the red jungle ...

  4. Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women

    NARCIS (Netherlands)

    Claessen, K. M. J. A.; Kloppenburg, M.; Kroon, H. M.; Bijsterbosch, J.; Pereira, A. M.; Romijn, J. A.; van der Straaten, T.; Nelissen, R. G. H. H.; Hofman, A.; Uitterlinden, A. G.; Duijnisveld, B. J.; Lakenberg, N.; Beekman, M.; van Meurs, J. B.; Slagboom, P. E.; Biermasz, N. R.; Meulenbelt, I.

    2014-01-01

    Background Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. Objective To study

  5. The exon-3 deleted growth hormone receptor polymorphism predisposes to long-term complications of acromegaly

    NARCIS (Netherlands)

    Wassenaar, M. J. E.; Biermasz, N. R.; Pereira, A. M.; van der Klaauw, A. A.; Smit, J. W. A.; Roelfsema, F.; van der Straaten, T.; Cazemier, M.; Hommes, D. W.; Kroon, H. M.; Kloppenburg, M.; Guchelaar, H.-J.; Romijn, J. A.

    2009-01-01

    The aim of the study was to evaluate the impact of the genomic deletion of exon 3 of the GH receptor (d3GHR) on long-term clinical outcome of acromegaly in a well-characterized cohort of patients with long-term remission of acromegaly. We conducted a cross-sectional study. The presence of the d3GHR

  6. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy.

    Science.gov (United States)

    Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita; Ferry, Arnaud; Arandel, Ludovic; Delalande, Olivier; Jollet, Arnaud; Dingli, Florent; Lee, Kuang-Yung; Peccate, Cécile; Lorain, Stéphanie; Kabashi, Edor; Athanasopoulos, Takis; Koo, Taeyoung; Loew, Damarys; Swanson, Maurice S; Le Rumeur, Elisabeth; Dickson, George; Allamand, Valérie; Marie, Joëlle; Furling, Denis

    2015-05-28

    Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1.

  7. Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene

    Directory of Open Access Journals (Sweden)

    Sue Fletcher

    2012-01-01

    Full Text Available Protein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin gene expression so that a disease-associated dystrophin pre-mRNA is processed into a Becker muscular dystrophy-like mature transcript. Despite genomic deletions that may encompass hundreds of kilobases of the gene, some dystrophin mutations appear “leaky”, and low levels of high molecular weight, and presumably semi-functional, dystrophin are produced. A likely causative mechanism is endogenous exon skipping, and Duchenne individuals with higher baseline levels of dystrophin may respond more efficiently to the administration of splice-switching antisense oligomers. We optimized excision of exons 8 and 9 in normal human myoblasts, and evaluated several oligomers in cells from eight Duchenne muscular dystrophy patients with deletions in a known “leaky” region of the dystrophin gene. Inter-patient variation in response to antisense oligomer induced skipping in vitro appeared minimal. We describe oligomers targeting exon 8, that unequivocally increase dystrophin above baseline in vitro, and propose that patients with leaky mutations are ideally suited for participation in antisense oligomer mediated splice-switching clinical studies.

  8. Immortalized Muscle Cell Model to Test the Exon Skipping Efficacy for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Quynh Nguyen

    2017-10-01

    Full Text Available Duchenne muscular dystrophy (DMD is a lethal genetic disorder that most commonly results from mutations disrupting the reading frame of the dystrophin (DMD gene. Among the therapeutic approaches employed, exon skipping using antisense oligonucleotides (AOs is one of the most promising strategies. This strategy aims to restore the reading frame, thus producing a truncated, yet functioning dystrophin protein. In 2016, the Food and Drug Administration (FDA conditionally approved the first AO-based drug, eteplirsen (Exondys 51, developed for DMD exon 51 skipping. An accurate and reproducible method to quantify exon skipping efficacy is essential for evaluating the therapeutic potential of different AOs sequences. However, previous in vitro screening studies have been hampered by the limited proliferative capacity and insufficient amounts of dystrophin expressed by primary muscle cell lines that have been the main system used to evaluate AOs sequences. In this paper, we illustrate the challenges associated with primary muscle cell lines and describe a novel approach that utilizes immortalized cell lines to quantitatively evaluate the exon skipping efficacy in in vitro studies.

  9. Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    van Ommen Gert Jan B

    2011-04-01

    Full Text Available Abstract Background Myostatin is a potent muscle growth inhibitor that belongs to the Transforming Growth Factor-β (TGF-β family. Mutations leading to non functional myostatin have been associated with hypermuscularity in several organisms. By contrast, Duchenne muscular dystrophy (DMD is characterized by a loss of muscle fibers and impaired regeneration. In this study, we aim to knockdown myostatin by means of exon skipping, a technique which has been successfully applied to reframe the genetic defect of dystrophin gene in DMD patients. Methods We targeted myostatin exon 2 using antisense oligonucleotides (AON in healthy and DMD-derived myotubes cultures. We assessed the exon skipping level, transcriptional expression of myostatin and its target genes, and combined myostatin and several dystrophin AONs. These AONs were also applied in the mdx mice models via intramuscular injections. Results Myostatin AON induced exon 2 skipping in cell cultures and to a lower extent in the mdx mice. It was accompanied by decrease in myostatin mRNA and enhanced MYOG and MYF5 expression. Furthermore, combination of myostatin and dystrophin AONs induced simultaneous skipping of both genes. Conclusions We conclude that two AONs can be used to target two different genes, MSTN and DMD, in a straightforward manner. Targeting multiple ligands of TGF-beta family will be more promising as adjuvant therapies for DMD.

  10. SNP discovery in candidate adaptive genes using exon capture in a free-ranging alpine ungulate

    Science.gov (United States)

    Gretchen H. Roffler; Stephen J. Amish; Seth Smith; Ted Cosart; Marty Kardos; Michael K. Schwartz; Gordon Luikart

    2016-01-01

    Identification of genes underlying genomic signatures of natural selection is key to understanding adaptation to local conditions. We used targeted resequencing to identify SNP markers in 5321 candidate adaptive genes associated with known immunological, metabolic and growth functions in ovids and other ungulates. We selectively targeted 8161 exons in protein-coding...

  11. Investigation of Exon 1 in FXN Gene in Patients with Clinical Symptomatic of Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    Naseroleslami M

    2013-01-01

    Full Text Available Background and Objectives: Friedreich’s ataxia (FRDA is an autosomal recessive disorder that is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. Approximately two-thirds of these patients suffer from cardiomyopathy and more than 30% have diabetes mellitus. Individuals with FRDA have identifiable mutations in the FXN gene. The most common type of mutation which is observed on both alleles in more than 98% of patients is an expansion of a GAA triplet-repeat in intron of FXN gene. Approximately 2% of individuals with FRDA are compound heterozygotes, who have a GAA expansion in the disease-causing range in one FXN allele and an inactivating FXN mutation in another allele. Aim of the present study was to investigate exon 1 in FRDA gene in patients with clinical symptoms of Friedreich’s Ataxia that have not GAA triplet-repeat expansion in intron 1 of FXN gene.Methods: In this study, exon 1 in 5 patients suspected of FRDA analyzed using PCR and sequencing. Results: An A to G transition at nucleotide number 815284, in exon 1 was observed in all patients. Conclusion: The results of this study showed that disease-causing homozygous mutations could be because of consanguinity marriage in Iran. Therefore, sequencing of all exons of the gene is necessary.

  12. Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping

    Czech Academy of Sciences Publication Activity Database

    Divina, Petr; Kvitkovicova, Andrea; Buratti, E.; Vorechovsky, I.

    2009-01-01

    Roč. 17, č. 6 (2009), s. 759-765 ISSN 1018-4813 Institutional research plan: CEZ:AV0Z50520514 Keywords : mutation * cryptic splice site * exon skipping Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.564, year: 2009

  13. Mucopolysaccharidosis IVA: Four new exonic mutations in patients with N-acetylgalactosamine-6-sulfate sulfatase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Tomatsu, Shunji; Fukuda, Seiji; Yamagishi, Atsushi [Gifu Univ. (Japan)] [and others

    1996-05-01

    We report four new mutations in Japanese patients with mucopolysaccharidosis IVA (MPSIVA) who were heterozygous for a common double gene deletion. A nonsense mutation of CAG to TAG at codon 148 in exon 4 was identified, resulting in a change of Q to a stop codon and three missense mutations: V (GTC) to A (GCC) at codon 138 in exon 4, P (CCC) to S (TCC) at codon 151 in exon 5, and P (CCC) to L (CTC) at codon 151 in exon 5. Introduction of these mutations into the normal GALNS cDNA and transient expression in cultured fibroblasts resulted in a significant decrease in the enzyme activity. V138A and Q148X mutations result in changes of restriction site, which were analyzed by restriction-enzyme assay. P151S and P151L mutations that did not alter the restriction site were detected by direct sequencing or allele specific oligohybridization. Detection of the double gene deletion was initially done using Southern blots and was confirmed by PCR. Haplotypes were determined using seven polymorphisms to the GALNS locus in families with the double gene deletion. Haplotype analysis showed that the common double gene deletion occurred on a single haplotype, except for some variation in a VNTR-like polymorphism. This finding is consistent with a common founder for all individuals with this mutation. 48 refs., 5 figs., 1 tab.

  14. Loss of Endocan tumorigenic properties after alternative splicing of exon 2

    International Nuclear Information System (INIS)

    Depontieu, Florence; Grigoriu, Bogdan-Dragos; Scherpereel, Arnaud; Adam, Estelle; Delehedde, Maryse; Gosset, Philippe; Lassalle, Philippe

    2008-01-01

    Endocan was originally described as a dermatan sulfate proteoglycan found freely circulating in the blood. Endocan expression confers tumorigenic properties to epithelial cell lines or accelerate the growth of already tumorigenic cells. This molecule is the product of a single gene composed of 3 exons. Previous data showed that endocan mRNA is subject to alternative splicing with possible generation of two protein products. In the present study we identified, and functionally characterized, the alternative spliced product of the endocan gene: the exon 2-deleted endocan, called endocanΔ2. Stable, endocanΔ2-overexpressing cell lines were generated to investigate the biological activities of this new alternatively spliced product of endocan gene. Tumorigenesis was studied by inoculating endocan and endocanΔ2 expressing cell lines subcutaneously in SCID mice. Biochemical properties of endocan and endocanΔ2 were studied after production of recombinant proteins in various cell lines of human and murine origin. Our results showed that the exon 2 deletion impairs synthesis of the glycan chain, known to be involved in the pro-tumoral effect of endocan. EndocanΔ2 did not promote tumor formation by 293 cells implanted in the skin of severe combined immunodeficient (SCID) mice. Our results emphasize the key role of the polypeptide sequence encoded by the exon 2 of endocan gene in tumorigenesis, and suggest that this sequence could be a target for future therapies against cancer

  15. Morpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse.

    Science.gov (United States)

    Fletcher, Sue; Honeyman, Kaite; Fall, Abbie M; Harding, Penny L; Johnsen, Russell D; Steinhaus, Joshua P; Moulton, Hong M; Iversen, Patrick L; Wilton, Stephen D

    2007-09-01

    Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterized by an absence of functional protein, whereas Becker muscular dystrophy, commonly caused by in-frame deletions, shows synthesis of partially functional protein. Anti-sense oligonucleotides can induce specific exon removal during processing of the dystrophin primary transcript, while maintaining or restoring the reading frame, and thereby overcome protein-truncating mutations. The mdx mouse has a non-sense mutation in exon 23 of the dystrophin gene that precludes functional dystrophin production, and this model has been used in the development of treatment strategies for dystrophinopathies. A phosphorodiamidate morpholino oligomer (PMO) has previously been shown to exclude exon 23 from the dystrophin gene transcript and induce dystrophin expression in the mdxmouse, in vivo and in vitro. In this report, a cell-penetrating peptide (CPP)-conjugated oligomer targeted to the mouse dystrophin exon 23 donor splice site was administered to mdxmice by intraperitoneal injection. We demonstrate dystrophin expression and near-normal muscle architecture in all muscles examined, except for cardiac muscle. The CPP greatly enhanced uptake of the PMO, resulting in widespread dystrophin expression.

  16. Comprehensive survey of SNPs in the Affymetrix exon array using the 1000 Genomes dataset.

    Directory of Open Access Journals (Sweden)

    Eric R Gamazon

    Full Text Available Microarray gene expression data has been used in genome-wide association studies to allow researchers to study gene regulation as well as other complex phenotypes including disease risks and drug response. To reach scientifically sound conclusions from these studies, however, it is necessary to get reliable summarization of gene expression intensities. Among various factors that could affect expression profiling using a microarray platform, single nucleotide polymorphisms (SNPs in target mRNA may lead to reduced signal intensity measurements and result in spurious results. The recently released 1000 Genomes Project dataset provides an opportunity to evaluate the distribution of both known and novel SNPs in the International HapMap Project lymphoblastoid cell lines (LCLs. We mapped the 1000 Genomes Project genotypic data to the Affymetrix GeneChip Human Exon 1.0ST array (exon array, which had been used in our previous studies and for which gene expression data had been made publicly available. We also evaluated the potential impact of these SNPs on the differentially spliced probesets we had identified previously. Though the 1000 Genomes Project data allowed a comprehensive survey of the SNPs in this particular array, the same approach can certainly be applied to other microarray platforms. Furthermore, we present a detailed catalogue of SNP-containing probesets (exon-level and transcript clusters (gene-level, which can be considered in evaluating findings using the exon array as well as benefit the design of follow-up experiments and data re-analysis.

  17. Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a ...

    Indian Academy of Sciences (India)

    RESEARCH ARTICLE. Deletion of SNURF/SNRPN U1B and U1B* upstream exons in a child ... whereby genes are expressed in a parent-of-origin dependent manner. One of the ... lity, neurodevelopmental delay, features of attention deficit hyperactivity .... Received 16 December 2015; accepted 8 January 2016. Unedited ...

  18. Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment

    NARCIS (Netherlands)

    Schür, R R; Boks, M P; Rutten, Bart P. F.; Daskalakis, N.P.; de Nijs, Laurence; van Zuiden, M.; Kavelaars, A; Heijnen, C J; Joëls, M; Kahn, R S; Geuze, E; Vermetten, E; Vinkers, C H

    2017-01-01

    Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1F region (GR-1F) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1F methylation changes over time in relation to trauma exposure and the

  19. Targeted exonic sequencing of GWAS loci in the high extremes of the plasma lipids distribution

    NARCIS (Netherlands)

    Patel, Aniruddh P.; Peloso, Gina M.; Pirruccello, James P.; Johansen, Christopher T.; Dubé, Joseph B.; Larach, Daniel B.; Ban, Matthew R.; Dallinge-Thie, Geesje M.; Gupta, Namrata; Boehnke, Michael; Abecasis, Gonçalo R.; Kastelein, John J. P.; Hovingh, G. Kees; Hegele, Robert A.; Rader, Daniel J.; Kathiresan, Sekar

    2016-01-01

    Genome-wide association studies (GWAS) for plasma lipid levels have mapped numerous genomic loci, with each region often containing many protein-coding genes. Targeted re-sequencing of exons is a strategy to pinpoint causal variants and genes. We performed solution-based hybrid selection of 9008

  20. Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Fiorella Guadagni

    2012-01-01

    Full Text Available The K-ras gene is frequently mutated in colorectal cancer and has been associated with tumor initiation and progression; approximately 90% of the activating mutations are found in codons 12 and 13 of exon 1 and just under 5% in codon 61 located in exon 2. These mutations determine single aminoacidic substitutions in the GTPase pocket leading to a block of the GTP hydrolytic activity of the K-ras p21 protein, and therefore to its constitutive activation. Point mutations in sites of the K-ras gene, other than codons 12, 13 and 61, and other types of genetic alterations, may occur in a minority of cases, such as in the less frequent cases of double mutations in the K-ras gene. However, all mutations in this gene, even those which occur in non-canonical sites or double mutations, are relevant oncogenic alterations in colorectal cancer and may underlie K-ras pathway hyperactivation. In the present study, we report the case of a patient with colorectal cancer presenting a concurrent point mutation in exons 1 and 2 of the K-ras gene, a GGT to TGT substitution (Glycine to Cysteine at codon 12, and a GAC to AAC substitution (Aspartic Acid to Asparagine at codon 57. In addition, we found in the same patient’s sample a silent polymorphism at codon 11 (Ala11Ala of exon 1. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 729–733

  1. Duchenne muscular dystrophy in a female with compound heterozygous contiguous exon deletions.

    Science.gov (United States)

    Takeshita, Eri; Minami, Narihiro; Minami, Kumiko; Suzuki, Mikiya; Awashima, Takeya; Ishiyama, Akihiko; Komaki, Hirofumi; Nishino, Ichizo; Sasaki, Masayuki

    2017-06-01

    Females with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) mutations rarely exhibit clinical symptoms from childhood, although potential mechanisms for symptoms associated with DMD and BMD in females have been reported. We report the case of a female DMD patient with a clinical course indistinguishable from that of a male DMD patient, and who possessed compound heterozygous contiguous exon deletions in the dystrophin gene. She exhibited Gowers' sign, calf muscle hypertrophy, and a high serum creatine kinase level at 2 years. Her muscle pathology showed most of the fibers were negative for dystrophin immunohistochemical staining. She lost ambulation at 11 years. Multiplex ligation-dependent probe amplification analysis of this gene detected one copy of exons 48-53; she was found to be a BMD carrier with an in-frame deletion. Messenger RNA from her muscle demonstrated out-of-frame deletions of exons 48-50 and 51-53 occurring on separate alleles. Genomic DNA from her lymphocytes demonstrated the accurate deletion region on each allele. To our knowledge, this is the first report on a female patient possessing compound heterozygous contiguous exon deletions in the dystrophin gene, leading to DMD. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Longitudinal changes in glucocorticoid receptor exon 1(F) methylation and psychopathology after military deployment

    NARCIS (Netherlands)

    Schür, R. R.; Boks, M. P.; Rutten, B. P. F.; Daskalakis, N. P.; de Nijs, L.; van Zuiden, M.; Kavelaars, A.; Heijnen, C. J.; Joëls, M.; Kahn, R. S.; Geuze, E.; Vermetten, E.; Vinkers, C. H.

    2017-01-01

    Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1(F) region (GR-1(F)) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1(F) methylation changes over time in relation to trauma exposure and the

  3. Determination of exon 7 SMN1 deletion in Iranian patients and ...

    Indian Academy of Sciences (India)

    In consideration of these defects and in line with the latter references, we have ... master mix (Roche, Mannheim, Germany), 5 ng of genomic. DNA, and 10 pmol of .... PCR test which can evaluate comprehensively the status of. SMN1 exon 7 ...

  4. Disease-causing mutations in exon 11 of the medium-chain acyl-CoA dehydrogenase gene

    DEFF Research Database (Denmark)

    Andresen, B S; Jensen, T G; Bross, P

    1994-01-01

    spot. Here we describe the results from sequence analysis of exon 11 and part of the flanking introns from 36 compound heterozygous patients with MCAD deficiency. We have identified four previously unknown disease-causing mutations (M301T, S311R, R324X, and E359X) and two silent mutations in exon 11...

  5. Applications of Slow Light in Telecommunications

    National Research Council Canada - National Science Library

    Boyd, Robert W; Gauthier, Daniel J; Gaeta, Alexander L

    2006-01-01

    .... Now, optical scientists are turning their attention toward developing useful applications of slow light, including controllable optical delay lines, optical buffers and true time delay methods...

  6. Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer.

    Directory of Open Access Journals (Sweden)

    Bankanidhi Sahoo

    Full Text Available Expansion of the polyglutamine (polyQ track of the Huntingtin (HTT protein above 36 is associated with a sharply enhanced risk of Huntington's disease (HD. Although there is general agreement that HTT toxicity resides primarily in N-terminal fragments such as the HTT exon1 protein, there is no consensus on the nature of the physical states of HTT exon1 that are induced by polyQ expansion, nor on which of these states might be responsible for toxicity. One hypothesis is that polyQ expansion induces an alternative, toxic conformation in the HTT exon1 monomer. Alternative hypotheses posit that the toxic species is one of several possible aggregated states. Defining the nature of the toxic species is particularly challenging because of facile interconversion between physical states as well as challenges to identifying these states, especially in vivo. Here we describe the use of fluorescence correlation spectroscopy (FCS to characterize the detailed time and repeat length dependent self-association of HTT exon1-like fragments both with chemically synthesized peptides in vitro and with cell-produced proteins in extracts and in living cells. We find that, in vitro, mutant HTT exon1 peptides engage in polyQ repeat length dependent dimer and tetramer formation, followed by time dependent formation of diffusible spherical and fibrillar oligomers and finally by larger, sedimentable amyloid fibrils. For expanded polyQ HTT exon1 expressed in PC12 cells, monomers are absent, with tetramers being the smallest molecular form detected, followed in the incubation time course by small, diffusible aggregates at 6-9 hours and larger, sedimentable aggregates that begin to build up at 12 hrs. In these cell cultures, significant nuclear DNA damage appears by 6 hours, followed at later times by caspase 3 induction, mitochondrial dysfunction, and cell death. Our data thus defines limits on the sizes and concentrations of different physical states of HTT exon1 along the

  7. Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease

    Directory of Open Access Journals (Sweden)

    Lorena Suarez-Artiles

    2018-01-01

    Full Text Available Mutations in the OCRL gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no additional clinical defects. It is not yet understood why some OCRL mutations cause the phenotype of Lowe syndrome, while others develop the milder phenotype of Dent-2 disease. Our goal was to gain new insights into the consequences of OCRL exonic mutations on pre-mRNA splicing. Using predictive bioinformatics tools, we selected thirteen missense mutations and one synonymous mutation based on their potential effects on splicing regulatory elements or splice sites. These mutations were analyzed in a minigene splicing assay. Results of the RNA analysis showed that three presumed missense mutations caused alterations in pre-mRNA splicing. Mutation c.741G>T; p.(Trp247Cys generated splicing silencer sequences and disrupted splicing enhancer motifs that resulted in skipping of exon 9, while mutations c.2581G>A; p.(Ala861Thr and c.2581G>C; p.(Ala861Pro abolished a 5′ splice site leading to skipping of exon 23. Mutation c.741G>T represents the first OCRL exonic variant outside the conserved splice site dinucleotides that results in alteration of pre-mRNA splicing. Our results highlight the importance of evaluating the effects of OCRL exonic mutations at the mRNA level.

  8. SNP discovery in candidate adaptive genes using exon capture in a free-ranging alpine ungulate

    Science.gov (United States)

    Roffler, Gretchen H.; Amish, Stephen J.; Smith, Seth; Cosart, Ted F.; Kardos, Marty; Schwartz, Michael K.; Luikart, Gordon

    2016-01-01

    Identification of genes underlying genomic signatures of natural selection is key to understanding adaptation to local conditions. We used targeted resequencing to identify SNP markers in 5321 candidate adaptive genes associated with known immunological, metabolic and growth functions in ovids and other ungulates. We selectively targeted 8161 exons in protein-coding and nearby 5′ and 3′ untranslated regions of chosen candidate genes. Targeted sequences were taken from bighorn sheep (Ovis canadensis) exon capture data and directly from the domestic sheep genome (Ovis aries v. 3; oviAri3). The bighorn sheep sequences used in the Dall's sheep (Ovis dalli dalli) exon capture aligned to 2350 genes on the oviAri3 genome with an average of 2 exons each. We developed a microfluidic qPCR-based SNP chip to genotype 476 Dall's sheep from locations across their range and test for patterns of selection. Using multiple corroborating approaches (lositan and bayescan), we detected 28 SNP loci potentially under selection. We additionally identified candidate loci significantly associated with latitude, longitude, precipitation and temperature, suggesting local environmental adaptation. The three methods demonstrated consistent support for natural selection on nine genes with immune and disease-regulating functions (e.g. Ovar-DRA, APC, BATF2, MAGEB18), cell regulation signalling pathways (e.g. KRIT1, PI3K, ORRC3), and respiratory health (CYSLTR1). Characterizing adaptive allele distributions from novel genetic techniques will facilitate investigation of the influence of environmental variation on local adaptation of a northern alpine ungulate throughout its range. This research demonstrated the utility of exon capture for gene-targeted SNP discovery and subsequent SNP chip genotyping using low-quality samples in a nonmodel species.

  9. JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis

    Science.gov (United States)

    Scott, Linda M.; Tong, Wei; Levine, Ross L.; Scott, Mike A.; Beer, Philip A.; Stratton, Michael R.; Futreal, P. Andrew; Erber, Wendy N.; McMullin, Mary Frances; Harrison, Claire N.; Warren, Alan J.; Gilliland, D. Gary; Lodish, Harvey F.; Green, Anthony R.

    2010-01-01

    BACKGROUND The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. METHODS We searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis. The mutations were characterized biochemically and in a murine model of bone marrow transplantation. RESULTS We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3. They also exhibited increased phosphorylation of JAK2 and extracellular regulated kinase 1 and 2, as compared with cells transduced by wild-type JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation. CONCLUSIONS JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis

  10. Use of epitope libraries to identify exon-specific monoclonal antibodies for characterization of altered dystrophins in muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen thi Man; Morris, G.E. (North East Wales Inst., Clwyd (United Kingdom))

    1993-06-01

    The majority of mutations in Xp21-linked muscular dystrophy (MD) can be identified by PCR or Southern blotting, as deletions or duplications of groups of exons in the dystrophin gene, but it is not always possible to predict how much altered dystrophin, if any, will be produced. Use of exon-specific monoclonal antibodies (mAbs) on muscle biopsies from MD patients can, in principle, provide information on both the amount of altered dystrophin produced and, when dystrophin is present, the nature of the genetic deletion or point mutation. For this purpose, mAbs which recognize regions of dystrophin encoded by known exons and whose binding is unaffected by the absence of adjacent exons are required. To map mAbs to specific exons, random [open quotes]libraries[close quotes] of expressed dystrophin fragments were created by cloning DNAseI digestion fragments of a 4.3-kb dystrophin cDNA into a pTEX expression vector. The libraries were then used to locate the epitopes recognized by 48 mAbs to fragments of 25--60 amino acids within the 1,434-amino-acid dystrophin fragment used to produce the antibodies. This is sufficiently detailed to allow further refinement by using synthetic peptides and, in many cases, to identify the exon in the DMD (Duchenne MD) gene which encodes the epitope. To illustrate their use in dystrophin analysis, a Duchenne patient with a frameshift deletion of exons 42 and 43 makes a truncated dystrophin encoded by exons 1--41, and the authors now show that this can be detected in the sarcolemma by mAbs up to and including those specific for exon 41 epitopes but not by mAbs specific for exon 43 or later epitopes. 38 refs., 2 figs., 4 tabs.

  11. Characterization of a spliced exon product of herpes simplex type-1 latency-associated transcript in productively infected cells

    International Nuclear Information System (INIS)

    Kang, Wen; Mukerjee, Ruma; Gartner, Jared J.; Hatzigeorgiou, Artemis G.; Sandri-Goldin, Rozanne M.; Fraser, Nigel W.

    2006-01-01

    The latency-associated transcripts (LATs) of herpes simplex virus type-1 (HSV-1) are the only viral RNAs accumulating during latent infections in the sensory ganglia of the peripheral nervous system. The major form of LAT that accumulates in latently infected neurons is a 2 kb intron, spliced from a much less abundant 8.3 primary transcript. The spliced exon mRNA has been hard to detect. However, in this study, we have examined the spliced exon RNA in productively infected cells using ribonuclease protection (RPA), and quantitative RT-PCR (q-PCR) assays. We were able to detect the LAT exon RNA in productively infected SY5Y cells (a human neuronal cell line). The level of the LAT exon RNA was found to be approximately 5% that of the 2 kb intron RNA and thus is likely to be relatively unstable. Quantitative RT-PCR (q-PCR) assays were used to examine the LAT exon RNA and its properties. They confirmed that the LAT exon mRNA is present at a very low level in productively infected cells, compared to the levels of other viral transcripts. Furthermore, experiments showed that the LAT exon mRNA is expressed as a true late gene, and appears to be polyadenylated. In SY5Y cells, in contrast to most late viral transcripts, the LAT exon RNA was found to be mainly nuclear localized during the late stage of a productive infection. Interestingly, more LAT exon RNA was found in the cytoplasm in differentiated compared to undifferentiated SY5Y cells, suggesting the nucleocytoplasmic distribution of the LAT exon RNA and its related function may be influenced by the differentiation state of cells

  12. Response of electret dosemeter to slow neutrons

    International Nuclear Information System (INIS)

    Ghilardi, A.J.P.; Pela, C.A.; Zimmerman, R.L.

    1987-01-01

    The response of electret dosemeter to slow neutrons exposure is cited, mentioning the preparation and the irradiation of dosemeter with Am-Be source. Some theory considerations about the response of electret dosemeter to slow and fast neutrons are also presented. (C.G.C.) [pt

  13. Tandem queue with server slow-down

    NARCIS (Netherlands)

    Miretskiy, D.I.; Scheinhardt, W.R.W.; Mandjes, M.R.H.

    2007-01-01

    We study how rare events happen in the standard two-node tandem Jackson queue and in a generalization, the socalled slow-down network, see [2]. In the latter model the service rate of the first server depends on the number of jobs in the second queue: the first server slows down if the amount of

  14. Slow-light pulses in moving media

    International Nuclear Information System (INIS)

    Fiurasek, J.; Leonhardt, U.; Parentani, R.

    2002-01-01

    Slow light in moving media reaches a counterintuitive regime when the flow speed of the medium approaches the group velocity of light. Pulses can penetrate a region where a counterpropagating flow exceeds the group velocity. When the counterflow slows down, pulses are reflected

  15. Can fast and slow intelligence be differentiated?

    NARCIS (Netherlands)

    Partchev, I.; de Boeck, P.

    2012-01-01

    Responses to items from an intelligence test may be fast or slow. The research issue dealt with in this paper is whether the intelligence involved in fast correct responses differs in nature from the intelligence involved in slow correct responses. There are two questions related to this issue: 1.

  16. Slow Movement/Slow University: Critical Engagements. Introduction to the Thematic Section

    Directory of Open Access Journals (Sweden)

    Maggie O'Neill

    2014-09-01

    Full Text Available This thematic section emerged from two seminars that took place at Durham University in England in November 2013 and March 2014 on the possibilities for thinking through what a change movement towards slow might mean for the University. Slow movements have emerged in relation to a number of topics: Slow food, Citta slow and more recently, slow science. What motivated us in the seminars was to explore how far these movements could help us address the acceleration and intensification of work within our own and other universities, and indeed, what new learning, research, philosophies, practices, structures and governance might emerge. This editorial introduction presents the concept of the "slow university" and introduces our critical engagements with slow. The articles presented here interrogate the potentialities, challenges, problems and pitfalls of the slow university in an era of corporate culture and management rationality. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1403166

  17. Connecting slow earthquakes to huge earthquakes.

    Science.gov (United States)

    Obara, Kazushige; Kato, Aitaro

    2016-07-15

    Slow earthquakes are characterized by a wide spectrum of fault slip behaviors and seismic radiation patterns that differ from those of traditional earthquakes. However, slow earthquakes and huge megathrust earthquakes can have common slip mechanisms and are located in neighboring regions of the seismogenic zone. The frequent occurrence of slow earthquakes may help to reveal the physics underlying megathrust events as useful analogs. Slow earthquakes may function as stress meters because of their high sensitivity to stress changes in the seismogenic zone. Episodic stress transfer to megathrust source faults leads to an increased probability of triggering huge earthquakes if the adjacent locked region is critically loaded. Careful and precise monitoring of slow earthquakes may provide new information on the likelihood of impending huge earthquakes. Copyright © 2016, American Association for the Advancement of Science.

  18. Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array

    Directory of Open Access Journals (Sweden)

    Sugnet Charles

    2006-12-01

    Full Text Available Abstract Background Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. Results We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic

  19. Novel exon-exon breakpoint in CIC-DUX4 fusion sarcoma identified by anchored multiplex PCR (Archer FusionPlex Sarcoma Panel).

    Science.gov (United States)

    Loke, Benjamin Nathanael; Lee, Victor Kwan Min; Sudhanshi, Jain; Wong, Meng Kang; Kuick, Chik Hong; Puhaindran, Mark; Chang, Kenneth Tou En

    2017-08-01

    We describe the clinical and pathological features and novel genetic findings of a case of CIC-DUX4 sarcoma occurring in the thigh of a 35-year-old man. Fusion gene detection using a next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) was used to identify the novel fusion breakpoints of this CIC-DUX4 sarcoma using formalin-fixed and paraffin-embedded tumour material. This CIC-DUX4 sarcoma has a novel fusion breakpoint between exon 20 of the CIC gene and exon 1 of the DUX4 gene. This case report describes an additional case of CIC-DUX4 sarcoma with a novel fusion breakpoint, and demonstrates the value of this next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) in both diagnosis for patient care and in identification of a novel fusion breakpoint in this tumour type. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Identification of small molecule and genetic modulators of AON-induced dystrophin exon skipping by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Debra A O'Leary

    Full Text Available One therapeutic approach to Duchenne Muscular Dystrophy (DMD recently entering clinical trials aims to convert DMD phenotypes to that of a milder disease variant, Becker Muscular Dystrophy (BMD, by employing antisense oligonucleotides (AONs targeting splice sites, to induce exon skipping and restore partial dystrophin function. In order to search for small molecule and genetic modulators of AON-dependent and independent exon skipping, we screened approximately 10,000 known small molecule drugs, >17,000 cDNA clones, and >2,000 kinase- targeted siRNAs against a 5.6 kb luciferase minigene construct, encompassing exon 71 to exon 73 of human dystrophin. As a result, we identified several enhancers of exon skipping, acting on both the reporter construct as well as endogenous dystrophin in mdx cells. Multiple mechanisms of action were identified, including histone deacetylase inhibition, tubulin modulation and pre-mRNA processing. Among others, the nucleolar protein NOL8 and staufen RNA binding protein homolog 2 (Stau2 were found to induce endogenous exon skipping in mdx cells in an AON-dependent fashion. An unexpected but recurrent theme observed in our screening efforts was the apparent link between the inhibition of cell cycle progression and the induction of exon skipping.

  1. Molecular effects of autoimmune-risk promoter polymorphisms on expression, exon choice, and translational efficiency of interferon regulatory factor 5.

    Science.gov (United States)

    Clark, Daniel N; Lambert, Jared P; Till, Rodney E; Argueta, Lissenya B; Greenhalgh, Kathryn E; Henrie, Brandon; Bills, Trieste; Hawkley, Tyson F; Roznik, Marinya G; Sloan, Jason M; Mayhew, Vera; Woodland, Loc; Nelson, Eric P; Tsai, Meng-Hsuan; Poole, Brian D

    2014-05-01

    The rs2004640 single nucleotide polymorphism and the CGGGG copy-number variant (rs77571059) are promoter polymorphisms within interferon regulatory factor 5 (IRF5). They have been implicated as susceptibility factors for several autoimmune diseases. IRF5 uses alternative promoter splicing, where any of 4 first exons begin the mRNA. The CGGGG indel is in exon 1A's promoter; the rs2004640 allele creates a splicing recognition site, enabling usage of exon 1B. This study aimed at characterizing alterations in IRF5 mRNA due to these polymorphisms. Cells with risk polymorphisms exhibited ~2-fold higher levels of IRF5 mRNA and protein, but demonstrated no change in mRNA stability. Quantitative PCR demonstrated decreased usage of exons 1C and 1D in cell lines with the risk polymorphisms. RNA folding analysis revealed a hairpin in exon 1B; mutational analysis showed that the hairpin shape decreased translation 5-fold. Although translation of mRNA that uses exon 1B is low due to a hairpin, increased IRF5 mRNA levels in individuals with the rs2004640 risk allele lead to higher overall protein expression. In addition, several new splice variants of IRF5 were sequenced. IRF5's promoter polymorphisms alter first exon usage and increase transcription levels. High levels of IRF5 may bias the immune system toward autoimmunity.

  2. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Putnam, E.A.; Cho, M.; Milewicz, D.M. [Univ. of Texas-Houston Medical School, Houston, TX (United States)] [and others

    1996-03-29

    Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.

  3. The role of germline promoters and I exons in cytokine-induced gene-specific class switch recombination.

    Science.gov (United States)

    Dunnick, Wesley A; Shi, Jian; Holden, Victoria; Fontaine, Clinton; Collins, John T

    2011-01-01

    Germline transcription precedes class switch recombination (CSR). The promoter regions and I exons of these germline transcripts include binding sites for activation- and cytokine-induced transcription factors, and the promoter regions/I exons are essential for CSR. Therefore, it is a strong hypothesis that the promoter/I exons regions are responsible for much of cytokine-regulated, gene-specific CSR. We tested this hypothesis by swapping the germline promoter and I exons for the murine γ1 and γ2a H chain genes in a transgene of the entire H chain C-region locus. We found that the promoter/I exon for γ1 germline transcripts can direct robust IL-4-induced recombination to the γ2a gene. In contrast, the promoter/I exon for the γ2a germline transcripts works poorly in the context of the γ1 H chain gene, resulting in expression of γ1 H chains that is level. Nevertheless, the small amount of recombination to the chimeric γ1 gene is induced by IFN-γ. These results suggest that cytokine regulation of CSR, but not the magnitude of CSR, is regulated by the promoter/I exons.

  4. KEK-IMSS Slow Positron Facility

    Energy Technology Data Exchange (ETDEWEB)

    Hyodo, T; Wada, K; Yagishita, A; Kosuge, T; Saito, Y; Kurihara, T; Kikuchi, T; Shirakawa, A; Sanami, T; Ikeda, M; Ohsawa, S; Kakihara, K; Shidara, T, E-mail: toshio.hyodo@kek.jp [High Energy Accelerator Research Organization (KEK) 1-1 Oho, Tsukuba, Ibaraki, 305-0801 (Japan)

    2011-12-01

    The Slow Positron Facility at the Institute of Material Structure Science (IMSS) of High Energy Accelerator Research Organization (KEK) is a user dedicated facility with an energy tunable (0.1 - 35 keV) slow positron beam produced by a dedicated 55MeV linac. The present beam line branches have been used for the positronium time-of-flight (Ps-TOF) measurements, the transmission positron microscope (TPM) and the photo-detachment of Ps negative ions (Ps{sup -}). During the year 2010, a reflection high-energy positron diffraction (RHEPD) measurement station is going to be installed. The slow positron generator (converter/ moderator) system will be modified to get a higher slow positron intensity, and a new user-friendly beam line power-supply control and vacuum monitoring system is being developed. Another plan for this year is the transfer of a {sup 22}Na-based slow positron beam from RIKEN. This machine will be used for the continuous slow positron beam applications and for the orientation training of those who are interested in beginning researches with a slow positron beam.

  5. Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing

    Directory of Open Access Journals (Sweden)

    Zhilong Chen

    2018-02-01

    Full Text Available Titin (TTN is a major disease-causing gene in cardiac muscle. Titin (TTN contains 363 exons in human encoding various sizes of TTN protein due to alternative splicing regulated mainly by RNA binding motif 20 (RBM20. Three isoforms of TTN protein are produced by mutually exclusive exons 45 (Novex 1, 46 (Novex 2, and 48 (Novex 3. Alternatively splicing in Novex isoforms across species and whether Novex isoforms are associated with heart disease remains completely unknown. Cross-species exon comparison with the mVISTA online tool revealed that exon 45 is more highly conserved across all species than exons 46 and 48. Importantly, a conserved region between exons 47 and 48 across species was revealed for the first time. Reverse transcript polymerase chain reaction (RT-PCR and DNA sequencing confirmed a new exon named as 48′ in Novex 3. In addition, with primer pairs for Novex 1, a new truncated form preserving introns 44 and 45 was discovered. We discovered that Novex 2 is not expressed in the pig, mouse, and rat with Novex 2 primer pairs. Unexpectedly, three truncated forms were identified. One TTN variant with intron 46 retention is mainly expressed in the human and frog heart, another variant with co-expression of exons 45 and 46 exists predominantly in chicken and frog heart, and a third with retention of introns 45 and 46 is mainly expressed in pig, mouse, rat, and chicken. Using Rbm20 knockout rat heart, we revealed that RBM20 is not a splicing regulator of Novex variants. Furthermore, the expression levels of Novex variants in human hearts with cardiomyopathies suggested that Novexes 2 and 3 could be associated with dilated cardiomyopathy (DCM and/or arrhythmogenic right ventricular cardiomyopathy (ARVC. Taken together, our study reveals that splicing diversity of Novex exons across species and Novex variants might play a role in cardiomyopathy.

  6. Vitamin D receptor B1 and exon 1d: functional and evolutionary analysis.

    Science.gov (United States)

    Gardiner, Edith M; Esteban, Luis M; Fong, Colette; Allison, Susan J; Flanagan, Judith L; Kouzmenko, Alexander P; Eisman, John A

    2004-05-01

    The vitamin D receptor (VDR) shares a conserved structural and functional organization with other nuclear receptor (NR) superfamily members. For many NRs, N-terminal variant isoforms that display distinct cell-, stage- and promoter-specific actions have been identified. The novel VDR isoform VDRB1, with a 50 amino acid N-terminal extension, is produced from low abundance transcripts that contain exon 1d of the human VDR locus. There is evidence for the conservation of this exon in other mammalian and avian species. The transactivation differences between VDRB1 and the original VDR, clarified here, provide insights into mechanisms that may contribute to functional differences and potentially distinct physiological roles for these two VDR isoforms.

  7. Exonization of active mouse L1s: a driver of transcriptome evolution?

    Directory of Open Access Journals (Sweden)

    Badge Richard

    2007-10-01

    Full Text Available Abstract Background Long interspersed nuclear elements (LINE-1s, L1s have been recently implicated in the regulation of mammalian transcriptomes. Results Here, we show that members of the three active mouse L1 subfamilies (A, GF and TF contain, in addition to those on their sense strands, conserved functional splice sites on their antisense strands, which trigger multiple exonization events. The latter is particularly intriguing in the light of the strong antisense orientation bias of intronic L1s, implying that the toleration of antisense insertions results in an increased potential for exonization. Conclusion In a genome-wide analysis, we have uncovered evidence suggesting that the mobility of the large number of retrotransposition-competent mouse L1s (~2400 potentially active L1s in NCBIm35 has significant potential to shape the mouse transcriptome by continuously generating insertions into transcriptional units.

  8. Hypertension and Biliary Ductopenia in a Patient with Duplication of Exon 6 of the Gene

    Directory of Open Access Journals (Sweden)

    J. Uberos

    2012-01-01

    Full Text Available We describe a neonatal patient with biliary ductopenia featuring duplication of exon 6 of the JAG1 gene. Facial alterations were observed, consisting of a prominent forehead, sunken eyes, upward slanting palpebral fissures, hypertelorism, flat nasal root and prominent chin. From birth, these were accompanied by the development of haematuria and renal failure and by renal Doppler findings indicative of peripheral renal artery stenosis. JAG1 gene mutations on chromosome 20 have been associated with various anomalies, including biliary cholestasis, vertebral abnormalities, eye disorders, heart defects and facial dysmorphia. This syndrome, first described by Alagille, is an infrequent congenital disorder caused by a dominant autosomal inheritance with variable expressivity. Anatomopathological effects include the destruction and disappearance of hepatic bile ducts (ductopenia. The duplication of exon 6 of JAG1 has not previously been described as an alteration related to the Alagille syndrome with peripheral renal artery stenosis.

  9. The cryogenic source of slow monochromatic positrons

    International Nuclear Information System (INIS)

    Meshkov, I.N.; Pavlov, V.N.; Sidorin, A.O.; Yakovenko, S.L.

    2008-01-01

    The cryogenic source of slow monochromatic positrons based on the 22 Na isotope has been designed and constructed at JINR. Positrons emitted from radioactive source 22 Na have a very broad energy spectrum up to 0.5 MeV. To generate monochromatic beam of slow positrons the solid neon is used as a moderator. The solid neon allows forming slow positron beam of the energy of 1.2 eV at the spectrum width of 1 eV. The efficiency of moderation is 1 % of total positron flux

  10. Dystonia Associated with Idiopathic Slow Orthostatic Tremor

    Directory of Open Access Journals (Sweden)

    Christopher Kobylecki

    2016-02-01

    Full Text Available Background: We aimed to characterize the clinical and electrophysiological features of patients with slow orthostatic tremor.Case Report: The clinical and neurophysiological data of patients referred for lower limb tremor on standing were reviewed. Patients with symptomatic or primary orthostatic tremor were excluded. Eight patients were identified with idiopathic slow 4–8 Hz orthostatic tremor, which was associated with tremor and dystonia in cervical and upper limb musculature. Coherence analysis in two patients showed findings different to those seen in primary orthostatic tremor.Discussion: Slow orthostatic tremor may be associated with dystonia and dystonic tremor.

  11. Revealing the cluster of slow transients behind a large slow slip event.

    Science.gov (United States)

    Frank, William B; Rousset, Baptiste; Lasserre, Cécile; Campillo, Michel

    2018-05-01

    Capable of reaching similar magnitudes to large megathrust earthquakes [ M w (moment magnitude) > 7], slow slip events play a major role in accommodating tectonic motion on plate boundaries through predominantly aseismic rupture. We demonstrate here that large slow slip events are a cluster of short-duration slow transients. Using a dense catalog of low-frequency earthquakes as a guide, we investigate the M w 7.5 slow slip event that occurred in 2006 along the subduction interface 40 km beneath Guerrero, Mexico. We show that while the long-period surface displacement, as recorded by Global Positioning System, suggests a 6-month duration, the motion in the direction of tectonic release only sporadically occurs over 55 days, and its surface signature is attenuated by rapid relocking of the plate interface. Our proposed description of slow slip as a cluster of slow transients forces us to re-evaluate our understanding of the physics and scaling of slow earthquakes.

  12. Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency

    OpenAIRE

    HaiFang Yin; Prisca Boisguerin; Hong M Moulton; Corinne Betts; Yiqi Seow; Jordan Boutilier; Qingsong Wang; Anthony Walsh; Bernard Lebleu; Matthew JA Wood

    2013-01-01

    We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was ...

  13. MED12 exon 2 mutations in phyllodes tumors of the breast

    International Nuclear Information System (INIS)

    Nagasawa, Satoi; Maeda, Ichiro; Fukuda, Takayo; Wu, Wenwen; Hayami, Ryosuke; Kojima, Yasuyuki; Tsugawa, Ko-ichiro; Ohta, Tomohiko

    2015-01-01

    Exon 2 of MED12, a subunit of the transcriptional mediator complex, has been frequently mutated in uterine leiomyomas and breast fibroadenomas; however, it has been rarely mutated in other tumors. Although the mutations were also found in uterine leiomyosarcomas, the frequency was significantly lower than in uterine leiomyomas. Here, we examined the MED12 mutation in phyllodes tumors, another biphasic tumor with epithelial and stromal components related to breast fibroadenomas. Mutations in MED12 exon 2 were analyzed in nine fibroadenomas and eleven phyllodes tumors via Sanger sequencing. A panel of cancer- and sarcoma-related genes was also analyzed using Ion Torrent next-generation sequencing. Six mutations in fibroadenomas, including those previously reported (6/9, 67%), and five mutations in phyllodes tumors (5/11, 45%) were observed. Three mutations in the phyllodes tumors were missense mutations at Gly44, which is common in uterine leiomyomas and breast fibroadenomas. In addition, two deletion mutations (in-frame c.133-144del12 and loss of splice acceptor c.100-68-137del106) were observed in the phyllodes tumors. No other recurrent mutation was observed with next-generation sequencing. Frequent mutations in MED12 exon 2 in the phyllodes tumors suggest that it may share genetic etiology with uterine leiomyoma, a subgroup of uterine leiomyosarcomas and breast fibroadenoma

  14. Dynamic ASXL1 Exon Skipping and Alternative Circular Splicing in Single Human Cells.

    Directory of Open Access Journals (Sweden)

    Winston Koh

    Full Text Available Circular RNAs comprise a poorly understood new class of noncoding RNA. In this study, we used a combination of targeted deletion, high-resolution splicing detection, and single-cell sequencing to deeply probe ASXL1 circular splicing. We found that efficient circular splicing required the canonical transcriptional start site and inverted AluSx elements. Sequencing-based interrogation of isoforms after ASXL1 overexpression identified promiscuous linear splicing between all exons, with the two most abundant non-canonical linear products skipping the exons that produced the circular isoforms. Single-cell sequencing revealed a strong preference for either the linear or circular ASXL1 isoforms in each cell, and found the predominant exon skipping product is frequently co-expressed with its reciprocal circular isoform. Finally, absolute quantification of ASXL1 isoforms confirmed our findings and suggests that standard methods overestimate circRNA abundance. Taken together, these data reveal a dynamic new view of circRNA genesis, providing additional framework for studying their roles in cellular biology.

  15. Un gene con intrones en vez de exones / Envejecimiento Prematuro de la Piel

    Directory of Open Access Journals (Sweden)

    Tobías Mojica

    1996-04-01

    Full Text Available Un gene con intrones en vez de exones. La noción de que los genes son discontinuos (compuestos de exones e intrones en forma alterna y en cuya organización los exones representan regiones presentes, por medio del código genético en las proteínas, y los intrones nadie sabe todavía que representan produjo una cierta cantidad de desasosiego entre los genetistas mayores de edad, pero hoy día es ampliamente aceptada, con poco o ningún dolor, y se ha convertido en parte del cánon científico. / Envejecimiento Prematuro de la Piel. La exposición a largo plazo de la piel a la luz ultravioleta proveniente del sol resulta en daño al colágeno de la piel y a la elastina de la matriz extracelular; se cree que este daño es responsable de la apariencia típicamente arrugadita de la piel expuesta al sol por mucho tiempo (como en los vaqueros de los comerciales de la televisión.

  16. VERY SLOW SPEED AXIAL MOTION RELUCTANCE MOTOR

    African Journals Online (AJOL)

    Dr Obe

    1984-09-01

    Sep 1, 1984 ... VERY SLOW SPEED AXIAL MOTION RELUCTANCE MOTOR by. L. A. Agu ... order as that of the screw-thread motor can be obtained. LIST OF .... The n stator have equal non- magnetic spacers .... induction motor. An.

  17. Slow and Fast Light, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — In response to the NASA Small Business Innovation Research (SBIR) Program 2015 Phase I Solicitation S3.08: Slow and Fast Light, Torch Technologies in partnership...

  18. Experimental demonstration of spinor slow light

    Science.gov (United States)

    Lee, Meng-Jung; Ruseckas, Julius; Lee, Chin-Yuan; Kudriašov, Viačeslav; Chang, Kao-Fang; Cho, Hung-Wen; JuzeliÅ«nas, Gediminas; Yu, Ite A.

    2016-03-01

    Over the last decade there has been a continuing interest in slow and stored light based on the electromagnetically induced transparency (EIT) effect, because of their potential applications in quantum information manipulation. However, previous experimental works all dealt with the single-component slow light which cannot be employed as a qubit. In this work, we report the first experimental demonstration of two-component or spinor slow light (SSL) using a double tripod (DT) atom-light coupling scheme. The oscillations between the two components, similar to the Rabi oscillation of a two-level system or a qubit, were observed. Single-photon SSL can be considered as two-color qubits. We experimentally demonstrated a possible application of the DT scheme as quantum memory and quantum rotator for the two-color qubits. This work opens up a new direction in the slow light research.

  19. Elastic scattering of slow positrons by helium

    International Nuclear Information System (INIS)

    Amusia, M.Ya.; Cherepkov, N.A.; Chernysheva, L.V.; Shapiro, S.G.

    1976-01-01

    The s-, p-, d- and f-wave phaseshifts for elastic scattering of slow positrons by He are calculated using a simplified version of the random phase approximation with exchange, with virtual positronium formation effect taken into account. (author)

  20. A tilted transversely isotropic slowness surface approximation

    KAUST Repository

    Stovas, A.; Alkhalifah, Tariq Ali

    2012-01-01

    for the vertical slowness that is highly accurate for all practical purposes. It also reveals some insights into the anisotropy parameter dependency of the dispersion relation including the low impact that the anelliptic parameter has on the vertical placement

  1. Frequency response of slow beam extraction process

    International Nuclear Information System (INIS)

    Toyama, Takeshi; Sato, Hikaru; Marutsuka, Katsumi; Shirakata, Masashi.

    1994-01-01

    A servo control system has been incorporated into the practical slow extraction system in order to stabilize the spill structure less than a few kHz. Frequency responses of the components of the servo-spill control system and the open-loop frequency response were measured. The beam transfer function of the slow extraction process was derived from the measured data and approximated using a simple function. This is utilized to improve the performance of the servo-loop. (author)

  2. Slow potentials in a melody recognition task.

    Science.gov (United States)

    Verleger, R; Schellberg, D

    1990-01-01

    In a previous study, slow negative shifts were found in the EEG of subjects listening to well-known melodies. The two experiments reported here were designed to investigate the variables to which these slow potentials are related. In the first experiment, two opposite hypotheses were tested: The slow shifts might express subjects' acquaintance with the melodies or, on the contrary, the effort invested to identify them. To this end, some of the melodies were presented in the rhythms of other melodies to make recognition more difficult. Further, melodies rated as very well-known and as very unknown were analysed separately. However, the slow shifts were not affected by these experimental variations. Therefore in the second experiment, on the one hand the purely physical parameters intensity and duration were varied, but this variation had no impact on the slow shifts either. On the other hand, recognition was made more difficult by monotonously repeating the pitch of the 4th tone for the rest of some melodies. The slow negative shifts were enhanced with these monotonous melodies. This enhancement supports the "effort" hypothesis. Accordingly, the ofter shifts obtained in both experiments might likewise reflect effort. But since the task was not demanding, it is suggested that these constant shifts reflect the effort invested for coping with the entire underarousing situation rather than with the task. Frequently, slow eye movements occurred in the same time range as the slow potentials, resulting in EOG potentials spreading to the EEG recording sites. Yet results did not change substantially when the EEG recordings were corrected for the influence of EOG potentials.

  3. Exon organization of the mouse entactin gene corresponds to the structural domains of the polypeptide and has regional homology to the low-density lipoprotein receptor gene

    DEFF Research Database (Denmark)

    Durkin, M E; Wewer, U M; Chung, A E

    1995-01-01

    of the mouse entactin gene closely corresponds to the organization of the polypeptide into distinct structural and functional domains. The two amino-terminal globular domains are encoded by three exons each. Single exons encode the two protease-sensitive, O-glycosylated linking regions. The six EGF......Entactin is a widespread basement membrane protein of 150 kDa that binds to type IV collagen and laminin. The complete exon-intron structure of the mouse entactin gene has been determined from lambda genomic DNA clones. The gene spans at least 65 kb and contains 20 exons. The exon organization...

  4. Acetylcholinesterase (AChE) gene modification in transgenic animals: functional consequences of selected exon and regulatory region deletion.

    Science.gov (United States)

    Camp, Shelley; Zhang, Limin; Marquez, Michael; de la Torre, Brian; Long, Jeffery M; Bucht, Goran; Taylor, Palmer

    2005-12-15

    AChE is an alternatively spliced gene. Exons 2, 3 and 4 are invariantly spliced, and this sequence is responsible for catalytic function. The 3' alternatively spliced exons, 5 and 6, are responsible for AChE disposition in tissue [J. Massoulie, The origin of the molecular diversity and functional anchoring of cholinesterases. Neurosignals 11 (3) (2002) 130-143; Y. Li, S. Camp, P. Taylor, Tissue-specific expression and alternative mRNA processing of the mammalian acetylcholinesterase gene. J. Biol. Chem. 268 (8) (1993) 5790-5797]. The splice to exon 5 produces the GPI anchored form of AChE found in the hematopoietic system, whereas the splice to exon 6 produces a sequence that binds to the structural subunits PRiMA and ColQ, producing AChE expression in brain and muscle. A third alternative RNA species is present that is not spliced at the 3' end; the intron 3' of exon 4 is used as coding sequence and produces the read-through, unanchored form of AChE. In order to further understand the role of alternative splicing in the expression of the AChE gene, we have used homologous recombination in stem cells to produce gene specific deletions in mice. Alternatively and together exon 5 and exon 6 were deleted. A cassette containing the neomycin gene flanked by loxP sites was used to replace the exon(s) of interest. Tissue analysis of mice with exon 5 deleted and the neomycin cassette retained showed very low levels of AChE expression, far less than would have been anticipated. Only the read-through species of the enzyme was produced; clearly the inclusion of the selection cassette disrupted splicing of exon 4 to exon 6. The selection cassette was then deleted in exon 5, exon 6 and exons 5 + 6 deleted mice by breeding to Ella-cre transgenic mice. AChE expression in serum, brain and muscle has been analyzed. Another AChE gene targeted mouse strain involving a region in the first intron, found to be critical for AChE expression in muscle cells [S. Camp, L. Zhang, M. Marquez, B

  5. Decreased Usage of Specific Scrib Exons Defines a More Malignant Phenotype of Breast Cancer With Worsened Survival

    Directory of Open Access Journals (Sweden)

    Gergana Metodieva

    2016-06-01

    Full Text Available SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.

  6. Nucleobase-modified antisense oligonucleotides containing 5-(phenyltriazol)-2′-deoxyuridine nucleotides induce exon-skipping

    DEFF Research Database (Denmark)

    Le, Bao T.; Hornum, Mick; Sharma, Pawan K.

    2017-01-01

    Chemically-modified antisense oligonucleotide-mediated exon-skipping has been validated as a therapeutic strategy for tackling several disease pathologies, particularly duchenne muscular dystrophy. To date, only sugar-modified and internucleotide linkage-modified oligonucleotide chemistries have...

  7. A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector

    International Nuclear Information System (INIS)

    Wang, Z.; Zhou, W.; Srivastava, T.; La Rosa, C.; Mandarino, A.; Forman, S.J.; Zaia, J.A.; Britt, W.J.; Diamond, D.J.

    2008-01-01

    A therapeutic CMV vaccine incorporating an antigenic repertoire capable of eliciting a cellular immune response has yet to be successfully implemented for patients who already have acquired an infection. To address this problem, we have developed a vaccine candidate derived from modified vaccinia Ankara (MVA) that expresses three immunodominant antigens (pp65, IE1, IE2) from CMV. The novelty of this vaccine is the fusion of two adjacent exons from the immediate-early region of CMV, their successful expression in MVA, and robust immunogenicity in both primary and memory response models. Evaluation of the immunogenicity of the viral vaccine in mouse models shows that it can stimulate primary immunity against all three antigens in both the CD4 + and CD8 + T cell subsets. Evaluation of human PBMC from healthy CMV-positive donors or patients within 6 months of receiving hematopoietic cell transplant shows robust stimulation of existing CMV-specific CD4 + and CD8 + T cell subsets

  8. High prevalence of exon 8 G533C mutation in apparently sporadic medullary thyroid carcinoma in Greece.

    Science.gov (United States)

    Sarika, H L; Papathoma, A; Garofalaki, M; Vasileiou, V; Vlassopoulou, B; Anastasiou, E; Alevizaki, M

    2012-12-01

    Genetic screening for ret mutation has become routine practice in the evaluation of medullary thyroid carcinoma (MTC). Approximately 25% of these tumours are familial, and they occur as components of the multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B) or familial MTC. In familial cases, the majority of mutations are found in exons 10, 11, 13, 14 or 15 of the ret gene. A rare mutation involving exon 8 (G533C) has recently been reported in familial cases of MTC in Brazil and Greece; some of these cases were originally thought to be sporadic. The aim of this study was to re-evaluate a series of sporadic cases of MTC, with negative family history, and screen them for germline mutations in exon 8. Genomic DNA was extracted from peripheral lymphocytes in 129 unrelated individuals who had previously been characterized as 'sporadic' based on the negative family history and negative screening for ret gene mutations. Samples were analysed in Applied Biosystems 7500 real-time PCR and confirmed by sequencing. The G533C exon 8 mutation was identified in 10 of 129 patients with sporadic MTC. Asymptomatic gene carriers were subsequently identified in other family members. In our study, we found that 7·75% patients with apparently sporadic MTC do carry G533C mutation involving exon 8 of ret. We feel that there is now a need to include exon 8 mutation screening in all patients diagnosed as sporadic MTC, in Greece. © 2012 Blackwell Publishing Ltd.

  9. Construction and applications of exon-trapping gene-targeting vectors with a novel strategy for negative selection.

    Science.gov (United States)

    Saito, Shinta; Ura, Kiyoe; Kodama, Miho; Adachi, Noritaka

    2015-06-30

    Targeted gene modification by homologous recombination provides a powerful tool for studying gene function in cells and animals. In higher eukaryotes, non-homologous integration of targeting vectors occurs several orders of magnitude more frequently than does targeted integration, making the gene-targeting technology highly inefficient. For this reason, negative-selection strategies have been employed to reduce the number of drug-resistant clones associated with non-homologous vector integration, particularly when artificial nucleases to introduce a DNA break at the target site are unavailable or undesirable. As such, an exon-trap strategy using a promoterless drug-resistance marker gene provides an effective way to counterselect non-homologous integrants. However, constructing exon-trapping targeting vectors has been a time-consuming and complicated process. By virtue of highly efficient att-mediated recombination, we successfully developed a simple and rapid method to construct plasmid-based vectors that allow for exon-trapping gene targeting. These exon-trap vectors were useful in obtaining correctly targeted clones in mouse embryonic stem cells and human HT1080 cells. Most importantly, with the use of a conditionally cytotoxic gene, we further developed a novel strategy for negative selection, thereby enhancing the efficiency of counterselection for non-homologous integration of exon-trap vectors. Our methods will greatly facilitate exon-trapping gene-targeting technologies in mammalian cells, particularly when combined with the novel negative selection strategy.

  10. Slow brushing reduces heat pain in humans.

    Science.gov (United States)

    Liljencrantz, J; Strigo, I; Ellingsen, D M; Krämer, H H; Lundblad, L C; Nagi, S S; Leknes, S; Olausson, H

    2017-08-01

    C-tactile (CT) afferents are unmyelinated low-threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation. In total, 44 healthy volunteers experienced heat pain and CT optimal (slow brushing) and CT sub-optimal (fast brushing or vibration) stimuli. Three different experimental paradigms were used: Concurrent application of heat pain and tactile (slow brushing or vibration) stimulation; Slow brushing, applied for variable duration and intervals, preceding heat pain; Slow versus fast brushing preceding heat pain. Slow brushing was effective in reducing pain, whereas fast brushing or vibration was not. The reduction in pain was significant not only when the CT optimal touch was applied simultaneously with the painful stimulus but also when the two stimuli were separated in time. For subsequent stimulation, the pain reduction was more pronounced for a shorter time interval between brushing and pain. Likewise, the effect was more robust when pain was preceded by a longer duration of brush stimulation. Strong CT-related pain reduction was associated with low anxiety and high calmness scores obtained by a state anxiety questionnaire. Slow brushing - optimal for CT activation - is effective in reducing pain from cutaneous heating. The precise mechanisms for the pain relief are as yet unknown but possible mechanisms include inhibition of nociceptive projection neurons at the level of the dorsal horn as well as analgesia through cortical mechanisms. Slow brushing stimuli - optimal for activation of C-tactile fibres - can reduce pain from cutaneous heating. No such effect was seen with fast brushing or vibration. These observations indicate the role of C-tactile fibres in pain modulation. © 2017 European Pain Federation - EFIC®.

  11. Slow electron contribution to inelastic reflection anisotropy

    International Nuclear Information System (INIS)

    Podsvirov, O.A.; Kuznetsov, Yu.A.

    1980-01-01

    Investigated is electron contribution with low energy (up to 1 keV) to the anisotropy of electron inelastic reflection (IRE) from silicon monocrystal (111) within 12-50 keV energy range of primary electrons. Experimental data on IRE anisotropy are presented: delay curves for silicon monocrystal, permitting to separate electrons with the energy up to 1 keV, dependences of IRE anisotropy on the energy of primary electrons for the systems - monocrystalline silicon-amorphous silicon film and delay curves for such systems (film thickness varies from 20 to 2000 A). Suggested is a phenomenologic model, permitting to take into account the contribution of slow electrons to IRE anisotropy: it is supposed, that three groups of electrons take part in the formation of the latter: elastic and inelastic reflected electrons, slow electrons, excited by primary electrons and slow electrons, generated by the reverse flow of the scattered electrons. Contribution of electrons, different by origin, to IRE anisotropy is evaluated in accordance with the experimental data on the basis of this model. It is stated, that slow electrons constitute approximately one half of the IRE anisotropy value, the contribution of both groups of slow electrons being approximately equal

  12. Human gamma oscillations during slow wave sleep.

    Directory of Open Access Journals (Sweden)

    Mario Valderrama

    Full Text Available Neocortical local field potentials have shown that gamma oscillations occur spontaneously during slow-wave sleep (SWS. At the macroscopic EEG level in the human brain, no evidences were reported so far. In this study, by using simultaneous scalp and intracranial EEG recordings in 20 epileptic subjects, we examined gamma oscillations in cerebral cortex during SWS. We report that gamma oscillations in low (30-50 Hz and high (60-120 Hz frequency bands recurrently emerged in all investigated regions and their amplitudes coincided with specific phases of the cortical slow wave. In most of the cases, multiple oscillatory bursts in different frequency bands from 30 to 120 Hz were correlated with positive peaks of scalp slow waves ("IN-phase" pattern, confirming previous animal findings. In addition, we report another gamma pattern that appears preferentially during the negative phase of the slow wave ("ANTI-phase" pattern. This new pattern presented dominant peaks in the high gamma range and was preferentially expressed in the temporal cortex. Finally, we found that the spatial coherence between cortical sites exhibiting gamma activities was local and fell off quickly when computed between distant sites. Overall, these results provide the first human evidences that gamma oscillations can be observed in macroscopic EEG recordings during sleep. They support the concept that these high-frequency activities might be associated with phasic increases of neural activity during slow oscillations. Such patterned activity in the sleeping brain could play a role in off-line processing of cortical networks.

  13. Magnon inflation: slow roll with steep potentials

    Energy Technology Data Exchange (ETDEWEB)

    Adshead, Peter [Department of Physics, University of Illinois at Urbana-Champaign,Urbana, IL 61801 (United States); Blas, Diego [Theoretical Physics Department, CERN,CH-1211 Geneva 23 (Switzerland); Burgess, C.P.; Hayman, Peter [Physics & Astronomy, McMaster University,Hamilton, ON, L8S 4M1 (Canada); Perimeter Institute for Theoretical Physics, Waterloo, Ontario N2L 2Y5 (Canada); Patil, Subodh P. [Department of Theoretical Physics, University of Geneva,24 Quai Ansermet, Geneva, CH-1211 (Switzerland)

    2016-11-04

    We find multi-scalar effective field theories (EFTs) that can achieve a slow inflationary roll despite having a scalar potential that does not satisfy G{sup ab}∂{sub a}V∂{sub b}V≪V{sup 2}/M{sub p}{sup 2} (where G{sub ab} is the target-space metric). They evade the usual slow-roll conditions on V because their kinetic energies are dominated by single-derivative terms rather than the usual two-derivative terms. Single derivatives dominate during slow roll and so do not require a breakdown of the usual derivative expansion that underpins calculational control in much of cosmology. The presence of such terms requires some sort of UV Lorentz-symmetry breaking during inflation (besides the usual cosmological breaking). Chromo-natural inflation provides one particular example of a UV theory that can generate the multi-field single-derivative terms we consider, and we argue that the EFT we find indeed captures the slow-roll conditions for its background evolution. We also show that our EFT can be understood as a multi-field generalization of the single-field Cuscuton models. The multi-field case introduces a new feature, however: the scalar kinetic terms define a target-space 2-form, F{sub ab}, whose antisymmetry gives new ways for slow roll to be achieved.

  14. Magnon Inflation: Slow Roll with Steep Potentials

    CERN Document Server

    Adshead, Peter; Burgess, C P; Hayman, Peter; Patil, Subodh P

    2016-01-01

    We find multi-scalar effective field theories (EFTs) that can achieve a slow inflationary roll despite having a scalar potential that does not satisfy the usual slow-roll condition (d V)^2 << V^2/Mp^2. They evade the usual slow-roll conditions on $V$ because their kinetic energies are dominated by single-derivative terms rather than the usual two-derivative terms. Single derivatives dominate during slow roll and so do not require a breakdown of the usual derivative expansion that underpins calculational control in much of cosmology. The presence of such terms requires some sort of UV Lorentz-symmetry breaking during inflation (besides the usual cosmological breaking). Chromo-natural inflation provides an example of a UV theory that can generate the multi-field single-derivative terms we consider, and we argue that the EFT we find indeed captures the slow-roll conditions for the background evolution for Chromo-natural inflation. We also show that our EFT can be understood as a multi-field generalization ...

  15. Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy.

    Science.gov (United States)

    van den Bergen, J C; Schade van Westrum, S M; Dekker, L; van der Kooi, A J; de Visser, M; Wokke, B H A; Straathof, C S; Hulsker, M A; Aartsma-Rus, A; Verschuuren, J J; Ginjaar, H B

    2014-01-01

    Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.

  16. Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency.

    Science.gov (United States)

    Yin, Haifang; Boisguerin, Prisca; Moulton, Hong M; Betts, Corinne; Seow, Yiqi; Boutilier, Jordan; Wang, Qingsong; Walsh, Anthony; Lebleu, Bernard; Wood, Matthew Ja

    2013-09-24

    We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO) and control peptide 3 (B-3-PMO and 3-B-PMO) were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO), further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO) was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG), indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.Molecular Therapy-Nucleic Acids (2013) 2, e124; doi:10.1038/mtna.2013

  17. Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency

    Directory of Open Access Journals (Sweden)

    HaiFang Yin

    2013-01-01

    Full Text Available We have recently reported that cell-penetrating peptides (CPPs and novel chimeric peptides containing CPP (referred as B peptide and muscle-targeting peptide (referred as MSP motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO and control peptide 3 (B-3-PMO and 3-B-PMO were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO, further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG, indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.

  18. Neutron slowing-down time in matter

    Energy Technology Data Exchange (ETDEWEB)

    Chabod, Sebastien P., E-mail: sebastien.chabod@lpsc.in2p3.fr [LPSC, Universite Joseph Fourier Grenoble 1, CNRS/IN2P3, Institut Polytechnique de Grenoble, 38000 Grenoble (France)

    2012-03-21

    We formulate the neutron slowing-down time through elastic collisions in a homogeneous, non-absorbing, infinite medium. Our approach allows taking into account for the first time the energy dependence of the scattering cross-section as well as the energy and temporal distribution of the source neutron population in the results. Starting from this development, we investigate the specific case of the propagation in matter of a mono-energetic neutron pulse. We then quantify the perturbation on the neutron slowing-down time induced by resonances in the scattering cross-section. We show that a resonance can induce a permanent reduction of the slowing-down time, preceded by two discontinuities: a first one at the resonance peak position and an echo one, appearing later. From this study, we suggest that a temperature increase of the propagating medium in presence of large resonances could modestly accelerate the neutron moderation.

  19. Kinetic slow mode-type solitons

    Directory of Open Access Journals (Sweden)

    K. Baumgärtel

    2005-01-01

    Full Text Available One-dimensional hybrid code simulations are presented, carried out in order both to study solitary waves of the slow mode branch in an isotropic, collisionless, medium-β plasma (βi=0.25 and to test the fluid based soliton interpretation of Cluster observed strong magnetic depressions (Stasiewicz et al., 2003; Stasiewicz, 2004 against kinetic theory. In the simulations, a variety of strongly oblique, large amplitude, solitons are seen, including solitons with Alfvenic polarization, similar to those predicted by the Hall-MHD theory, and robust, almost non-propagating, solitary structures of slow magnetosonic type with strong magnetic field depressions and perpendicular ion heating, which have no counterpart in fluid theory. The results support the soliton-based interpretation of the Cluster observations, but reveal substantial deficiencies of Hall-MHD theory in describing slow mode-type solitons in a plasma of moderate beta.

  20. Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, M; Vissing, J

    2013-01-01

    Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic......, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest...

  1. the characterization of exon-1 mutation(s) of beta globin gene in beta thalassemia

    International Nuclear Information System (INIS)

    Abass, M.M.E.

    2004-01-01

    β-thalassemia constitutes one of the most serious health problems worldwide, it is the most common chronic hemolytic anemia in egypt. the aim of this work is to study the mutations of exon-1 of β-globin gene in β-thalassaemic children in sharkia governorate. the present study was included 25 healthy children and 50 patients diagnosed as β-thalassemia. this work showed that the thalassaemic patients had significantly decrease in Hb conc . than the control group (p 2 showed a significant increase as compared with the control group

  2. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran

    OpenAIRE

    BARZEGAR, Mohammad; HABIBI, Parinaz; BONYADY, Mortaza; TOPCHIZADEH, Vahideh; SHIVA, Shadi

    2015-01-01

    How to Cite This Article: Barzegar M, Habibi P, Bonyady M, Topchizadeh V, Shiva Sh. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran. Iran J Child Neurol. 2015 Winter; 9(1): 42-48.AbstractObjectiveDuchene and Becker Muscular Dystrophy (DMD/ BMD) are x-linked disorders that both are the result of heterogeneous mutations in the dystrophin gene. The frequency and distribution of dystrophin gene deletions in DMD/ BMD patients show different patterns among different popula...

  3. Generalized slow roll for noncanonical kinetic terms

    International Nuclear Information System (INIS)

    Hu, Wayne

    2011-01-01

    We show that the generalized slow roll approach for calculating the power spectrum where the inflationary slow roll parameters are neither small nor slowly varying can be readily extended to models with noncanonical kinetic terms in the inflaton action. For example, rapid sound speed variations can arise in Dirac-Born-Infeld models with features in the warp factor leading to features in the power spectrum. Nonetheless there remains a single source function for deviations that is simply related to the power spectrum. Empirical constraints on this source function can be readily interpreted in the context of features in the inflaton potential or sound speed.

  4. Fast and slow spindles during the sleep slow oscillation: disparate coalescence and engagement in memory processing.

    Science.gov (United States)

    Mölle, Matthias; Bergmann, Til O; Marshall, Lisa; Born, Jan

    2011-10-01

    Thalamo-cortical spindles driven by the up-state of neocortical slow (memory consolidation during sleep. We examined interactions between SOs and spindles in human slow wave sleep, focusing on the presumed existence of 2 kinds of spindles, i.e., slow frontocortical and fast centro-parietal spindles. Two experiments were performed in healthy humans (24.5 ± 0.9 y) investigating undisturbed sleep (Experiment I) and the effects of prior learning (word paired associates) vs. non-learning (Experiment II) on multichannel EEG recordings during sleep. Only fast spindles (12-15 Hz) were synchronized to the depolarizing SO up-state. Slow spindles (9-12 Hz) occurred preferentially at the transition into the SO down-state, i.e., during waning depolarization. Slow spindles also revealed a higher probability to follow rather than precede fast spindles. For sequences of individual SOs, fast spindle activity was largest for "initial" SOs, whereas SO amplitude and slow spindle activity were largest for succeeding SOs. Prior learning enhanced this pattern. The finding that fast and slow spindles occur at different times of the SO cycle points to disparate generating mechanisms for the 2 kinds of spindles. The reported temporal relationships during SO sequences suggest that fast spindles, driven by the SO up-state feed back to enhance the likelihood of succeeding SOs together with slow spindles. By enforcing such SO-spindle cycles, particularly after prior learning, fast spindles possibly play a key role in sleep-dependent memory processing.

  5. Exon sequencing of PKD1 gene in an Iranian patient with autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Hafizi, Atousa; Khatami, Saeid Reza; Galehdari, Hamid; Shariati, Gholamreza; Saberi, Ali Hossein; Hamid, Mohammad

    2014-07-01

    Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with the incidence of 1 in 1,000 births. ADPKD is genetically heterogeneous with two genes identified: PKD1 (16p13.3, 46 exons) and PKD2 (4q21, 15 exons). Eighty five percent of the patients with ADPKD have at least one mutation in the PKD1 gene. Genetic studies have demonstrated an important allelic variability among patients, but very few data are known about the genetic variation among Iranian populations. In this study, exon direct sequencing of PKD1 was performed in a seven-year old boy with ADPKD and in his parents. The patient's father was ADPKD who was affected without any kidney dysfunction, and the patient's mother was congenitally missing one kidney. Molecular genetic testing found a mutation in all three members of this family. It was a missense mutation GTG>ATG at position 3057 in exon 25 of PKD1. On the other hand, two novel missense mutations were reported just in the 7-year-old boy: ACA>GCA found in exon 15 at codon 2241 and CAC>AAC found in exon 38 at codon 3710. For checking the pathogenicity of these mutations, exons 15, 25, and 38 of 50 unrelated normal cases were sequenced. our findings suggested that GTG>ATG is a polymorphism with high frequency (60%) as well as ACA>GCA and CAC>AAC are polymorphisms with frequencies of 14% and 22%, respectively in the population of Southwest Iran.

  6. Exon sequence requirements for excision in vivo of the bacterial group II intron RmInt1

    Directory of Open Access Journals (Sweden)

    Toro Nicolás

    2011-05-01

    Full Text Available Abstract Background Group II intron splicing proceeds through two sequential transesterification reactions in which the 5' and 3'-exons are joined together and the lariat intron is released. The intron-encoded protein (IEP assists the splicing of the intron in vivo and remains bound to the excised intron lariat RNA in a ribonucleoprotein particle (RNP that promotes intron mobility. Exon recognition occurs through base-pairing interactions between two guide sequences on the ribozyme domain dI known as EBS1 and EBS2 and two stretches of sequence known as IBS1 and IBS2 on the 5' exon, whereas the 3' exon is recognized through interaction with the sequence immediately upstream from EBS1 [(δ-δ' interaction (subgroup IIA] or with a nucleotide [(EBS3-IBS3 interaction (subgroup IIB and IIC] located in the coordination-loop of dI. The δ nucleotide is involved in base pairing with another intron residue (δ' in subgroup IIB introns and this interaction facilitates base pairing between the 5' exon and the intron. Results In this study, we investigated nucleotide requirements in the distal 5'- and 3' exon regions, EBS-IBS interactions and δ-δ' pairing for excision of the group IIB intron RmInt1 in vivo. We found that the EBS1-IBS1 interaction was required and sufficient for RmInt1 excision. In addition, we provide evidence for the occurrence of canonical δ-δ' pairing and its importance for the intron excision in vivo. Conclusions The excision in vivo of the RmInt1 intron is a favored process, with very few constraints for sequence recognition in both the 5' and 3'-exons. Our results contribute to understand how group II introns spread in nature, and might facilitate the use of RmInt1 in gene targeting.

  7. Light storage via slow-light four-wave mixing

    International Nuclear Information System (INIS)

    Fan, Yun-Fei; Wang, Hai-Hua; Wei, Xiao-Gang; Li, Ai-Jun; Kang, Zhi-Hui; Wu, Jin-Hui; Zhang, Han-Zhuang; Xu, Huai-Liang; Gao, Jin-Yue

    2012-01-01

    We experimentally demonstrate a light storage via slow-light four-wave mixing in a solid-state medium with a four-level double lambda scheme. Using slow light based on electromagnetically induced transparency, we obtain a slowed four-wave mixing signal pulse together with the slowed probe pulse. During the propagation of light pulses, the storage and retrieval of both the slowed four-wave mixing pulse and the slowed probe pulse are studied by manipulating the intensities of the control fields. -- Highlights: ► A light storage via slow-light four-wave mixing is observed in a solid. ► The probe pulse is slowed under electromagnetically induced transparency. ► A slowed four-wave mixing pulse is obtained by slow light. ► The storage of slowed double pulses is studied.

  8. Slow evaporation method and enhancement in photoluminescence ...

    Indian Academy of Sciences (India)

    nescence (PL) properties and decay time of phosphors were studied at room temperature. The YPO4 ... Keywords. Slow evaporation method; YPO4 : Eu3+, Bi3+; quenching effect; optical material. 1. ... intensity of Eu3+-doped compounds such as CaMoO4 : Bi3+, .... Figure 4 shows FESEM images of YPO4 : Eu3+ and Bi3+.

  9. Quick-Connect, Slow-Disconnect Bolt

    Science.gov (United States)

    Weddendorf, Bruce

    1995-01-01

    Proposed bolt functions similarly to device described in article "Quick-Connect, Slow-Disconnect Nut" (MFS-28833). Bolt installed in standard threaded hole simply by pushing it into hole. Once inserted, bolt withdrawn only by turning it in conventional way.

  10. A slow component of classic Stroop interference

    NARCIS (Netherlands)

    Phaf, R. Hans; Horsman, Hark H.; van der Moolen, Bas; Roos, Yvo B. W. E. M.; Schmand, Ben

    2010-01-01

    The interference in colour naming may extend beyond critical Stroop trials. This "slow'' effect was first discovered in emotional Stroop tasks, but is extended here to classical Stroop. In two experiments, meaningless coloured letter strings followed a colour word or neutral word. Student

  11. Slow Reading: Reading along "Lectio" Lines

    Science.gov (United States)

    Badley, K. Jo-Ann; Badley, Ken

    2011-01-01

    The medieval monastic movement preserved and developed reading practices--lectio--from ancient Greek pedagogy as a slow, mindful approach to reading for formation. This ancient way of reading, now better known as lectio divina, challenges the fast, pragmatic reading so characteristic of our time. We propose that the present moment may be ripe for…

  12. Slowed ageing, welfare, and population problems.

    Science.gov (United States)

    Wareham, Christopher

    2015-10-01

    Biological studies have demonstrated that it is possible to slow the ageing process and extend lifespan in a wide variety of organisms, perhaps including humans. Making use of the findings of these studies, this article examines two problems concerning the effect of life extension on population size and welfare. The first--the problem of overpopulation--is that as a result of life extension too many people will co-exist at the same time, resulting in decreases in average welfare. The second--the problem of underpopulation--is that life extension will result in too few people existing across time, resulting in decreases in total welfare. I argue that overpopulation is highly unlikely to result from technologies that slow ageing. Moreover, I claim that the problem of underpopulation relies on claims about life extension that are false in the case of life extension by slowed ageing. The upshot of these arguments is that the population problems discussed provide scant reason to oppose life extension by slowed ageing.

  13. Response of electret dosemeter to slow neutrons

    International Nuclear Information System (INIS)

    Ghilardi, A.J.P.; Pela, C.A.; Zimmerman, R.L.

    1987-01-01

    The response of the electret dosemeter to exposition of slow neutrons is studied. Different external coatings are used on the dosemeter (polyethylene, alminium, polyethylene + boron, aluminium + boron) and exposure curves (with and without water) are compared. (M.A.C.) [pt

  14. Analysis of the neutron slowing down equation

    International Nuclear Information System (INIS)

    Sengupta, A.; Karnick, H.

    1978-01-01

    The infinite series solution of the elementary neutron slowing down equation is studied using the theory of entire functions of exponential type and nonharmonic Fourier series. It is shown from Muntz--Szasz and Paley--Wiener theorems, that the set of exponentials ]exp(ilambda/sub n/u) ]/sup infinity//sub n/=-infinity, where ]lambda/sub n/]/sup infinity//sub n/=-infinity are the roots of the transcendental equation in slowing down theory, is complete and forms a basis in a lethargy interval epsilon. This distinctive role of the maximum lethargy change per collision is due to the Fredholm character of the slowing down operator which need not be quasinilpotent. The discontinuities in the derivatives of the collision density are examined by treating the slowing down equation in its differential-difference form. The solution (Hilbert) space is the union of a countable number of subspaces L 2 (-epsilon/2, epsilon/2) over each of which the exponential functions are complete

  15. Probabilistic Slow Features for Behavior Analysis

    NARCIS (Netherlands)

    Zafeiriou, Lazaros; Nicolaou, Mihalis A.; Zafeiriou, Stefanos; Nikitidis, Symeon; Pantic, Maja

    A recently introduced latent feature learning technique for time-varying dynamic phenomena analysis is the so-called slow feature analysis (SFA). SFA is a deterministic component analysis technique for multidimensional sequences that, by minimizing the variance of the first-order time derivative

  16. Learning slow features for behavior analysis

    NARCIS (Netherlands)

    Zafeiriou, Lazaros; Nicolaou, Mihalis A.; Zafeiriou, Stefanos; Nikitids, Symeon; Pantic, Maja

    2013-01-01

    A recently introduced latent feature learning technique for time varying dynamic phenomena analysis is the socalled Slow Feature Analysis (SFA). SFA is a deterministic component analysis technique for multi-dimensional sequences that by minimizing the variance of the first order time derivative

  17. Proton energy dependence of slow neutron intensity

    International Nuclear Information System (INIS)

    Teshigawara, Makoto; Harada, Masahide; Watanabe, Noboru; Kai, Tetsuya; Sakata, Hideaki; Ikeda, Yujiro

    2001-01-01

    The choice of the proton energy is an important issue for the design of an intense-pulsed-spallation source. The optimal proton beam energy is rather unique from a viewpoint of the leakage neutron intensity but no yet clear from the slow-neutron intensity view point. It also depends on an accelerator type. Since it is also important to know the proton energy dependence of slow-neutrons from the moderators in a realistic target-moderator-reflector assembly (TMRA). We studied on the TMRA proposed for Japan Spallation Neutron Source. The slow-neutron intensities from the moderators per unit proton beam power (MW) exhibit the maximum at about 1-2 GeV. At higher proton energies the intensity per MW goes down; at 3 and 50 GeV about 0.91 and 0.47 times as low as that at 1 GeV. The proton energy dependence of slow-neutron intensities was found to be almost the same as that of total neutron yield (leakage neutrons) from the same bare target. It was also found that proton energy dependence was almost the same for the coupled and decoupled moderators, regardless the different moderator type, geometry and coupling scheme. (author)

  18. Preliminary characterization of slow growing rhizobial strains ...

    African Journals Online (AJOL)

    In this paper, we did some preliminary characterization of six slow growing rhizobial strains, isolated from Retama monosperma (L.) Boiss. root nodules sampled from 3 sites along the coast of Oran (CapeFalcon, Bousfer and MersElHadjadj) in Northwestern Algeria. Results of this study showed that all strains had a very ...

  19. Preliminary characterization of slow growing rhizobial strains ...

    African Journals Online (AJOL)

    COMPAQ

    2016-05-18

    May 18, 2016 ... strains had a very slow growth rate in yeast malt (YM) agar medium, forming colonies less than 1 mm in ... dominant genus of symbiotic nitrogen-fixing bacteria ... Single colonies were picked up and checked for purity by.

  20. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis.

    Science.gov (United States)

    Bonnet, Crystel; Grati, M'hamed; Marlin, Sandrine; Levilliers, Jacqueline; Hardelin, Jean-Pierre; Parodi, Marine; Niasme-Grare, Magali; Zelenika, Diana; Délépine, Marc; Feldmann, Delphine; Jonard, Laurence; El-Amraoui, Aziz; Weil, Dominique; Delobel, Bruno; Vincent, Christophe; Dollfus, Hélène; Eliot, Marie-Madeleine; David, Albert; Calais, Catherine; Vigneron, Jacqueline; Montaut-Verient, Bettina; Bonneau, Dominique; Dubin, Jacques; Thauvin, Christel; Duvillard, Alain; Francannet, Christine; Mom, Thierry; Lacombe, Didier; Duriez, Françoise; Drouin-Garraud, Valérie; Thuillier-Obstoy, Marie-Françoise; Sigaudy, Sabine; Frances, Anne-Marie; Collignon, Patrick; Challe, Georges; Couderc, Rémy; Lathrop, Mark; Sahel, José-Alain; Weissenbach, Jean; Petit, Christine; Denoyelle, Françoise

    2011-05-11

    Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

  1. Polymorphysims of Gene in the Exons Were Associated with the Reproductive Endocrine of Japanese Flounder (

    Directory of Open Access Journals (Sweden)

    R. Q. Ma

    2012-06-01

    Full Text Available The cytochrome P450c17-I (CYP17-I is one of the enzymes critical to gonadal development and the synthesis of androgens. Two single nucleotide polymorphisms (SNPs were detected within the coding region of the CYP17-I gene in a population of 75 male Japanese flounder (Paralichthys olivaceus. They were SNP1 (c.C445T located in exon2 and SNP2 (c.T980C (p.Phe307Leu located in exon5. Four physiological indices, which were serum testosterone (T, serum 17β-estradiol (E2, Hepatosomatic index (HSI, and Gonadosomatic index (GSI, were studied to examine the effect of the two SNPs on the reproductive endocrines of Japanese flounder. Multiple comparisons revealed that CT genotype of SNP1 had a much lower T level than CC genotype (p<0.05 and the GSI of individuals with CC genotype of SNP2 was higher than those with TT genotype (p<0.05. Four diplotypes were constructed based on the two SNPs and the diplotype D3 had a significantly lower T level and GSI. In conclusion, the two SNPs were significantly associated with reproductive traits of Japanese flounder.

  2. Exon skipping and translation in patients with frameshift deletions in the dystrophin gene

    Energy Technology Data Exchange (ETDEWEB)

    Sherratt, T.G.; Dubowitz, V.; Sewry, C.A.; Strong, P.N. (Royal Postgraduate Medical School, London (United Kingdom)); Vulliamy, T. (Hammersmith Hospital, London (United Kingdom))

    1993-11-01

    Although many Duchenne muscular dystrophy patients have a deletion in the dystrophin gene which disrupts the translational reading frame, they express dystrophin in a small proportion of skeletal muscle fibers ([open quotes]revertant fibers[close quotes]). Antibody studies have shown, indirectly, that dystrophin synthesis in revertant fibers is facilitated by a frame-restoring mechanism; in the present study, the feasibility of mRNA splicing was investigated. Dystrophin transcripts were analyzed in skeletal muscle from individuals possessing revertant fibers and a frameshift deletion in the dystrophin gene. In each case a minor in-frame transcript was detected, in which exons adjacent to those deleted from the genome had been skipped. There appeared to be some correlation between the levels of in-frame transcripts and the predicted translation products. Low levels of alternatively spliced transcripts were also present in normal muscle. The results provide further evidence of exon skipping in the dystrophin gene and indicate that this may be involved in the synthesis of dystrophin by revertant fibers. 44 refs., 12 figs.

  3. Global analysis of aberrant pre-mRNA splicing in glioblastoma using exon expression arrays

    Directory of Open Access Journals (Sweden)

    Nixon Tamara J

    2008-05-01

    Full Text Available Abstract Background Tumor-predominant splice isoforms were identified during comparative in silico sequence analysis of EST clones, suggesting that global aberrant alternative pre-mRNA splicing may be an epigenetic phenomenon in cancer. We used an exon expression array to perform an objective, genome-wide survey of glioma-specific splicing in 24 GBM and 12 nontumor brain samples. Validation studies were performed using RT-PCR on glioma cell lines, patient tumor and nontumor brain samples. Results In total, we confirmed 14 genes with glioma-specific splicing; seven were novel events identified by the exon expression array (A2BP1, BCAS1, CACNA1G, CLTA, KCNC2, SNCB, and TPD52L2. Our data indicate that large changes (> 5-fold in alternative splicing are infrequent in gliomagenesis ( Conclusion While we observed some tumor-specific alternative splicing, the number of genes showing exclusive tumor-specific isoforms was on the order of tens, rather than the hundreds suggested previously by in silico mining. Given the important role of alternative splicing in neural differentiation, there may be selective pressure to maintain a majority of splicing events in order to retain glial-like characteristics of the tumor cells.

  4. Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon.

    Directory of Open Access Journals (Sweden)

    Albert Ruzo

    Full Text Available Huntington's disease (HD is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT. HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease.

  5. Discovery of Novel Isoforms of Huntingtin Reveals a New Hominid-Specific Exon

    Science.gov (United States)

    Popowski, Melissa; Haremaki, Tomomi; Croft, Gist F.; Deglincerti, Alessia; Brivanlou, Ali H.

    2015-01-01

    Huntington’s disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC) lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease. PMID:26010866

  6. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome.

    Science.gov (United States)

    Carmignac, Virginie; Thevenon, Julien; Adès, Lesley; Callewaert, Bert; Julia, Sophie; Thauvin-Robinet, Christel; Gueneau, Lucie; Courcet, Jean-Benoit; Lopez, Estelle; Holman, Katherine; Renard, Marjolijn; Plauchu, Henri; Plessis, Ghislaine; De Backer, Julie; Child, Anne; Arno, Gavin; Duplomb, Laurence; Callier, Patrick; Aral, Bernard; Vabres, Pierre; Gigot, Nadège; Arbustini, Eloisa; Grasso, Maurizia; Robinson, Peter N; Goizet, Cyril; Baumann, Clarisse; Di Rocco, Maja; Sanchez Del Pozo, Jaime; Huet, Frédéric; Jondeau, Guillaume; Collod-Beroud, Gwenaëlle; Beroud, Christophe; Amiel, Jeanne; Cormier-Daire, Valérie; Rivière, Jean-Baptiste; Boileau, Catherine; De Paepe, Anne; Faivre, Laurence

    2012-11-02

    Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Analysis of Prolactin Gene Exon 4 Diversity in Peking, White Mojosari, and Peking White Mojosari Crossbreed

    Directory of Open Access Journals (Sweden)

    M. Indriati

    2016-04-01

    Full Text Available Genetic marker linked to loci reproductive traits could be used to increase an effectiveness of improvement in animal breeding. Association between DNA polymorphism and a trait could be considered as candidate genetic marker for marker assisted selection (MAS programs. Prolactin (PRL is one of polypeptide hormones secreted by anterior pituitary gland in vertebrates. PRL plays an important role in onset of poultry incubation and brooding behavior. The aim of this study was to investigate the diversity of prolactin gene and to characterize the type of mutation in partial intron 3, intron 4 and exon 4 of duck prolactin gene. Blood extraction was collected from 168 ducks consisted of 19 Peking, 36 Mojosari, and 113 Peking White Mojosari (Peking Mojosari putih ducks. Polymerase chain reaction of fragment prolactin gene exon 4 and partial intron 3 and 4 have been successfully amplified with length of base pair were 496 bp. A total of 30 µL PCR product from each sample were sequenced for forward sequence using BIOTRACE 3730 by First Base Company, Malaysia. Alignment analysis found six SNP consisted of g.3941T>G, g.3975C>A, g.4110T>C, INDEL 3724A, INDEL 34031, and INDEL 3939A. Analysis of SNP frequency result indicated mutation of INDEL 3724A, g.3941T>G, g.3975C>A, INDEL 4031A and g.4110T>A in duck sample were polymorphic and INDEL 3939A were monomorphic.

  8. Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms.

    Science.gov (United States)

    Pietra, Daniela; Brisci, Angela; Rumi, Elisa; Boggi, Sabrina; Elena, Chiara; Pietrelli, Alessandro; Bordoni, Roberta; Ferrari, Maurizio; Passamonti, Francesco; De Bellis, Gianluca; Cremonesi, Laura; Cazzola, Mario

    2011-04-01

    Somatic mutations of MPL exon 10, mainly involving a W515 substitution, have been described in JAK2 (V617F)-negative patients with essential thrombocythemia and primary myelofibrosis. We used direct sequencing and high-resolution melt analysis to identify mutations of MPL exon 10 in 570 patients with myeloproliferative neoplasms, and allele specific PCR and deep sequencing to further characterize a subset of mutated patients. Somatic mutations were detected in 33 of 221 patients (15%) with JAK2 (V617F)-negative essential thrombocythemia or primary myelofibrosis. Only one patient with essential thrombocythemia carried both JAK2 (V617F) and MPL (W515L). High-resolution melt analysis identified abnormal patterns in all the MPL mutated cases, while direct sequencing did not detect the mutant MPL in one fifth of them. In 3 cases carrying double MPL mutations, deep sequencing analysis showed identical load and location in cis of the paired lesions, indicating their simultaneous occurrence on the same chromosome.

  9. α-Synuclein and huntingtin exon 1 amyloid fibrils bind laterally to the cellular membrane.

    Science.gov (United States)

    Monsellier, Elodie; Bousset, Luc; Melki, Ronald

    2016-01-13

    Fibrillar aggregates involved in neurodegenerative diseases have the ability to spread from one cell to another in a prion-like manner. The underlying molecular mechanisms, in particular the binding mode of the fibrils to cell membranes, are poorly understood. In this work we decipher the modality by which aggregates bind to the cellular membrane, one of the obligatory steps of the propagation cycle. By characterizing the binding properties of aggregates made of α-synuclein or huntingtin exon 1 protein displaying similar composition and structure but different lengths to mammalian cells we demonstrate that in both cases aggregates bind laterally to the cellular membrane, with aggregates extremities displaying little or no role in membrane binding. Lateral binding to artificial liposomes was also observed by transmission electron microscopy. In addition we show that although α-synuclein and huntingtin exon 1 fibrils bind both laterally to the cellular membrane, their mechanisms of interaction differ. Our findings have important implications for the development of future therapeutic tools that aim to block protein aggregates propagation in the brain.

  10. Variable pathogenicity of exon 43del (FAA) in four Fanconi anaemia patients within a consanguineous family.

    Science.gov (United States)

    Koc, A; Pronk, J C; Alikasifoglu, M; Joenje, H; Altay, C

    1999-01-01

    Four Fanconi anaemia group A (FAA) patients within two related consanguineous families are presented: the propositus (male, 13 years, transplanted at age 10), and his three cousins (one male, 8 years, and two female newborns). Assignment of the patients to FAA was based on the functional complementation analysis by somatic cell hybridization and confirmed by mutation screening showing a homozygous deletion of exon 43 (4267-4404del) in the FAA gene to be present in all four patients. The newborn patients had been diagnosed prenatally by DNA analysis. In spite of identical molecular pathology and close familial relationship the clinical phenotypes of the four patients were not concordant. Discordant symptoms included birthweight, pigmentation abnormalities, skeletal, renal and genital abnormalities, whereas microcephaly and possibly the haematological course were concordant. Differences in environmental conditions and/or genetic make-up along with chance effects during development may explain discordant phenotypes despite identical molecular pathology in these patients. However, our results do not rule out the possibility that the exon 43del mutation may have prognostic value for the haematological course of the disease.

  11. A novel whole exon deletion in WWOX gene causes early epilepsy, intellectual disability and optic atrophy.

    Science.gov (United States)

    Ben-Salem, Salma; Al-Shamsi, Aisha M; John, Anne; Ali, Bassam R; Al-Gazali, Lihadh

    2015-05-01

    Recent studies have implicated the WW domain-containing oxidoreductase encoding gene (WWOX) in a severe form of autosomal recessive neurological disorder. This condition showed an overlapping spectrum of clinical features including spinocerebellar ataxia associated with generalized seizures and delayed psychomotor development to growth retardation, spasticity, and microcephaly. We evaluated a child from a consanguineous Emirati family that presented at birth with growth retardation, microcephaly, epileptic seizures, and later developed spasticity and delayed psychomotor development. Screening for deletions and duplications using whole-chromosomal microarray analysis identified a novel homozygous microdeletion encompassing exon 5 of the WWOX gene. Analysis of parental DNA indicated that this deletion was inherited from both parents and lies within a large region of homozygosity. Sanger sequencing of the cDNA showed that the deletion resulted in exon 5 skipping leading to a frame-shift and creating a premature stop codon at amino acid position 212. Quantification of mRNA revealed striking low level of WWOX expression in the child and moderate level of expression in the mother compared to a healthy control. To the best of our knowledge, this is the first homozygous germline structural variation in WWOX gene resulting in truncated transcripts that were presumably subject to NMD pathway. Our findings extend the clinical and genetic spectrum of WWOX mutations and support a crucial role of this gene in neurological development.

  12. Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.

    Science.gov (United States)

    Lanikova, Lucie; Lorenzo, Felipe; Yang, Chunzhang; Vankayalapati, Hari; Drachtman, Richard; Divoky, Vladimir; Prchal, Josef T

    2013-05-09

    Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 3' VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL(P138L) has perturbed interaction with hypoxia-inducible transcription factor (HIF)1α. Further, VHL(P138L) protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL(P138L) erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL(P138L) granulocytes.

  13. Clinical Characteristics and Outcomes of Lung Cancer Patients 
with EGFR Mutations in Exons 19 and 21

    Directory of Open Access Journals (Sweden)

    Renwang LIU

    2014-11-01

    Full Text Available Background and objective Studies on the epidermal growth factor receptor (EGFR signaling pathways and the therapeutic effects of EGFR-tyrosine kinase inhibitors (EGFR-TKIs have recently proven that targeted therapy has a major role in the treatment of lung cancer. However, the therapeutic effects of EGFR-TKIs on lung cancers with different EGFR mutation subtypes remain unclear. And if there is a significant difference in the effects of EGFR-TKIs, the mechanisms for the difference remain unclear. The aim of this study was to investigate the clinical importance of EGFR mutations in exons 19 and 21 of lung cancer patients and to compare the outcomes of these patients. Methods The study recruited 113 patients who had non-small cell lung cancer (NSCLC with EGFR mutations. EGFR mutations were detected for 47 patients using Real-time PCR or DNA sequencinag. The mutations of the remaining patients were determined using xTag-EGFR liquid chip technology. All stages I-III patients underwent radical resection followed by 4 cycles of postoperative chemotherapy. Patients with pleural metastases underwent pleural biopsy, pleurodesis, and chemotherapy only. Patients with distant metastases underwent biopsy and chemotherapy only. Collected clinical data were analyzed using SPSS 19.0 software. Results EGFR exon mutations 19 and 21 were found in 56 and 57 patients, respectively. The mean age of patients with exon 19 mutations was lower than the age of the patients with exon 21 mutations (57.02±11.31 years vs 62.25±7.76 years, respectively; P0.05 between the patients with exon 19 and 21 mutations; and survival analysis of 91 (80.5% patients with complete clinical data found no differences in overall survival. Stratification analysis found out that patients with exon 19 mutations had longer overall survival associated with age>61 years, male gender, ever smoking, and stage IV disease; although the differences were not significant. Conclusion Compared to the lung

  14. The NRG1 exon 11 missense variant is not associated with autism in the Central Valley of Costa Rica

    Directory of Open Access Journals (Sweden)

    Fallas Marietha

    2007-05-01

    Full Text Available Abstract Background We are conducting a genetic study of autism in the isolated population of the Central Valley of Costa Rica (CVCR. A novel Neuregulin 1 (NRG1 missense variant (exon 11 G>T was recently associated with psychosis and schizophrenia (SCZ in the same population isolate. Methods We genotyped the NRG1 exon 11 missense variant in 146 cases with autism, or autism spectrum disorder, with CVCR ancestry, and both parents when available (N = 267 parents from 143 independent families. Additional microsatellites were genotyped to examine haplotypes bearing the exon 11 variant. Results The NRG1 exon 11 G>T variant was found in 4/146 cases including one de novo occurrence. The frequency of the variant in case chromosomes was 0.014 and 0.045 in the parental non-transmitted chromosomes. At least 6 haplotypes extending 0.229 Mb were associated with the T allele. Three independent individuals, with no personal or family history of psychiatric disorder, shared at least a 1 megabase haplotype 5' to the T allele. Conclusion The NRG1 exon 11 missense variant is not associated with autism in the CVCR.

  15. Evaluation of 2’-Deoxy-2’-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Silvana M G Jirka

    2015-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is a severe muscle wasting disorder typically caused by frame-shifting mutations in the DMD gene. Restoration of the reading frame would allow the production of a shorter but partly functional dystrophin protein as seen in Becker muscular dystrophy patients. This can be achieved with antisense oligonucleotides (AONs that induce skipping of specific exons during pre-mRNA splicing. Different chemical modifications have been developed to improve AON properties. The 2’-deoxy-2’-fluoro (2F RNA modification is attractive for exon skipping due to its ability to recruit ILF2/3 proteins to the 2F/pre-mRNA duplex, which resulted in enhanced exon skipping in spinal muscular atrophy models. In this study, we examined the effect of two different 2’-substituted AONs (2’-F phosphorothioate (2FPS and 2’-O-Me phosphorothioate (2OMePS on exon skipping in DMD cell and animal models. In human cell cultures, 2FPS AONs showed higher exon skipping levels than their isosequential 2OMePS counterparts. Interestingly, in the mdx mouse model, 2FPS was less efficient than 2OMePS and suggested safety issues as evidenced by increased spleen size and weight loss. Our results do not support a clinical application for 2FPS AON.

  16. Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females.

    Science.gov (United States)

    Bartnik, Magdalena; Derwińska, Katarzyna; Gos, Monika; Obersztyn, Ewa; Kołodziejska, Katarzyna E; Erez, Ayelet; Szpecht-Potocka, Agnieszka; Fang, Ping; Terczyńska, Iwona; Mierzewska, Hanna; Lohr, Naomi J; Bellus, Gary A; Reimschisel, Tyler; Bocian, Ewa; Mazurczak, Tadeusz; Cheung, Sau Wai; Stankiewicz, Paweł

    2011-05-01

    Mutations in the CDKL5 gene have been associated with an X-linked dominant early infantile epileptic encephalopathy-2. The clinical presentation is usually of severe encephalopathy with refractory seizures and Rett syndrome (RTT)-like phenotype. We attempted to assess the role of mosaic intragenic copy number variation in CDKL5. We have used comparative genomic hybridization with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5. We have identified mosaic exonic deletions of CDKL5 in one male and two females with developmental delay and medically intractable seizures. These three mosaic changes represent 60% of all deletions detected in 12,000 patients analyzed by array comparative genomic hybridization and involving the exonic portion of CDKL5. We report the first case of an exonic deletion of CDKL5 in a male and emphasize the importance of underappreciated mosaic exonic copy number variation in patients with early-onset seizures and RTT-like features of both genders.

  17. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy)

    DEFF Research Database (Denmark)

    Vorwerk, P; Christoffersen, C T; Müller, J

    1999-01-01

    to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase......The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found...... domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing...

  18. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....... associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1 1/2 years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy...

  19. AON-mediated Exon Skipping Restores Ciliation in Fibroblasts Harboring the Common Leber Congenital Amaurosis CEP290 Mutation

    Directory of Open Access Journals (Sweden)

    Xavier Gerard

    2012-01-01

    Full Text Available Leber congenital amaurosis (LCA is a severe hereditary retinal dystrophy responsible for congenital or early-onset blindness. The most common disease-causing mutation (>10% is located deep in intron 26 of the CEP290 gene (c.2991+1655A>G. It creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. In the present study, we show that the use of antisense oligonucleotides (AONs allow an efficient skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients. These data support the feasibility of an AON-mediated exon skipping strategy to correct the aberrant splicing.

  20. Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools

    Science.gov (United States)

    Soukarieh, Omar; Gaildrat, Pascaline; Hamieh, Mohamad; Drouet, Aurélie; Baert-Desurmont, Stéphanie; Frébourg, Thierry; Tosi, Mario; Martins, Alexandra

    2016-01-01

    The identification of a causal mutation is essential for molecular diagnosis and clinical management of many genetic disorders. However, even if next-generation exome sequencing has greatly improved the detection of nucleotide changes, the biological interpretation of most exonic variants remains challenging. Moreover, particular attention is typically given to protein-coding changes often neglecting the potential impact of exonic variants on RNA splicing. Here, we used the exon 10 of MLH1, a gene implicated in hereditary cancer, as a model system to assess the prevalence of RNA splicing mutations among all single-nucleotide variants identified in a given exon. We performed comprehensive minigene assays and analyzed patient’s RNA when available. Our study revealed a staggering number of splicing mutations in MLH1 exon 10 (77% of the 22 analyzed variants), including mutations directly affecting splice sites and, particularly, mutations altering potential splicing regulatory elements (ESRs). We then used this thoroughly characterized dataset, together with experimental data derived from previous studies on BRCA1, BRCA2, CFTR and NF1, to evaluate the predictive power of 3 in silico approaches recently described as promising tools for pinpointing ESR-mutations. Our results indicate that ΔtESRseq and ΔHZEI-based approaches not only discriminate which variants affect splicing, but also predict the direction and severity of the induced splicing defects. In contrast, the ΔΨ-based approach did not show a compelling predictive power. Our data indicates that exonic splicing mutations are more prevalent than currently appreciated and that they can now be predicted by using bioinformatics methods. These findings have implications for all genetically-caused diseases. PMID:26761715

  1. Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools.

    Directory of Open Access Journals (Sweden)

    Omar Soukarieh

    2016-01-01

    Full Text Available The identification of a causal mutation is essential for molecular diagnosis and clinical management of many genetic disorders. However, even if next-generation exome sequencing has greatly improved the detection of nucleotide changes, the biological interpretation of most exonic variants remains challenging. Moreover, particular attention is typically given to protein-coding changes often neglecting the potential impact of exonic variants on RNA splicing. Here, we used the exon 10 of MLH1, a gene implicated in hereditary cancer, as a model system to assess the prevalence of RNA splicing mutations among all single-nucleotide variants identified in a given exon. We performed comprehensive minigene assays and analyzed patient's RNA when available. Our study revealed a staggering number of splicing mutations in MLH1 exon 10 (77% of the 22 analyzed variants, including mutations directly affecting splice sites and, particularly, mutations altering potential splicing regulatory elements (ESRs. We then used this thoroughly characterized dataset, together with experimental data derived from previous studies on BRCA1, BRCA2, CFTR and NF1, to evaluate the predictive power of 3 in silico approaches recently described as promising tools for pinpointing ESR-mutations. Our results indicate that ΔtESRseq and ΔHZEI-based approaches not only discriminate which variants affect splicing, but also predict the direction and severity of the induced splicing defects. In contrast, the ΔΨ-based approach did not show a compelling predictive power. Our data indicates that exonic splicing mutations are more prevalent than currently appreciated and that they can now be predicted by using bioinformatics methods. These findings have implications for all genetically-caused diseases.

  2. Dissecting an alternative splicing analysis workflow for GeneChip® Exon 1.0 ST Affymetrix arrays

    Directory of Open Access Journals (Sweden)

    Calogero Raffaele A

    2008-11-01

    Full Text Available Abstract Background A new microarray platform (GeneChip® Exon 1.0 ST has recently been developed by Affymetrix http://www.affymetrix.com. This microarray platform changes the conventional view of transcript analysis since it allows the evaluation of the expression level of a transcript by querying each exon component. The Exon 1.0 ST platform does however raise some issues regarding the approaches to be used in identifying genome-wide alternative splicing events (ASEs. In this study an exon-level data analysis workflow is dissected in order to detect limit and strength of each step, thus modifying the overall workflow and thereby optimizing the detection of ASEs. Results This study was carried out using a semi-synthetic exon-skipping benchmark experiment embedding a total of 268 exon skipping events. Our results point out that summarization methods (RMA, PLIER do not affect the efficacy of statistical tools in detecting ASEs. However, data pre-filtering is mandatory if the detected number of false ASEs are to be reduced. MiDAS and Rank Product methods efficiently detect true ASEs but they suffer from the lack of multiple test error correction. The intersection of MiDAS and Rank Product results efficiently moderates the detection of false ASEs. Conclusion To optimize the detection of ASEs we propose the following workflow: i data pre-filtering, ii statistical selection of ASEs using both MiDAS and Rank Product, iii intersection of results derived from the two statistical analyses in order to moderate family-wise errors (FWER.

  3. Identification of POMC exonic variants associated with substance dependence and body mass index.

    Directory of Open Access Journals (Sweden)

    Fan Wang

    Full Text Available Risk of substance dependence (SD and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC.POMC exons were Sanger sequenced in 280 African Americans (AAs and 308 European Americans (EAs. Among them, 311 (167 AAs and 114 EAs were affected with substance (alcohol, cocaine, opioid and/or marijuana dependence and 277 (113 AAs and164 EAs were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571 and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI, with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj = 0.005; Obese: P(adj = 0.018; Overweight+Obese: P(adj = 0.002 but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df = 0.026; alcohol dependence: P(FET,1df = 0.027; cocaine dependence: P(FET,1df = 0.007; marijuana dependence: P(FET,1df = 0.050 (the P-value from cocaine dependence analysis survived Bonferroni correction. There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD.These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert

  4. Polymeric membrane studied using slow positron beam

    International Nuclear Information System (INIS)

    Hung, W.-S.; Lo, C.-H.; Cheng, M.-L.; Chen Hongmin; Liu Guang; Chakka, Lakshmi; Nanda, D.; Tung, K.-L.; Huang, S.-H.; Lee, Kueir-Rarn; Lai, J.-Y.; Sun Yiming; Yu Changcheng; Zhang Renwu; Jean, Y.C.

    2008-01-01

    A radioisotope slow positron beam has been built at the Chung Yuan Christian University in Taiwan for the research and development in membrane science and technology. Doppler broadening energy spectra and positron annihilation lifetime have been measured as a function of positron energy up to 30 keV in a polyamide membrane prepared by the interfacial polymerization between triethylenetetraamine (TETA) and trimesoyl chloride (TMC) on modified porous polyacrylonitrile (PAN) asymmetric membrane. The multilayer structures and free-volume depth profile for this asymmetric membrane system are obtained. Positron annihilation spectroscopy coupled with a slow beam could provide new information about size selectivity of transporting molecules and guidance for molecular designs in polymeric membranes

  5. A tilted transversely isotropic slowness surface approximation

    KAUST Repository

    Stovas, A.

    2012-05-09

    The relation between vertical and horizontal slownesses, better known as the dispersion relation, for transversely isotropic media with a tilted symmetry axis (TTI) requires solving a quartic polynomial equation, which does not admit a practical explicit solution to be used, for example, in downward continuation. Using a combination of the perturbation theory with respect to the anelliptic parameter and Shanks transform to improve the accuracy of the expansion, we develop an explicit formula for the vertical slowness that is highly accurate for all practical purposes. It also reveals some insights into the anisotropy parameter dependency of the dispersion relation including the low impact that the anelliptic parameter has on the vertical placement of reflectors for a small tilt in the symmetry angle. © 2012 European Association of Geoscientists & Engineers.

  6. Slow and fast light in semiconductor waveguides

    DEFF Research Database (Denmark)

    Mørk, Jesper; Hansen, Per Lunnemann; Xue, Weiqi

    2010-01-01

    Investigations of slow and fast light effects in semiconductor waveguides entail interesting physics and point to a number of promising applications. In this review we give an overview of recent progress in the field, in particular focusing on the physical mechanisms of electromagnetically induced...... transparency and coherent population oscillations. While electromagnetically induced transparency has been the most important effect in realizing slowdown effects in atomic gasses, progress has been comparatively slow in semiconductors due to inherent problems of fast dephasing times and inhomogeneous...... broadening in quantum dots. The physics of electromagnetically induced transparency in semiconductors is discussed, emphasizing these limitations and recent suggestions for overcoming them. On the other hand, the mechanism of coherent population oscillations relies on wave mixing effects and is well suited...

  7. Slow Invariant Manifolds in Chemically Reactive Systems

    Science.gov (United States)

    Paolucci, Samuel; Powers, Joseph M.

    2006-11-01

    The scientific design of practical gas phase combustion devices has come to rely on the use of mathematical models which include detailed chemical kinetics. Such models intrinsically admit a wide range of scales which renders their accurate numerical approximation difficult. Over the past decade, rational strategies, such as Intrinsic Low Dimensional Manifolds (ILDM) or Computational Singular Perturbations (CSP), for equilibrating fast time scale events have been successfully developed, though their computation can be challenging and their accuracy in most cases uncertain. Both are approximations to the preferable slow invariant manifold which best describes how the system evolves in the long time limit. Strategies for computing the slow invariant manifold are examined, and results are presented for practical combustion systems.

  8. Revised genomic structure of the human ghrelin gene and identification of novel exons, alternative splice variants and natural antisense transcripts

    Directory of Open Access Journals (Sweden)

    Herington Adrian C

    2007-08-01

    Full Text Available Abstract Background Ghrelin is a multifunctional peptide hormone expressed in a range of normal tissues and pathologies. It has been reported that the human ghrelin gene consists of five exons which span 5 kb of genomic DNA on chromosome 3 and includes a 20 bp non-coding first exon (20 bp exon 0. The availability of bioinformatic tools enabling comparative analysis and the finalisation of the human genome prompted us to re-examine the genomic structure of the ghrelin locus. Results We have demonstrated the presence of an additional novel exon (exon -1 and 5' extensions to exon 0 and 1 using comparative in silico analysis and have demonstrated their existence experimentally using RT-PCR and 5' RACE. A revised exon-intron structure demonstrates that the human ghrelin gene spans 7.2 kb and consists of six rather than five exons. Several ghrelin gene-derived splice forms were detected in a range of human tissues and cell lines. We have demonstrated ghrelin gene-derived mRNA transcripts that do not code for ghrelin, but instead may encode the C-terminal region of full-length preproghrelin (C-ghrelin, which contains the coding region for obestatin and a transcript encoding obestatin-only. Splice variants that differed in their 5' untranslated regions were also found, suggesting a role of these regions in the post-transcriptional regulation of preproghrelin translation. Finally, several natural antisense transcripts, termed ghrelinOS (ghrelin opposite strand transcripts, were demonstrated via orientation-specific RT-PCR, 5' RACE and in silico analysis of ESTs and cloned amplicons. Conclusion The sense and antisense alternative transcripts demonstrated in this study may function as non-coding regulatory RNA, or code for novel protein isoforms. This is the first demonstration of putative obestatin and C-ghrelin specific transcripts and these findings suggest that these ghrelin gene-derived peptides may also be produced independently of preproghrelin

  9. The JAK2V617F and CALR exon 9 mutations are shared immunogenic neoantigens in hematological malignancy

    DEFF Research Database (Denmark)

    Holmstrom, Morten Orebo; Hasselbalch, Hans Carl; Andersen, Mads Hald

    2017-01-01

    Approximately 90% of patients with the hematological malignancies termed the chronic myeloproliferative neoplasms harbor either the JAK2V617F-mutation or CALR exon 9 mutation. Both of these are recognized by T-cells, which make the mutations ideal targets for cancer immune therapy as they are sha......Approximately 90% of patients with the hematological malignancies termed the chronic myeloproliferative neoplasms harbor either the JAK2V617F-mutation or CALR exon 9 mutation. Both of these are recognized by T-cells, which make the mutations ideal targets for cancer immune therapy...

  10. Germline mutation of RET proto-oncogene’s exons 17 and 18 in Iranian medullary thyroid carcinoma patients

    Directory of Open Access Journals (Sweden)

    Marjan Zarif Yeganeh

    2017-03-01

    Full Text Available Background: Thyroid carcinoma is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC approximately accounts for 5-10% of all thyroid carcinoma. Nowadays, it is obviously, the mutations in REarranged during transfection (RET proto-oncogene, especially, mutations in exons 10, 11 and 16 are associated with MTC pathogenesis and occurrence. Thus, early diagnosis of MTC by mutation detection in RET proto-oncogene allows to identify patients who do not have any developed symptoms. The aim of this study was to screening of germline mutations in RET proto-oncogene exons 17 and 18 in MTC patients and their first degree relatives in Iranian population. Methods: In this cross-sectional study, three hundred eleven participates (190 patients, 121 their relatives were referred to endocrine research center, Shahid Beheshti University of Medical Science during September 2013 until September 2015. The inclusion criteria were pathological and clinical diagnosis. After whole blood sampling, genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection in exons 17 and 18 was performed using PCR and direct DNA sequencing methods. Results: In this study, twenty missense mutations [CGC>TGC, c.2944C>T, p.Arg982Cys (rs17158558] which included 16 heterozygote and 4 homozygote mutations were found in codon 982 (exon 18. In the present study, 154 G>A (rs2742236 and 4 C>T (rs370072408 nucleotide changes were detected in exons 18 and intron 17 respectively. There was no mutation in exon 17. Conclusion: It seems that because of arginine to cysteine substitutions in RET tyrosine kinase protein structure and its polyphen score (0.955 and SIFT score (0.01 the mutation in codon 982 (exon 18 could be have pathogenic effects. On the other hands, the mentioned mutation frequency was 6.4% among MTC patients, so this mutation of exon 18 could be checked in genetic screening tests of RET

  11. Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development.

    Directory of Open Access Journals (Sweden)

    Sushma Grellscheid

    2011-12-01

    Full Text Available Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2β (Sfrs10 is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2β is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2β binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specific Sfrs10 knock-out mouse (Sfrs10(fl/fl; Nestin-Cre(tg/+. This mouse has defects in brain development and allowed correlation of genuine physiologically Tra2β regulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2β binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2β protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2β. Versions of Tra2β lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2β protein.

  12. Slowed demand ushers in summer season

    International Nuclear Information System (INIS)

    Anon.

    1996-01-01

    This article is the June 1996 market summary in uranium market. During this reporting period, there were six deals in the U3O8 spot market and three long-term deals for U3O8. There were four deals for UF6 conversion, and the spot market for uranium separation services had no transactions. This was little change from the previous month's activities, and this slowness was reflected in the price trends of little or no increase

  13. Fundamental research with polarized slow neutrons

    International Nuclear Information System (INIS)

    Krupchitsky, P.A.

    1987-01-01

    In the last twenty years polarized beams of slow neutrons have been used effectively in fundamental research in nuclear physics. This book gives a thorough introduction to these experimental methods including the most recent techniques of generating and analyzing polarized neutron beams. It clearly shows the close relationship between elementary particle physics and nuclear physics. The book not only addresses specialists but also those interested in the foundations of elementary particle and nuclear physics. With 42 figs

  14. Testing algorithms for critical slowing down

    Directory of Open Access Journals (Sweden)

    Cossu Guido

    2018-01-01

    Full Text Available We present the preliminary tests on two modifications of the Hybrid Monte Carlo (HMC algorithm. Both algorithms are designed to travel much farther in the Hamiltonian phase space for each trajectory and reduce the autocorrelations among physical observables thus tackling the critical slowing down towards the continuum limit. We present a comparison of costs of the new algorithms with the standard HMC evolution for pure gauge fields, studying the autocorrelation times for various quantities including the topological charge.

  15. SOFTWARE Manual for VMM3 Slow Control

    CERN Document Server

    Guth, Manuel

    2017-01-01

    For the New Small Wheel upgrade of the ATLAS detector a new readout chip, called VMM3(a), was developed. In order to provide this new technology to a larger community, the RD51 collaboration is integrating the VMM3 in their scalable readout system (SRS). For this purpose, a new slow control and calibration tool is necessary. This new software was developed and improved within a CERN Summer Student project.

  16. Theory of a slow-light catastrophe

    International Nuclear Information System (INIS)

    Leonhardt, Ulf

    2002-01-01

    In diffraction catastrophes such as the rainbow, the wave nature of light resolves ray singularities and draws delicate interference patterns. In quantum catastrophes such as the black hole, the quantum nature of light resolves wave singularities and creates characteristic quantum effects related to Hawking radiation. This paper describes the theory behind a recent proposal [U. Leonhardt, Nature (London) 415, 406 (2002)] to generate a quantum catastrophe of slow light

  17. Theory of a slow-light catastrophe

    Science.gov (United States)

    Leonhardt, Ulf

    2002-04-01

    In diffraction catastrophes such as the rainbow, the wave nature of light resolves ray singularities and draws delicate interference patterns. In quantum catastrophes such as the black hole, the quantum nature of light resolves wave singularities and creates characteristic quantum effects related to Hawking radiation. This paper describes the theory behind a recent proposal [U. Leonhardt, Nature (London) 415, 406 (2002)] to generate a quantum catastrophe of slow light.

  18. Theory of a Slow-Light Catastrophe

    OpenAIRE

    Leonhardt, Ulf

    2001-01-01

    In diffraction catastrophes such as the rainbow the wave nature of light resolves ray singularities and draws delicate interference patterns. In quantum catastrophes such as the black hole the quantum nature of light resolves wave singularities and creates characteristic quantum effects related to Hawking radiation. The paper describes the theory behind a recent proposal [U. Leonhardt, arXiv:physics/0111058, Nature (in press)] to generate a quantum catastrophe of slow light.

  19. Magnetic energy analyser for slow electrons

    International Nuclear Information System (INIS)

    Limberg, W.

    1974-08-01

    A differential spectrometer with high time and energy resolution has been developed using the principle of energy analysis with a longitudinal homogeneous magnetic field. This way it is possible to measure the energy distribution of low energy electrons (eV-range) in the presence of high energy electrons without distortions by secondary electrons. The functioning and application of the analyzer is demonstrated by measuring the energy distributions of slow electrons emitted by a filament. (orig.) [de

  20. γ-ray emission from slow pulsars

    International Nuclear Information System (INIS)

    Morini, M.; Treves, A.

    1981-01-01

    The scope of this communication is to calculate the expected γ-ray flux from slow pulsars, neglecting the problem of the reliability of the observations. The key hypothesis is that since the γ-ray luminosity is a substantial fraction of Lsub(T) (the intrinsic energy loss), it should be produced in the vicinity of the speed of light radius. This comes from the well known argument of simultaneous conservation of energy and angular momentum. (Auth.)

  1. Slowing down modernity: A critique : A critique

    OpenAIRE

    Vostal , Filip

    2017-01-01

    International audience; The connection between modernization and social acceleration is now a prominent theme in critical social analysis. Taking a cue from these debates, I explore attempts that aim to 'slow down modernity' by resisting the dynamic tempo of various social processes and experiences. The issue of slowdown now accounts for a largely unquestioned measure, expected to deliver unhasty tempo conditioning good and ethical life, mental well-being and accountable democracy. In princip...

  2. Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

    Science.gov (United States)

    Witting, N; Duno, M; Vissing, J

    2013-01-01

    Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. An 8bp indel in exon 1 of Ghrelin gene associated with chicken growth.

    Science.gov (United States)

    Fang, Meixia; Nie, Qinghua; Luo, Chenglong; Zhang, Dexiang; Zhang, Xiquan

    2007-04-01

    Ghrelin, acts as the endogenous ligand for growth hormone secretagogues receptor (GHS-R), is a novel growth hormone (GH) releasing peptide with reported effects on food intake in chickens. In this study, an 8 bp indel polymorphism in exon 1 of the chicken Ghrelin (cGHRL) gene was genotyped in a F(2) designed full-sib population to analyze its associations with chicken growth and carcass traits. Later, mRNA level in the proventriculus was determined by real-time PCR to reveal the expression feature of cGHRL gene. Result showed that this 8 bp indel was significantly associated with body weight at the age of 28 days (BW28) and 56 days (BW56), eviscerated weight (EW) and leg muscle weight (LMW) (PGhrelin on chicken growth were indicated by this study.

  4. Characterization of six mutations in Exon 37 of neurofibromatosis type 1 gene

    Energy Technology Data Exchange (ETDEWEB)

    Upadhyaya, M.; Osborn, M.; Maynard, J.; Harper, P. [Institute of Medical Genetics, Cardiff, Wales (United Kingdom)

    1996-07-26

    Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders, with an incidence of 1 in 3,000. We screened a total of 320 unrelated NF1 patients for mutations in exon 37 of the NF1 gene. Six independent mutations were identified, of which three are novel, and these include a recurrent nonsense mutation identified in 2 unrelated patients at codon 2281 (G2281X), a 1-bp insertion (6791 ins A) resulting in a change of TAG (tyrosine) to a TAA (stop codon), and a 3-bp deletion (6839 del TAC) which generated a frameshift. Another recurrent nonsense mutation, Y2264X, which was detected in 2 unrelated patients in this study, was also previously reported in 2 NF1 individuals. All the mutations were identified within a contiguous 49-bp sequence. Further studies are warranted to support the notion that this region of the gene contains highly mutable sequences. 17 refs., 2 figs., 1 tab.

  5. Exonic deletion of OPHN1 resulting in seizures, intellectual disability, and brain malformations

    Directory of Open Access Journals (Sweden)

    Larson A

    2014-07-01

    Full Text Available Austin Larson,1 Jamie LeRoux,2 Ellen Roy Elias11Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; 2Colorado Genetics Laboratory, Denver, CO, USAAbstract: We report the case of a 9-year-old boy with autism, intellectual disability, and complex partial seizures as well as cerebellar vermian hypoplasia, caudate nucleus hypoplasia, and ventriculomegaly. He was found to have a deletion within the oligophrenin 1 gene (OPHN1, affecting exons 2–5. OPHN1 mutations result in a rare but well-characterized syndrome of neuroanatomical anomalies, epilepsy, and intellectual disability. This is a novel mutation in OPHN1 that adds to the spectrum of pathogenic variants of the gene. Additionally, the case illustrates the significant benefit that patients and families can derive from a definitive genetic diagnosis, even in the absence of direct therapeutic interventions.Keywords: X-linked intellectual disability, autism, cerebellar hypoplasia, chromosomal microarray, oligophrenin 1

  6. Efficient Detection of Copy Number Mutations in PMS2 Exons with a Close Homolog.

    Science.gov (United States)

    Herman, Daniel S; Smith, Christina; Liu, Chang; Vaughn, Cecily P; Palaniappan, Selvi; Pritchard, Colin C; Shirts, Brian H

    2018-07-01

    Detection of 3' PMS2 copy-number mutations that cause Lynch syndrome is difficult because of highly homologous pseudogenes. To improve the accuracy and efficiency of clinical screening for these mutations, we developed a new method to analyze standard capture-based, next-generation sequencing data to identify deletions and duplications in PMS2 exons 9 to 15. The approach captures sequences using PMS2 targets, maps sequences randomly among regions with equal mapping quality, counts reads aligned to homologous exons and introns, and flags read count ratios outside of empirically derived reference ranges. The method was trained on 1352 samples, including 8 known positives, and tested on 719 samples, including 17 known positives. Clinical implementation of the first version of this method detected new mutations in the training (N = 7) and test (N = 2) sets that had not been identified by our initial clinical testing pipeline. The described final method showed complete sensitivity in both sample sets and false-positive rates of 5% (training) and 7% (test), dramatically decreasing the number of cases needing additional mutation evaluation. This approach leveraged the differences between gene and pseudogene to distinguish between PMS2 and PMS2CL copy-number mutations. These methods enable efficient and sensitive Lynch syndrome screening for 3' PMS2 copy-number mutations and may be applied similarly to other genomic regions with highly homologous pseudogenes. Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  7. Evidence for widespread exonic small RNAs in the glaucophyte alga Cyanophora paradoxa.

    Directory of Open Access Journals (Sweden)

    Jeferson Gross

    Full Text Available RNAi (RNA interference relies on the production of small RNAs (sRNAs from double-stranded RNA and comprises a major pathway in eukaryotes to restrict the propagation of selfish genetic elements. Amplification of the initial RNAi signal by generation of multiple secondary sRNAs from a targeted mRNA is catalyzed by RNA-dependent RNA polymerases (RdRPs. This phenomenon is known as transitivity and is particularly important in plants to limit the spread of viruses. Here we describe, using a genome-wide approach, the distribution of sRNAs in the glaucophyte alga Cyanophora paradoxa. C. paradoxa is a member of the supergroup Plantae (also known as Archaeplastida that includes red algae, green algae, and plants. The ancient (>1 billion years ago split of glaucophytes within Plantae suggests that C. paradoxa may be a useful model to learn about the early evolution of RNAi in the supergroup that ultimately gave rise to plants. Using next-generation sequencing and bioinformatic analyses we find that sRNAs in C. paradoxa are preferentially associated with mRNAs, including a large number of transcripts that encode proteins arising from different functional categories. This pattern of exonic sRNAs appears to be a general trend that affects a large fraction of mRNAs in the cell. In several cases we observe that sRNAs have a bias for a specific strand of the mRNA, including many instances of antisense predominance. The genome of C. paradoxa encodes four sequences that are homologous to RdRPs in Arabidopsis thaliana. We discuss the possibility that exonic sRNAs in the glaucophyte may be secondarily derived from mRNAs by the action of RdRPs. If this hypothesis is confirmed, then transitivity may have had an ancient origin in Plantae.

  8. Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment.

    Science.gov (United States)

    Schür, R R; Boks, M P; Rutten, B P F; Daskalakis, N P; de Nijs, L; van Zuiden, M; Kavelaars, A; Heijnen, C J; Joëls, M; Kahn, R S; Geuze, E; Vermetten, E; Vinkers, C H

    2017-07-25

    Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1 F region (GR-1 F ) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1 F methylation changes over time in relation to trauma exposure and the development of post-deployment psychopathology. GR-1 F methylation (52 loci) was quantified using pyrosequencing in whole blood of 92 military men 1 month before and 6 months after a 4-month deployment period to Afghanistan. GR-1 F methylation overall (mean methylation and the number of methylated loci) and functional methylation (methylation at loci associated with GR exon 1 F expression) measures were examined. We first investigated the effect of exposure to potentially traumatic events during deployment on these measures. Subsequently, changes in GR-1 F methylation were related to changes in mental health problems (total Symptom Checklist-90 score) and posttraumatic stress disorder (PTSD) symptoms (Self-Report Inventory for PTSD). Trauma exposure during deployment was associated with an increase in all methylation measures, but development of mental health problems 6 months after deployment was only significantly associated with an increased functional methylation. Emergence of post-deployment PTSD symptoms was not related to increased functional methylation over time. Pre-deployment methylation levels did not predict post-deployment psychopathology. To our knowledge, this is the first study to prospectively demonstrate trauma-related increases in GR-1 F methylation, and it shows that only increases at specific functionally relevant sites predispose for post-deployment psychopathology.

  9. SinEx DB: a database for single exon coding sequences in mammalian genomes.

    Science.gov (United States)

    Jorquera, Roddy; Ortiz, Rodrigo; Ossandon, F; Cárdenas, Juan Pablo; Sepúlveda, Rene; González, Carolina; Holmes, David S

    2016-01-01

    Eukaryotic genes are typically interrupted by intragenic, noncoding sequences termed introns. However, some genes lack introns in their coding sequence (CDS) and are generally known as 'single exon genes' (SEGs). In this work, a SEG is defined as a nuclear, protein-coding gene that lacks introns in its CDS. Whereas, many public databases of Eukaryotic multi-exon genes are available, there are only two specialized databases for SEGs. The present work addresses the need for a more extensive and diverse database by creating SinEx DB, a publicly available, searchable database of predicted SEGs from 10 completely sequenced mammalian genomes including human. SinEx DB houses the DNA and protein sequence information of these SEGs and includes their functional predictions (KOG) and the relative distribution of these functions within species. The information is stored in a relational database built with My SQL Server 5.1.33 and the complete dataset of SEG sequences and their functional predictions are available for downloading. SinEx DB can be interrogated by: (i) a browsable phylogenetic schema, (ii) carrying out BLAST searches to the in-house SinEx DB of SEGs and (iii) via an advanced search mode in which the database can be searched by key words and any combination of searches by species and predicted functions. SinEx DB provides a rich source of information for advancing our understanding of the evolution and function of SEGs.Database URL: www.sinex.cl. © The Author(s) 2016. Published by Oxford University Press.

  10. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

    Directory of Open Access Journals (Sweden)

    Lacombe Didier

    2011-05-01

    Full Text Available Abstract Background Usher syndrome (USH combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3. Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. Methods We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3. Results Biallelic mutations were detected in 39 patients (72% and monoallelic mutations in an additional 10 patients (18.5%. In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%, and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48% were novel. Conclusions Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

  11. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping.

    Science.gov (United States)

    Vulin, Adeline; Barthélémy, Inès; Goyenvalle, Aurélie; Thibaud, Jean-Laurent; Beley, Cyriaque; Griffith, Graziella; Benchaouir, Rachid; le Hir, Maëva; Unterfinger, Yves; Lorain, Stéphanie; Dreyfus, Patrick; Voit, Thomas; Carlier, Pierre; Blot, Stéphane; Garcia, Luis

    2012-11-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.

  12. Nonlinear dynamical triggering of slow slip

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Paul A [Los Alamos National Laboratory; Knuth, Matthew W [WISCONSIN; Kaproth, Bryan M [PENN STATE; Carpenter, Brett [PENN STATE; Guyer, Robert A [Los Alamos National Laboratory; Le Bas, Pierre - Yves [Los Alamos National Laboratory; Daub, Eric G [Los Alamos National Laboratory; Marone, Chris [PENN STATE

    2010-12-10

    Among the most fascinating, recent discoveries in seismology have been the phenomena of triggered slip, including triggered earthquakes and triggered-tremor, as well as triggered slow, silent-slip during which no seismic energy is radiated. Because fault nucleation depths cannot be probed directly, the physical regimes in which these phenomena occur are poorly understood. Thus determining physical properties that control diverse types of triggered fault sliding and what frictional constitutive laws govern triggered faulting variability is challenging. We are characterizing the physical controls of triggered faulting with the goal of developing constitutive relations by conducting laboratory and numerical modeling experiments in sheared granular media at varying load conditions. In order to simulate granular fault zone gouge in the laboratory, glass beads are sheared in a double-direct configuration under constant normal stress, while subject to transient perturbation by acoustic waves. We find that triggered, slow, silent-slip occurs at very small confining loads ({approx}1-3 MPa) that are smaller than those where dynamic earthquake triggering takes place (4-7 MPa), and that triggered slow-slip is associated with bursts of LFE-like acoustic emission. Experimental evidence suggests that the nonlinear dynamical response of the gouge material induced by dynamic waves may be responsible for the triggered slip behavior: the slip-duration, stress-drop and along-strike slip displacement are proportional to the triggering wave amplitude. Further, we observe a shear-modulus decrease corresponding to dynamic-wave triggering relative to the shear modulus of stick-slips. Modulus decrease in response to dynamical wave amplitudes of roughly a microstrain and above is a hallmark of elastic nonlinear behavior. We believe that the dynamical waves increase the material non-affine elastic deformation during shearing, simultaneously leading to instability and slow-slip. The inferred

  13. Slow movement execution in event-related potentials (P300).

    Science.gov (United States)

    Naruse, Kumi; Sakuma, Haruo; Hirai, Takane

    2002-02-01

    We examined whether slow movement execution has an effect on cognitive and information processing by measuring the P300 component. 8 subjects performed a continuous slow forearm rotational movement using 2 task speeds. Slow (a 30-50% decrease from the subject's Preferred speed) and Very Slow (a 60-80% decrease). The mean coefficient of variation for rotation speed under Very Slow was higher than that under Slow, showing that the subjects found it difficult to perform the Very Slow task smoothly. The EEG score of alpha-1 (8-10 Hz) under Slow Condition was increased significantly more than under the Preferred Condition; however, the increase under Very Slow was small when compared with Preferred. After performing the task. P300 latency under Very Slow increased significantly as compared to that at pretask. Further, P300 amplitude decreased tinder both speed conditions when compared to that at pretask, and a significant decrease was seen under the Slow Condition at Fz, whereas the decrease under the Very Slow Condition was small. These differences indicated that a more complicated neural composition and an increase in subjects' attention might have been involved when the task was performed under the Very Slow Condition. We concluded that slow movement execution may have an influence on cognitive function and may depend on the percentage of decrease from the Preferred speed of the individual.

  14. Two genetic determinants acquired late in Mus evolution regulate the inclusion of exon 5, which alters mouse APOBEC3 translation efficiency.

    Directory of Open Access Journals (Sweden)

    Jun Li

    2012-01-01

    Full Text Available Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 (mA3, an intracellular antiviral factor, has 2 allelic variations that are linked with different susceptibilities to beta- and gammaretrovirus infections among various mouse strains. In virus-resistant C57BL/6 (B6 mice, mA3 transcripts are more abundant than those in susceptible BALB/c mice both in the spleen and bone marrow. These strains of mice also express mA3 transcripts with different splicing patterns: B6 mice preferentially express exon 5-deficient (Δ5 mA3 mRNA, while BALB/c mice produce exon 5-containing full-length mA3 mRNA as the major transcript. Although the protein product of the Δ5 mRNA exerts stronger antiretroviral activities than the full-length protein, how exon 5 affects mA3 antiviral activity, as well as the genetic mechanisms regulating exon 5 inclusion into the mA3 transcripts, remains largely uncharacterized. Here we show that mA3 exon 5 is indeed a functional element that influences protein synthesis at a post-transcriptional level. We further employed in vitro splicing assays using genomic DNA clones to identify two critical polymorphisms affecting the inclusion of exon 5 into mA3 transcripts: the number of TCCT repeats upstream of exon 5 and the single nucleotide polymorphism within exon 5 located 12 bases upstream of the exon 5/intron 5 boundary. Distribution of the above polymorphisms among different Mus species indicates that the inclusion of exon 5 into mA3 mRNA is a relatively recent event in the evolution of mice. The widespread geographic distribution of this exon 5-including genetic variant suggests that in some Mus populations the cost of maintaining an effective but mutagenic enzyme may outweigh its antiviral function.

  15. Comprehensive detection of diverse exon 19 deletion mutations of EGFR in lung Cancer by a single probe set.

    Science.gov (United States)

    Bae, Jin Ho; Jo, Seong-Min; Kim, Hak-Sung

    2015-12-15

    Detection of exon 19 deletion mutation of EGFR, one of the most frequently occurring mutations in lung cancer, provides the crucial information for diagnosis and treatment guideline in non-small-cell lung cancer (NSCLC). Here, we demonstrate a simple and efficient method to detect various exon 19 deletion mutations of EGFR using a single probe set comprising of an oligo-quencher (oligo-Q) and a molecular beacon (MB). While the MB hybridizes to both the wild and mutant target DNA, the oligo-Q only binds to the wild target DNA, leading to a fluorescent signal in case of deletion mutation. This enables the comprehensive detection of the diverse exon 19 deletion mutations using a single probe set. We demonstrated the utility and efficiency of the approach by detecting the frequent exon 19 deletion mutations of EGFR through a real-time PCR and in situ fluorescence imaging. Our approach enabled the detection of genomic DNA as low as 0.02 ng, showing a detection limit of 2% in a heterogeneous DNA mixture, and could be used for detecting mutations in a single cell level. The present MB and oligo-Q dual probe system can be used for diagnosis and treatment guideline in NSCLC. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Lack of association of DRD4 exon 3 VNTR genotype with reactivity to dynamic smoking cues in movies

    NARCIS (Netherlands)

    Lochbühler, K.C.; Verhagen, M.; Munafò, M.R.; Engels, R.C.M.E.

    2013-01-01

    Background: The objective of the present study was first to examine whether dynamic smoking cues in movies trigger craving, and second to explore whether the DRD4 48 bp variable number of tandem repeat (VNTR) exon 3 genotype modifies this relationship. Using an experimental design, daily adult

  17. Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells

    DEFF Research Database (Denmark)

    Bruun, Gitte H; Bang, Jeanne Mv; Christensen, Lise L

    2018-01-01

    designed splice switching oligonucleotides (SSO) that blocks the intronic hnRNP A1 binding site, and demonstrate that this completely rescues splicing of IKBKAP exon 20 in FD patient fibroblasts and increases the amounts of IKAP protein. We propose that this may be developed into a potential new specific...

  18. Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis.

    Science.gov (United States)

    Boyd, Elaine M; Bench, Anthony J; Goday-Fernández, Andrea; Anand, Shubha; Vaghela, Krishna J; Beer, Phillip; Scott, Mike A; Bareford, David; Green, Anthony R; Huntly, Brian; Erber, Wendy N

    2010-04-01

    Approximately 50% of essential thrombocythaemia and primary myelo-fibrosis patients do not have a JAK2 V617F mutation. Up to 5% of these are reported to have a MPL exon 10 mutation but testing for MPL is not routine as there are multiple mutation types. The ability to routinely assess both JAK2 and MPL mutations would be beneficial in the differential diagnosis of unexplained thrombocytosis or myelofibrosis. We developed and applied a high resolution melt (HRM) assay, capable of detecting all known MPL mutations in a single analysis, for the detection of MPL exon 10 mutations. We assessed 175 ET and PMF patients, including 67 that were JAK2 V617F-negative by real time polymerase chain reaction (PCR). Overall, 19/175 (11%) patients had a MPL exon 10 mutation, of whom 16 were JAK2 V617F-negative (16/67; 24%). MPL mutation types were W515L (11), W515K (4), W515R (2) and W515A (1). One patient had both W515L and S505N MPL mutations and these were present in the same haemopoietic colonies. Real time PCR for JAK2 V617F analysis and HRM for MPL exon 10 status identified one or more clonal marker in 71% of patients. This combined genetic approach increases the sensitivity of meeting the World Health Organization diagnostic criteria for these myeloproliferative neoplasms.

  19. Reduced anxiety-like behavior and altered hippocampal morphology in female p75NTR exon IV-/- mice.

    Directory of Open Access Journals (Sweden)

    Zoe ePuschban

    2016-06-01

    Full Text Available The presence of the neurotrophin receptor p75NTR in adult basal forebrain cholinergic neurons, precursor cells in the subventricular cell layer and the subgranular cell layer of the hippocampus has been linked to alterations in learning as well as anxiety- and depression- related behaviors. In contrast to previous studies performed in a p75NTR exonIII-/- model still expressing the short isoform of the p75NTR, we focused on locomotor and anxiety–associated behavior in p75NTR exonIV-/- mice lacking both p75NTR isoforms. Comparing p75NTR exonIV-/- and wildtype mice for both male and female animals showed an anxiolytic-like behavior as evidenced by increased central activities in the open field paradigm and flex field activity system as well as higher numbers of open arm entries in the elevated plus maze test in female p75NTR knockout mice.Morphometrical analyses of dorsal and ventral hippocampus revealed a reduction of width of the dentate gyrus and the granular cell layer in the dorsal but not ventral hippocampus in male and female p75NTR exonIV -/- mice. We conclude that germ-line deletion of p75NTR seems to differentially affect morphometry of dorsal and ventral dentate gyrus and that p75NTR may play a role in anxiety-like behavior, specifically in female mice.

  20. Identification and characterization of a tandem repeat in exon III of the dopamine receptor D4 (DRD4) gene in cetaceans

    DEFF Research Database (Denmark)

    Mogensen, Line; Kinze, Carl Christian; Werge, Thomas

    2006-01-01

    A large number of mammalian species harbor a tandem repeat in exon III of the gene encoding dopamine receptor D4 (DRD4), a receptor associated with cognitive functions. In this study, a DRD4 gene exon III tandem repeat from the order Cetacea was identified and characterized. Included in our study...

  1. Cloning of the pig aminopeptidase N gene. Identification of possible regulatory elements and the exon distribution in relation to the membrane-spanning region

    DEFF Research Database (Denmark)

    Sjöström, H; Norén, O; Olsen, Jørgen

    1989-01-01

    . By sequence comparisons we have found three domains showing similarity to promoter regions of the genes encoding human alpha 1-antitrypsin and human intestinal alkaline phosphatase. The gene sequence includes the first three exons and two introns. It shows that a single exon encodes the cytoplasmic tail...

  2. Evolution of alternative splicing regulation: changes in predicted exonic splicing regulators are not associated with changes in alternative splicing levels in primates

    DEFF Research Database (Denmark)

    Irimia, Manuel; Rukov, Jakob Lewin; Roy, Scott William

    2009-01-01

    and changes in alternative splicing levels. This observation holds across different ESR exon positions, exon lengths, and 5' splice site strengths. We suggest that this lack of association is mainly due to the great importance of context for ESR functionality: many ESR-like motifs in primates may have little...

  3. Counting graphene layers with very slow electrons

    Energy Technology Data Exchange (ETDEWEB)

    Frank, Ludĕk; Mikmeková, Eliška; Müllerová, Ilona [Institute of Scientific Instruments AS CR, v.v.i., Královopolská 147, 61264 Brno (Czech Republic); Lejeune, Michaël [Laboratoire de Physique de la Matière Condensée, Faculté des Sciences d' Amiens, Universite de Picardie Jules Verne, 33 rue Saint Leu, 80039 Amiens Cedex 2 (France)

    2015-01-05

    The study aimed at collection of data regarding the transmissivity of freestanding graphene for electrons across their full energy scale down to the lowest energies. Here, we show that the electron transmissivity of graphene drops with the decreasing energy of the electrons and remains below 10% for energies below 30 eV, and that the slow electron transmissivity value is suitable for reliable determination of the number of graphene layers. Moreover, electrons incident below 50 eV release adsorbed hydrocarbon molecules and effectively clean graphene in contrast to faster electrons that decompose these molecules and create carbonaceous contamination.

  4. Slow relaxation in weakly open rational polygons.

    Science.gov (United States)

    Kokshenev, Valery B; Vicentini, Eduardo

    2003-07-01

    The interplay between the regular (piecewise-linear) and irregular (vertex-angle) boundary effects in nonintegrable rational polygonal billiards (of m equal sides) is discussed. Decay dynamics in polygons (of perimeter P(m) and small opening Delta) is analyzed through the late-time survival probability S(m) approximately equal t(-delta). Two distinct slow relaxation channels are established. The primary universal channel exhibits relaxation of regular sliding orbits, with delta=1. The secondary channel is given by delta>1 and becomes open when m>P(m)/Delta. It originates from vertex order-disorder dual effects and is due to relaxation of chaoticlike excitations.

  5. Quasistatic modelling of the coaxial slow source

    International Nuclear Information System (INIS)

    Hahn, K.D.; Pietrzyk, Z.A.; Vlases, G.C.

    1986-01-01

    A new 1-D Lagrangian MHD numerical code in flux coordinates has been developed for the Coaxial Slow Source (CSS) geometry. It utilizes the quasistatic approximation so that the plasma evolves as a succession of equilibria. The P=P (psi) equilibrium constraint, along with the assumption of infinitely fast axial temperature relaxation on closed field lines, is incorporated. An axially elongated, rectangular plasma is assumed. The axial length is adjusted by the global average condition, or assumed to be fixed. In this paper predictions obtained with the code, and a limited amount of comparison with experimental data are presented

  6. Hot big bang or slow freeze?

    Science.gov (United States)

    Wetterich, C.

    2014-09-01

    We confront the big bang for the beginning of the universe with an equivalent picture of a slow freeze - a very cold and slowly evolving universe. In the freeze picture the masses of elementary particles increase and the gravitational constant decreases with cosmic time, while the Newtonian attraction remains unchanged. The freeze and big bang pictures both describe the same observations or physical reality. We present a simple ;crossover model; without a big bang singularity. In the infinite past space-time is flat. Our model is compatible with present observations, describing the generation of primordial density fluctuations during inflation as well as the present transition to a dark energy-dominated universe.

  7. Lead Slowing Down Spectrometer Status Report

    International Nuclear Information System (INIS)

    Warren, Glen A.; Anderson, Kevin K.; Bonebrake, Eric; Casella, Andrew M.; Danon, Yaron; Devlin, M.; Gavron, Victor A.; Haight, R.C.; Imel, G.R.; Kulisek, Jonathan A.; O'Donnell, J.M.; Weltz, Adam

    2012-01-01

    This report documents the progress that has been completed in the first half of FY2012 in the MPACT-funded Lead Slowing Down Spectrometer project. Significant progress has been made on the algorithm development. We have an improve understanding of the experimental responses in LSDS for fuel-related material. The calibration of the ultra-depleted uranium foils was completed, but the results are inconsistent from measurement to measurement. Future work includes developing a conceptual model of an LSDS system to assay plutonium in used fuel, improving agreement between simulations and measurement, design of a thorium fission chamber, and evaluation of additional detector techniques.

  8. Sustainable Development of Slow Fashion Businesses: Customer Value Approach

    Directory of Open Access Journals (Sweden)

    Sojin Jung

    2016-06-01

    Full Text Available As an alternative to the prevalent fast fashion model, slow fashion has emerged as a way of enhancing sustainability in the fashion industry, yet how slow fashion can enhance profitability is still largely unknown. Based on a customer value creation framework, this study empirically tested a structural model that specified the slow fashion attributes that contribute to creating perceived customer value, which subsequently increases a consumer’s intention to buy and pay a price premium for slow fashion products. An analysis of 221 U.S. consumer data revealed that delivering exclusive product value is significantly critical in creating customer value for slow fashion, and customer value, in turn, positively affects consumers’ purchase intentions. Further analysis also revealed that different slow fashion attributes distinctively affect customer value. This provides potential strategies on which slow fashion businesses can focus to secure an economically sustainable business model, thereby continuously improving environmental and social sustainability with the slow fashion ideal.

  9. A DNMT3B alternatively spliced exon and encoded peptide are novel biomarkers of human pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Sailesh Gopalakrishna-Pillai

    Full Text Available A major obstacle in human stem cell research is the limited number of reagents capable of distinguishing pluripotent stem cells from partially differentiated or incompletely reprogrammed derivatives. Although human embryonic stem cells (hESCs and induced pluripotent stem cells (iPSCs express numerous alternatively spliced transcripts, little attention has been directed at developing splice variant-encoded protein isoforms as reagents for stem cell research. In this study, several genes encoding proteins involved in important signaling pathways were screened to detect alternatively spliced transcripts that exhibited differential expression in pluripotent stem cells (PSCs relative to spontaneously differentiated cells (SDCs. Transcripts containing the alternatively spliced exon 10 of the de novo DNA methyltransferase gene, DNMT3B, were identified that are expressed in PSCs. To demonstrate the utility and superiority of splice variant specific reagents for stem cell research, a peptide encoded by DNMT3B exon 10 was used to generate an antibody, SG1. The SG1 antibody detects a single DNMT3B protein isoform that is expressed only in PSCs but not in SDCs. The SG1 antibody is also demonstrably superior to other antibodies at distinguishing PSCs from SDCs in mixed cultures containing both pluripotent stem cells and partially differentiated derivatives. The tightly controlled down regulation of DNMT3B exon 10 containing transcripts (and exon 10 encoded peptide upon spontaneous differentiation of PSCs suggests that this DNMT3B splice isoform is characteristic of the pluripotent state. Alternatively spliced exons, and the proteins they encode, represent a vast untapped reservoir of novel biomarkers that can be used to develop superior reagents for stem cell research and to gain further insight into mechanisms controlling stem cell pluripotency.

  10. A DEL phenotype attributed to RHD Exon 9 sequence deletion: slipped-strand mispairing and blood group polymorphisms.

    Science.gov (United States)

    Lopez, Genghis H; Turner, Robyn M; McGowan, Eunike C; Schoeman, Elizna M; Scott, Stacy A; O'Brien, Helen; Millard, Glenda M; Roulis, Eileen V; Allen, Amanda J; Liew, Yew-Wah; Flower, Robert L; Hyland, Catherine A

    2018-03-01

    The RhD blood group antigen is extremely polymorphic and the DEL phenotype represents one such class of polymorphisms. The DEL phenotype prevalent in East Asian populations arises from a synonymous substitution defined as RHD*1227A. However, initially, based on genomic and cDNA studies, the genetic basis for a DEL phenotype in Taiwan was attributed to a deletion of RHD Exon 9 that was never verified at the genomic level by any other independent group. Here we investigate the genetic basis for a Caucasian donor with a DEL partial D phenotype and compare the genomic findings to those initial molecular studies. The 3'-region of the RHD gene was amplified by long-range polymerase chain reaction (PCR) for massively parallel sequencing. Primers were designed to encompass a deletion, flanking Exon 9, by standard PCR for Sanger sequencing. Targeted sequencing of exons and flanking introns was also performed. Genomic DNA exhibited a 1012-bp deletion spanning from Intron 8, across Exon 9 into Intron 9. The deletion breakpoints occurred between two 25-bp repeat motifs flanking Exon 9 such that one repeat sequence remained. Deletion mutations bordered by repeat sequences are a hallmark of slipped-strand mispairing (SSM) event. We propose this genetic mechanism generated the germline deletion in the Caucasian donor. Extensive studies show that the RHD*1227A is the most prevalent DEL allele in East Asian populations and may have confounded the initial molecular studies. Review of the literature revealed that the SSM model explains some of the extreme polymorphisms observed in the clinically significant RhD blood group antigen. © 2017 AABB.

  11. A mutation in an alternative untranslated exon of hexokinase 1 associated with Hereditary Motor and Sensory Neuropathy – Russe (HMSNR)

    Science.gov (United States)

    Hantke, Janina; Chandler, David; King, Rosalind; Wanders, Ronald JA; Angelicheva, Dora; Tournev, Ivailo; McNamara, Elyshia; Kwa, Marcel; Guergueltcheva, Velina; Kaneva, Radka; Baas, Frank; Kalaydjieva, Luba

    2009-01-01

    Hereditary Motor and Sensory Neuropathy – Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to ∼70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to ∼26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS). PMID:19536174

  12. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR).

    Science.gov (United States)

    Hantke, Janina; Chandler, David; King, Rosalind; Wanders, Ronald J A; Angelicheva, Dora; Tournev, Ivailo; McNamara, Elyshia; Kwa, Marcel; Guergueltcheva, Velina; Kaneva, Radka; Baas, Frank; Kalaydjieva, Luba

    2009-12-01

    Hereditary Motor and Sensory Neuropathy -- Russe (HMSNR) is a severe autosomal recessive disorder, identified in the Gypsy population. Our previous studies mapped the gene to 10q22-q23 and refined the gene region to approximately 70 kb. Here we report the comprehensive sequencing analysis and fine mapping of this region, reducing it to approximately 26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1). We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls. Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation. Analysis of the Hk1 upstream region in mouse mRNA from testis and neural tissues showed an abundance of AltT2-containing transcripts generated by extensive, developmentally regulated alternative splicing. Expression is very low compared with ubiquitous Hk1 and all transcripts skip exon1, which encodes the protein domain responsible for binding to the outer mitochondrial membrane, and regulation of energy production and apoptosis. Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown and could involve disrupted translational regulation leading to increased anti-apoptotic activity (suggested by the profuse regenerative activity in affected nerves), or impairment of an unknown HK1 function in the peripheral nervous system (PNS).

  13. Intronic L1 retrotransposons and nested genes cause transcriptional interference by inducing intron retention, exonization and cryptic polyadenylation.

    Directory of Open Access Journals (Sweden)

    Kristel Kaer

    Full Text Available Transcriptional interference has been recently recognized as an unexpectedly complex and mostly negative regulation of genes. Despite a relatively few studies that emerged in recent years, it has been demonstrated that a readthrough transcription derived from one gene can influence the transcription of another overlapping or nested gene. However, the molecular effects resulting from this interaction are largely unknown.Using in silico chromosome walking, we searched for prematurely terminated transcripts bearing signatures of intron retention or exonization of intronic sequence at their 3' ends upstream to human L1 retrotransposons, protein-coding and noncoding nested genes. We demonstrate that transcriptional interference induced by intronic L1s (or other repeated DNAs and nested genes could be characterized by intron retention, forced exonization and cryptic polyadenylation. These molecular effects were revealed from the analysis of endogenous transcripts derived from different cell lines and tissues and confirmed by the expression of three minigenes in cell culture. While intron retention and exonization were comparably observed in introns upstream to L1s, forced exonization was preferentially detected in nested genes. Transcriptional interference induced by L1 or nested genes was dependent on the presence or absence of cryptic splice sites, affected the inclusion or exclusion of the upstream exon and the use of cryptic polyadenylation signals.Our results suggest that transcriptional interference induced by intronic L1s and nested genes could influence the transcription of the large number of genes in normal as well as in tumor tissues. Therefore, this type of interference could have a major impact on the regulation of the host gene expression.

  14. First report of a deletion encompassing an entire exon in the homogentisate 1,2-dioxygenase gene causing alkaptonuria.

    Science.gov (United States)

    Zouheir Habbal, Mohammad; Bou-Assi, Tarek; Zhu, Jun; Owen, Renius; Chehab, Farid F

    2014-01-01

    Alkaptonuria is often diagnosed clinically with episodes of dark urine, biochemically by the accumulation of peripheral homogentisic acid and molecularly by the presence of mutations in the homogentisate 1,2-dioxygenase gene (HGD). Alkaptonuria is invariably associated with HGD mutations, which consist of single nucleotide variants and small insertions/deletions. Surprisingly, the presence of deletions beyond a few nucleotides among over 150 reported deleterious mutations has not been described, raising the suspicion that this gene might be protected against the detrimental mechanisms of gene rearrangements. The quest for an HGD mutation in a proband with AKU revealed with a SNP array five large regions of homozygosity (5-16 Mb), one of which includes the HGD gene. A homozygous deletion of 649 bp deletion that encompasses the 72 nucleotides of exon 2 and surrounding DNA sequences in flanking introns of the HGD gene was unveiled in a proband with AKU. The nature of this deletion suggests that this in-frame deletion could generate a protein without exon 2. Thus, we modeled the tertiary structure of the mutant protein structure to determine the effect of exon 2 deletion. While the two β-pleated sheets encoded by exon 2 were missing in the mutant structure, other β-pleated sheets are largely unaffected by the deletion. However, nine novel α-helical coils substituted the eight coils present in the native HGD crystal structure. Thus, this deletion results in a deleterious enzyme, which is consistent with the proband's phenotype. Screening for mutations in the HGD gene, particularly in the Middle East, ought to include this exon 2 deletion in order to determine its frequency and uncover its origin.

  15. First report of a deletion encompassing an entire exon in the homogentisate 1,2-dioxygenase gene causing alkaptonuria.

    Directory of Open Access Journals (Sweden)

    Mohammad Zouheir Habbal

    Full Text Available Alkaptonuria is often diagnosed clinically with episodes of dark urine, biochemically by the accumulation of peripheral homogentisic acid and molecularly by the presence of mutations in the homogentisate 1,2-dioxygenase gene (HGD. Alkaptonuria is invariably associated with HGD mutations, which consist of single nucleotide variants and small insertions/deletions. Surprisingly, the presence of deletions beyond a few nucleotides among over 150 reported deleterious mutations has not been described, raising the suspicion that this gene might be protected against the detrimental mechanisms of gene rearrangements. The quest for an HGD mutation in a proband with AKU revealed with a SNP array five large regions of homozygosity (5-16 Mb, one of which includes the HGD gene. A homozygous deletion of 649 bp deletion that encompasses the 72 nucleotides of exon 2 and surrounding DNA sequences in flanking introns of the HGD gene was unveiled in a proband with AKU. The nature of this deletion suggests that this in-frame deletion could generate a protein without exon 2. Thus, we modeled the tertiary structure of the mutant protein structure to determine the effect of exon 2 deletion. While the two β-pleated sheets encoded by exon 2 were missing in the mutant structure, other β-pleated sheets are largely unaffected by the deletion. However, nine novel α-helical coils substituted the eight coils present in the native HGD crystal structure. Thus, this deletion results in a deleterious enzyme, which is consistent with the proband's phenotype. Screening for mutations in the HGD gene, particularly in the Middle East, ought to include this exon 2 deletion in order to determine its frequency and uncover its origin.

  16. Evolution of the histones: free play with exon shuffling Evolucion de las histonas: Juego libre con reordenamiento de exones al azar

    Directory of Open Access Journals (Sweden)

    G. CECILIA TORO

    2001-03-01

    Full Text Available In higher eukaryotes, the nuclear DNA is organized for transcription, replication and mitosis in competent chromatin and chromosomes. The basic unit of chromatin is the nucleosome. This entity is formed by 168 base pairs of DNA wound around an octamer of histones, this octamer of histones consist of two copies of H2A, H2B, H3 and H4. The DNA is sealed in its input and output point by a histone linker: histone H1. Histones were supposed to be very conserved proteins. However, during the past few years it was found that these proteins present a high degree of divergency in several lower eukaryotes. In Trypanosoma, it was found that histones H3 and H4, which are at the center of the nucleosomal organization, showed more than 30 % of divergency, while histone H1 corresponded to only one of the three peptide domains present in higher eukaryotes. These features of Trypanosoma histones may explain, at least in part, the unability of chromatin to condense into chromosomes during the cell division in these parasites. Evolution of histones was usually considered as peculiar, with several proposals which are difficult to reconcile with experimental data. In the present work, it is proposed that histones followed the same evolutionary route as many other proteins. Considering that exons code for structural and functional domains in proteins and that, at the origin of eukaryotes, the histones, as other proteins, could be formed by "units" (mecano theory, it was expected that these units or domains eventually would be found in living organisms exhibiting primitive features. Furthermore, those units could work independently. Our results on the structure of Trypanosoma cruzi histone genes and proteins as well as the analysis of other histones from different species fit with this proposalEn los eucariontes superiores, el DNA nuclear se organiza en cromatina competente y en cromosomas para la transcripción, replicación y mitosis. La unidad básica de la

  17. Slow-light dynamics in nonlinear periodic waveguides couplers

    DEFF Research Database (Denmark)

    Sukhorukov, A.A.; Ha, S.; Powell, D.A.

    2009-01-01

    We predict pulse switching and reshaping through nonlinear mixing of two slow-light states with different phase velocities in the same frequency range, and report on the first experimental observation of slow-light tunneling between coupled periodic waveguides.......We predict pulse switching and reshaping through nonlinear mixing of two slow-light states with different phase velocities in the same frequency range, and report on the first experimental observation of slow-light tunneling between coupled periodic waveguides....

  18. Slow-light effects in photonic crystal membrane lasers

    DEFF Research Database (Denmark)

    Xue, Weiqi; Yu, Yi; Ottaviano, Luisa

    2015-01-01

    In this paper, we present a systematic investigation of photonic crystal cavity laser operating in the slow-light regime. The dependence of lasing threshold on the effect of slow-light will be particularly highlighted.......In this paper, we present a systematic investigation of photonic crystal cavity laser operating in the slow-light regime. The dependence of lasing threshold on the effect of slow-light will be particularly highlighted....

  19. Nonlinear Gain Saturation in Active Slow Light Photonic Crystal Waveguides

    DEFF Research Database (Denmark)

    Chen, Yaohui; Mørk, Jesper

    2013-01-01

    We present a quantitative three-dimensional analysis of slow-light enhanced traveling wave amplification in an active semiconductor photonic crystal waveguides. The impact of slow-light propagation on the nonlinear gain saturation of the device is investigated.......We present a quantitative three-dimensional analysis of slow-light enhanced traveling wave amplification in an active semiconductor photonic crystal waveguides. The impact of slow-light propagation on the nonlinear gain saturation of the device is investigated....

  20. Interaction of slow pions with atomic nuclei

    International Nuclear Information System (INIS)

    Troitskij, M.A.; Tsybul'nikov, A.V.; Chekunaev, N.I.

    1984-01-01

    Interactions of slow pions with atomic nuclei near to pion condensation are investigated. From comparison of experimental data with the theoretical calculation results on the basis of precise microscopic approach not bound with the random phase approximation (RPA) nuclear matter fundamental parameters near a critical point can be found. Optical potential of slow pions in nuclei, πN-scattering amplitudes and lengths, π-atom level isotopic shift, phenomenon of single-nucleon pion absorption by nucleus, phenomenon of nuclear critical opalescence are considered. The results of πN-scattering lengths calculation, sup(40-44)Ca, sup(24-29)Mg, sup(16-18)O π-atom level shift are presented. It is shown that the presence of π-condensate in nuclei can explain the observed suppression of p-wave potential terms. The phenomenon of single-nucleon pion absorption by nucleus is one of direct experiments which permits to reveal the π-condensate. The nuclear opalescence phenomenon is manifested in increase of pion photoproduction reaction cross section for account of nucleus proximity to π-condensation as compared with the calculated in the Fermi-gas model. The suggested method for calculating precondensate phenomena operates the better, the nearer is the system to the condensation threshold whereas the RPA method in this region is inapplicable

  1. Factors Contributing Decreased Performance Of Slow Learners

    Directory of Open Access Journals (Sweden)

    Dr. L. Kannan

    2015-03-01

    Full Text Available Back ground Even experienced teaching faculty and administrators can be challenged by learners who have not able to perform up to expected need in their annual performance of their students these students are called as slow learnersStruggle learners. There should be a designed study to foster discussion about diagnosing particular problems that contribute with meeting objectives of slow learners. Methodology The study was performed on the entire current first year of Medical students were all the three internal assessments of 250 students performance is taken in to consideration for the study. This study is of cross section type.After obtaining the list of all students marks in internal examination from medical education unit supporting mentors are contacted to meet the students and confidentiality is maintained throughout the study. After obtaining informed consent a questionnaire was administered to the students by the investigator. The questionnaire contains the following sections. Section I will be on the background characteristics of the student name age sex type of family. Section II will be on the details of their learning capabilities. Section III will focus on the awareness of the slow learners in which the precipitating factors contributing to them. Results The prevalence of slow learners as low achievers were contributed to be 32.4 percentages.The performance of the students is based on combination of all three internal assessment marks including theory and practical performance. In this the students age ranges from 17 to 21 years the mean age of student was contributed to be 17.81 and majority of the students were in the age group of 18 years which contributed to be 16867.2.In the present study majority were males 13252.8 compared to females 11847.2.but when study is compared to percentage of attendance majority of the individual 15177 scored more than 50 percentage of marks have more than 80 percentage of attendance but when

  2. Good, Clean, Fair: The Rhetoric of the Slow Food Movement

    Science.gov (United States)

    Schneider, Stephen

    2008-01-01

    This article outlines the origins of the Slow Food movement before examining the ways in which Slow Food rhetoric seeks to redefine gastronomy and combat the more deleterious effects of globalization. In articulating a new gastronomy, Slow Food founder Carlo Petrini attempts to reconstruct the gastronomy of Jean Anthelme Brillat-Savarin, at once…

  3. DEDB: a database of Drosophila melanogaster exons in splicing graph form

    Directory of Open Access Journals (Sweden)

    Tan Tin

    2004-12-01

    Full Text Available Abstract Background A wealth of quality genomic and mRNA/EST sequences in recent years has provided the data required for large-scale genome-wide analysis of alternative splicing. We have capitalized on this by constructing a database that contains alternative splicing information organized as splicing graphs, where all transcripts arising from a single gene are collected, organized and classified. The splicing graph then serves as the basis for the classification of the various types of alternative splicing events. Description DEDB http://proline.bic.nus.edu.sg/dedb/index.html is a database of Drosophila melanogaster exons obtained from FlyBase arranged in a splicing graph form that permits the creation of simple rules allowing for the classification of alternative splicing events. Pfam domains were also mapped onto the protein sequences allowing users to access the impact of alternative splicing events on domain organization. Conclusions DEDB's catalogue of splicing graphs facilitates genome-wide classification of alternative splicing events for genome analysis. The splicing graph viewer brings together genome, transcript, protein and domain information to facilitate biologists in understanding the implications of alternative splicing.

  4. Defective splicing, disease and therapy: searching for master checkpoints in exon definition.

    Science.gov (United States)

    Buratti, Emanuele; Baralle, Marco; Baralle, Francisco E

    2006-01-01

    The number of aberrant splicing processes causing human disease is growing exponentially and many recent studies have uncovered some aspects of the unexpectedly complex network of interactions involved in these dysfunctions. As a consequence, our knowledge of the various cis- and trans-acting factors playing a role on both normal and aberrant splicing pathways has been enhanced greatly. However, the resulting information explosion has also uncovered the fact that many splicing systems are not easy to model. In fact we are still unable, with certainty, to predict the outcome of a given genomic variation. Nonetheless, in the midst of all this complexity some hard won lessons have been learned and in this survey we will focus on the importance of the wide sequence context when trying to understand why apparently similar mutations can give rise to different effects. The examples discussed in this summary will highlight the fine 'balance of power' that is often present between all the various regulatory elements that define exon boundaries. In the final part, we shall then discuss possible therapeutic targets and strategies to rescue genetic defects of complex splicing systems.

  5. Polymorphism in exon2 of BMP15 gene in Iranian sangsari sheep

    Directory of Open Access Journals (Sweden)

    zana pirkhezranian

    2015-04-01

    Full Text Available Fertility rate is an economically important trait in sheep, which is influenced by genetic and environment. So far, three genes have been identified that affects this trait, one of them would be the BMP family, the most famous one is BMP15. Different mutations in the BMP15 gene, increases reproductive performance and growth rate in sheep. The aim of this study was to investigate the genetic and phylogenetic of BMP15 gene sequence in Iranian Sangsari sheep. For this purpose, the blood samples from 20 animal of Damghan station were collected. After DNA extracting, a segment of 222 bp of exon 2 of BMP15 gene was amplified using polymerase chain reaction. Then, all of the PCR products were sequenced. The results showed existence of four haplotypes and three significant mutations of the gene that which one of them was seen for first. In order to determine the genetic distance of Sansari sheep with other animals especially sheep breeds about 103 sequences were taken from Genebank, Then, phylogenetic trees were drawn. Genetic distances and nucleotide differences were calculated. The results showed that goat, cattle and buffalo have minimum genetic distance and monkey, human and mouse have maximum distance with Sangsari sheep and native Hindi and Kashmiri sheep have not any differences with Iranian Sangsari sheep.

  6. Live Cell Genomics: RNA Exon-Specific RNA-Binding Protein Isolation.

    Science.gov (United States)

    Bell, Thomas J; Eberwine, James

    2015-01-01

    RNA-binding proteins (RBPs) are essential regulatory proteins that control all modes of RNA processing and regulation. New experimental approaches to isolate these indispensable proteins under in vivo conditions are needed to advance the field of RBP biology. Historically, in vitro biochemical approaches to isolate RBP complexes have been useful and productive, but biological relevance of the identified RBP complexes can be imprecise or erroneous. Here we review an inventive experimental to isolate RBPs under the in vivo conditions. The method is called peptide nucleic acid (PNA)-assisted identification of RBP (PAIR) technology and it uses cell-penetrating peptides (CPPs) to deliver photo-activatible RBP-capture molecule to the cytoplasm of the live cells. The PAIR methodology provides two significant advantages over the most commonly used approaches: (1) it overcomes the in vitro limitation of standard biochemical approaches and (2) the PAIR RBP-capture molecule is highly selective and adaptable which allows investigators to isolate exon-specific RBP complexes. Most importantly, the in vivo capture conditions and selectivity of the RBP-capture molecule yield biologically accurate and relevant RBP data.

  7. SEQUENCING AND SEQUENCE ANALYSIS OF MYOSTATIN GENE IN THE EXON 1 OF THE CAMEL (CAMELUS DROMEDARIUS

    Directory of Open Access Journals (Sweden)

    M. G. SHAH, A. S. QURESHI1, M. REISSMANN2 AND H. J. SCHWARTZ3

    2006-10-01

    Full Text Available Myostatin, also called growth differentiation factor-8 (GDF-8, is a member of the mammalian growth transforming family (TGF-beta superfamily, which is expressed specifically in developing an adult skeletal muscle. Muscular hypertrophy allele (mh allele in the double muscle breeds involved mutation within the myostatin gene. Genomic DNA was isolated from the camel hair using NucleoSpin Tissue kit. Two animals of each of the six breeds namely, Marecha, Dhatti, Larri, Kohi, Sakrai and Cambelpuri were used for sequencing. For PCR amplification of the gene, a primer pair was designed from homolog regions of already published sequences of farm animals from GenBank. Results showed that camel myostatin possessed more than 90% homology with that of cattle, sheep and pig. Camel formed separate cluster from the pig in spite of having high homology (98% and showed 94% homology with cattle and sheep as reported in literature. Sequence analysis of the PCR amplified part of exon 1 (256 bp of the camel myostatin was identical among six camel breeds.

  8. A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

    Science.gov (United States)

    Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Davey Smith, G; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

    2016-08-01

    Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

  9. Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta.

    Science.gov (United States)

    Smith, Claire E L; Murillo, Gina; Brookes, Steven J; Poulter, James A; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2016-08-15

    Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. Amelotin (AMTN) is a secreted protein thought to act as a promoter of matrix mineralization in the final stage of enamel development, and is strongly expressed, almost exclusively, in maturation stage ameloblasts. Amtn overexpression and Amtn knockout mouse models have defective enamel with no other associated phenotypes, highlighting AMTN as an excellent candidate gene for human AI. However, no AMTN mutations have yet been associated with human AI. Using whole exome sequencing, we identified an 8,678 bp heterozygous genomic deletion encompassing exons 3-6 of AMTN in a Costa Rican family segregating dominant hypomineralised AI. The deletion corresponds to an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 residues. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects at least some of which appeared to be associated with organic material as evidenced using elemental analysis. This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function. © The Author 2016. Published by Oxford University Press.

  10. Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly.

    Directory of Open Access Journals (Sweden)

    Hanqian Mao

    2016-09-01

    Full Text Available The exon junction complex (EJC is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling. Using a new conditional allele, we first show that Eif4a3 haploinsufficiency phenocopies aberrant neurogenesis and microcephaly of Magoh and Rbm8a mutant mice. Transcriptomic and proteomic analyses of embryonic brains at the onset of neurogenesis identifies common pathways altered in each of the 3 EJC mutants, including ribosome, proteasome, and p53 signaling components. We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expression. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as a major node of neurodevelopmental pathogenesis following EJC impairment. Altogether our study reveals new mechanisms to help explain how EJC mutations influence neurogenesis and underlie neurodevelopmental disease.

  11. Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

    Directory of Open Access Journals (Sweden)

    Brewster Brooke L

    2010-05-01

    Full Text Available Abstract Background Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs remains a challenge. Methods This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches. Results Analysis of BRCA2 c.8308 G > A (p.Ala2770Thr by mRNA analysis, and BRCA2 c.8962A > G (p.Ser2988Gly, BRCA2 c.8972G > A (p.Arg2991His, BRCA2 c.9172A > G (p.Ser3058Gly, and BRCA2 c.9213G > T (p.Glu3071Asp by a minigene assay, revealed no evidence for aberrant splicing. Conclusions These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.

  12. Transcription and splicing regulation in human umbilical vein endothelial cells under hypoxic stress conditions by exon array

    Directory of Open Access Journals (Sweden)

    Wu Yonghong

    2009-03-01

    Full Text Available Abstract Background The balance between endothelial cell survival and apoptosis during stress is an important cellular process for vessel integrity and vascular homeostasis, and it is also pivotal in angiogenesis during the development of many vascular diseases. However, the underlying molecular mechanisms remain largely unknown. Although both transcription and alternative splicing are important in regulating gene expression in endothelial cells under stress, the regulatory mechanisms underlying this state and their interactions have not yet been studied on a genome-wide basis. Results Human umbilical vein endothelial cells (HUVECs were treated with cobalt chloride (CoCl2 both to mimic hypoxia and to induce cell apoptosis and alternative splicing responses. Cell apoptosis rate analysis indicated that HUVECs exposed to 300 μM CoCl2 for 24 hrs were initially counterbalancing apoptosis with cell survival. We therefore used the Affymetrix exon array system to determine genome-wide transcript- and exon-level differential expression. Other than 1583 differentially expressed transcripts, 342 alternatively spliced exons were detected and classified by different splicing types. Sixteen alternatively spliced exons were validated by RT-PCR. Furthermore, direct evidence for the ongoing balance between HUVEC survival and apoptosis was provided by Gene Ontology (GO and protein function, as well as protein domain and pathway enrichment analyses of the differentially expressed transcripts. Importantly, a novel molecular module, in which the heat shock protein (HSP families play a significant role, was found to be activated under mimicked hypoxia conditions. In addition, 46% of the transcripts containing stress-modulated exons were differentially expressed, indicating the possibility of combinatorial regulation of transcription and splicing. Conclusion The exon array system effectively profiles gene expression and splicing on the genome-wide scale. Based on

  13. Hot big bang or slow freeze?

    Energy Technology Data Exchange (ETDEWEB)

    Wetterich, C.

    2014-09-07

    We confront the big bang for the beginning of the universe with an equivalent picture of a slow freeze — a very cold and slowly evolving universe. In the freeze picture the masses of elementary particles increase and the gravitational constant decreases with cosmic time, while the Newtonian attraction remains unchanged. The freeze and big bang pictures both describe the same observations or physical reality. We present a simple “crossover model” without a big bang singularity. In the infinite past space–time is flat. Our model is compatible with present observations, describing the generation of primordial density fluctuations during inflation as well as the present transition to a dark energy-dominated universe.

  14. Interaction of slow electrons with surfaces. II

    International Nuclear Information System (INIS)

    Komolov, S.A.; Chadderton, L.T.

    1976-01-01

    Total current spectroscopy (TCS) has been used to study the growth of films of gold and silver on (100) vanadium surfaces. A slow transition from TCS curves characteristic of vanadium to curves characteristic of the noble metals is observed, accompanied by an increase in the net work function - more rapid for silver than for gold. Vanadium characteristics are lost from the TCS curves for mean overlayer thicknesses > approximately 15A, and a simple analysis shows that the thickness of the surface zone from which TCS signals originate is approximately given by the electron mean free path. Observations of progressive attenuation of a characteristic vanadium feature with increasing mean thickness of overlayer permits separation into stages of nucleation and growth. There is a critical nucleus size of approximately 2A for silver and approximately 4A for gold. (Auth.)

  15. Limits of slow light in photonic crystals

    DEFF Research Database (Denmark)

    Pedersen, Jesper Goor; Xiao, Sanshui; Mortensen, N. Asger

    2008-01-01

    in the group velocity acquiring a finite value above zero at the band-gap edges while attaining uperluminal values within the band gap. Simple scalings of the minimum and maximum group velocities with the imaginary part of the dielectric function or, equivalently, the linewidth of the broadened states......While ideal photonic crystals would support modes with a vanishing group velocity, state-of-the-art structures have still only provided a slow down by roughly two orders of magnitude. We find that the induced density of states caused by lifetime broadening of the electromagnetic modes results...... are presented. The results obtained are entirely general and may be applied to any effect which results in a broadening of the electromagnetic states, such as loss, disorder, and finite-size effects. This significantly limits the reduction in group velocity attainable via photonic crystals....

  16. Slow neutron scattering by water molecules

    Energy Technology Data Exchange (ETDEWEB)

    Stancic, V [Boris Kidric Institute of Nuclear Sciences Vinca, Beograd (Yugoslavia)

    1970-07-01

    In this work some new, preliminary formulae for slow neutron scattering cross section calculation by heavy and light water molecules have been done. The idea was to find, from the sum which exists in well known Nelkin model, other cross sections in a more simple analytical form, so that next approximations may be possible. In order to sum a series it was starting from Euler-Mclaurin formula. Some new summation formulae have been derived there, and defined in two theorems. Extensive calculations, especially during the evaluation of residues, have been made at the CDC 3600 computer. validation of derived formulae was done by comparison with the BNL-325 results. Good agreement is shown. (author)

  17. Acoustic slow waves and the consolidation transition

    International Nuclear Information System (INIS)

    Johnson, D.L.; Plona, T.J.

    1982-01-01

    We have investigated the ultrasonic properties of unconsolidated (loose) glass beads and of lightly fused (consolidated) glass beads when the pore space is saturated with water. At a frequency of 500 kHz we have observed a single compressional wave in the former whose speed is 1.79 km/s and two distinct compressional waves with speeds 2.81 km/s and 0.96 km/s in the latter. The Biot theory is shown to give an accurate description of this phenomenon. We also analyze the acoustics of low temperature He ii in packed powder superleaks; either the fast wave for unconsolidated systems or the slow wave in a highly consolidated (fused) frame may be considered to be the 4th sound mode. In all such systems, the acoustic properties can be very simply understood by considering the velocities of propagation as continuous functions of the elastic moduli of the solid skeletal frames

  18. Hot big bang or slow freeze?

    International Nuclear Information System (INIS)

    Wetterich, C.

    2014-01-01

    We confront the big bang for the beginning of the universe with an equivalent picture of a slow freeze — a very cold and slowly evolving universe. In the freeze picture the masses of elementary particles increase and the gravitational constant decreases with cosmic time, while the Newtonian attraction remains unchanged. The freeze and big bang pictures both describe the same observations or physical reality. We present a simple “crossover model” without a big bang singularity. In the infinite past space–time is flat. Our model is compatible with present observations, describing the generation of primordial density fluctuations during inflation as well as the present transition to a dark energy-dominated universe

  19. Slow speed object detection for haul trucks

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2009-09-15

    Caterpillar integrates radar technology with its current camera based system. Caterpillar has developed the Integrated Object Detection System, a slow speed object detection system for mining haul trucks. Object detection is a system that aids the truck operator's awareness of their surroundings. The system consists of a color touch screen display along with medium- and short-range radar as well as cameras, harnesses and mounting hardware. It is integrated into the truck's Work Area Vision System (WAVS). After field testing in 2007, system commercialization began in 2008. Prototype systems are in operation in Australia, Utah and Arizona and the Integrated Object Detection System will be available in the fourth quarter of 2009 and on production trucks 785C, 789C, 793D and 797B. The article is adapted from a presentation by Mark Richards of Caterpillar to the Haulage & Loading 2009 conference, May, held in Phoenix, AZ. 1 fig., 5 photos.

  20. Slow neutron scattering by water molecules

    International Nuclear Information System (INIS)

    Stancic, V.

    1970-01-01

    In this work some new, preliminary formulae for slow neutron scattering cross section calculation by heavy and light water molecules have been done. The idea was to find, from the sum which exists in well known Nelkin model, other cross sections in a more simple analytical form, so that next approximations may be possible. In order to sum a series it was starting from Euler-Mclaurin formula. Some new summation formulae have been derived there, and defined in two theorems. Extensive calculations, especially during the evaluation of residues, have been made at the CDC 3600 computer. validation of derived formulae was done by comparison with the BNL-325 results. Good agreement is shown. (author)

  1. Hot big bang or slow freeze?

    Directory of Open Access Journals (Sweden)

    C. Wetterich

    2014-09-01

    Full Text Available We confront the big bang for the beginning of the universe with an equivalent picture of a slow freeze — a very cold and slowly evolving universe. In the freeze picture the masses of elementary particles increase and the gravitational constant decreases with cosmic time, while the Newtonian attraction remains unchanged. The freeze and big bang pictures both describe the same observations or physical reality. We present a simple “crossover model” without a big bang singularity. In the infinite past space–time is flat. Our model is compatible with present observations, describing the generation of primordial density fluctuations during inflation as well as the present transition to a dark energy-dominated universe.

  2. Slow creep in soft granular packings.

    Science.gov (United States)

    Srivastava, Ishan; Fisher, Timothy S

    2017-05-14

    Transient creep mechanisms in soft granular packings are studied numerically using a constant pressure and constant stress simulation method. Rapid compression followed by slow dilation is predicted on the basis of a logarithmic creep phenomenon. Characteristic scales of creep strain and time exhibit a power-law dependence on jamming pressure, and they diverge at the jamming point. Microscopic analysis indicates the existence of a correlation between rheology and nonaffine fluctuations. Localized regions of large strain appear during creep and grow in magnitude and size at short times. At long times, the spatial structure of highly correlated local deformation becomes time-invariant. Finally, a microscale connection between local rheology and local fluctuations is demonstrated in the form of a linear scaling between granular fluidity and nonaffine velocity.

  3. Structure of genes for dermaseptins B, antimicrobial peptides from frog skin. Exon 1-encoded prepropeptide is conserved in genes for peptides of highly different structures and activities.

    Science.gov (United States)

    Vouille, V; Amiche, M; Nicolas, P

    1997-09-01

    We cloned the genes of two members of the dermaseptin family, broad-spectrum antimicrobial peptides isolated from the skin of the arboreal frog Phyllomedusa bicolor. The dermaseptin gene Drg2 has a 2-exon coding structure interrupted by a small 137-bp intron, wherein exon 1 encoded a 22-residue hydrophobic signal peptide and the first three amino acids of the acidic propiece; exon 2 contained the 18 additional acidic residues of the propiece plus a typical prohormone processing signal Lys-Arg and a 32-residue dermaseptin progenitor sequence. The dermaseptin genes Drg2 and Drg1g2 have conserved sequences at both untranslated ends and in the first and second coding exons. In contrast, Drg1g2 comprises a third coding exon for a short version of the acidic propiece and a second dermaseptin progenitor sequence. Structural conservation between the two genes suggests that Drg1g2 arose recently from an ancestral Drg2-like gene through amplification of part of the second coding exon and 3'-untranslated region. Analysis of the cDNAs coding precursors for several frog skin peptides of highly different structures and activities demonstrates that the signal peptides and part of the acidic propieces are encoded by conserved nucleotides encompassed by the first coding exon of the dermaseptin genes. The organization of the genes that belong to this family, with the signal peptide and the progenitor sequence on separate exons, permits strikingly different peptides to be directed into the secretory pathway. The recruitment of such a homologous 'secretory' exon by otherwise non-homologous genes may have been an early event in the evolution of amphibian.

  4. The sensitivity and efficacy method of PIK3CA exon 9 E545A as a high diagnostic accuracy in breast cancer

    Directory of Open Access Journals (Sweden)

    Desriani

    2018-06-01

    Full Text Available The phosphatidylinositol 3-kinases (PIK3s are lipid kinases. Mutation in the exon 9 and exon 20 determined as a predictive factor in anti-HER-2 therapy. In some countries, such as Singapore, China, and Peru, PIK3CA exon 9 E545A was reported to produce the highest rate of mutation. In this research, we developed and optimized PIK3CA exon 9 E545A detection methods with intercalating dye SYBR Green I based on the Tm Shift approach by using prepared recombinant plasmid pGEMT-easy PIK3CA exon 9 and PIK3CA exon 9 E545A. Recombinant plasmid was used due to the limited number of samples. Methods: Recombinant plasmid was prepared based on manufactured procedures, and this process was then followed by Tm prediction with Poland software, Tm Shift SYBR Green I development, and its characterization (reproducibility, repeatability, sensitivity, qPCR efficiency, and qPCR amplification, respectively. Result: A method for PIK3CA E545A detection based on TM shift SYBR Green I has been successfully developed. The melting temperature for PIK3CA exon 9 was 78.1 ± 0.1 °C, while that for PIK3CA exon E545A was 80.20 °C. The Tm of mutant was the same as that predicted using Polland Software. The reproducibility of the methods was high, with the coefficient values for inter and intra assays were below 10% with a high sensitivity at 1%, while R2 0.99 and PCR efficiency was 97.75%. Conclusion: The results presented here demonstrate that the PIK3CA exon 9 E545A detection method has a good sensitivity and efficacy assay, which proves that the method has a high diagnostic accuracy in breast cancer. Keywords: SYBR Green I, PIK3CA E545A, Breast cancer, Real time PCR, Recombinant plasmid

  5. Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.

    Science.gov (United States)

    Dimitrova, Desislava; Ruscito, Ilary; Olek, Sven; Richter, Rolf; Hellwag, Alexander; Türbachova, Ivana; Woopen, Hannah; Baron, Udo; Braicu, Elena Ioana; Sehouli, Jalid

    2016-09-01

    Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

  6. Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Vissing, John

    2011-01-01

    With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....

  7. To Screen Inactivation Mutation of Exon 1 of FSHR Gene in Polycystic Ovarian Syndrome: A South Indian Cohort Study

    Science.gov (United States)

    Sekar, Nishu; Yeole, Samiksha; Pradeep, Rashmi; Prabhu, Yogamaya D.; Renu, Kaviyarasi; Ramgir, Shalaka S.; Abilash, V. G.

    2017-11-01

    Polycystic ovary syndrome is an endocrine disorder. Irregular menstrual cycle, acne, facial hair and elevated androgen levels are the most common signs for PCOS. PCOS has an estimated prevalence of 4-12% among reproductive age women, thus making it a forerunner in female infertility. FSHR plays an important role in FSH signaling pathway making it an important gene for PCOS. In this study, we aim to focus on any association between the FSHR gene and PCOS. Our study was to evaluate any polymorphism of exon 1 of FSHR gene associated with PCOS.PCR-RFLP technique was performed on the PCOS samples. Hormonal changes were found in the patients. Exon 1 inactivation mutation of FSHR gene was not observed in the patient sample. A study of this association needs to be done using large sample size.

  8. Slow Earthquake Hunters: A New Citizen Science Project to Identify and Catalog Slow Slip Events in Geodetic Data

    Science.gov (United States)

    Bartlow, N. M.

    2017-12-01

    Slow Earthquake Hunters is a new citizen science project to detect, catalog, and monitor slow slip events. Slow slip events, also called "slow earthquakes", occur when faults slip too slowly to generate significant seismic radiation. They typically take between a few days and over a year to occur, and are most often found on subduction zone plate interfaces. While not dangerous in and of themselves, recent evidence suggests that monitoring slow slip events is important for earthquake hazards, as slow slip events have been known to trigger damaging "regular" earthquakes. Slow slip events, because they do not radiate seismically, are detected with a variety of methods, most commonly continuous geodetic Global Positioning System (GPS) stations. There is now a wealth of GPS data in some regions that experience slow slip events, but a reliable automated method to detect them in GPS data remains elusive. This project aims to recruit human users to view GPS time series data, with some post-processing to highlight slow slip signals, and flag slow slip events for further analysis by the scientific team. Slow Earthquake Hunters will begin with data from the Cascadia subduction zone, where geodetically detectable slow slip events with a duration of at least a few days recur at regular intervals. The project will then expand to other areas with slow slip events or other transient geodetic signals, including other subduction zones, and areas with strike-slip faults. This project has not yet rolled out to the public, and is in a beta testing phase. This presentation will show results from an initial pilot group of student participants at the University of Missouri, and solicit feedback for the future of Slow Earthquake Hunters.

  9. Detection of MPL exon10 mutations in 103 Chinese patients with JAK2V617F-negative myeloproliferative neoplasms.

    Science.gov (United States)

    Chen, Xiuhua; Qi, Xiling; Tan, Yanhong; Xu, Zhifang; Xu, Aining; Zhang, Linlin; Wang, Hongwei

    2011-06-15

    JAK2V617F mutation has been reported in 90% of patients with polycythemia vera (PV) and about 50% of patients with essential thromobocythemia (ET) and primary myelofibrosis (PMF). Recently, acquired mutations in the transmembrane-juxtamembrane region of MPL (MPLW515 mutations) have been reported in approximately 5% of JAK2V617F-negative PMF and about 1% of all cases of ET. MPL is the receptor for thrombopoietin that regulates the production of platelets by bone marrow. It is likely that some mutations more closely related to ET in MPL exon10 may have been missed by current assays. We inferred that there might be other mutations in MPL exon10 for MPN patients in addition to MPLW515 mutations. To investigate its mutation types and prevalence in Chinese patients with myeloproliferative neoplasms (MPN), we performed mutation detection on MPL exon10 in 103 JAK2V617F-negative MPN patients by single strand conformation polymorphism (SSCP) and allele-specific PCR (AS-PCR) combined with sequencing. As a result, one previously unrecognized MPL mutation (12-bp in-frame insertion) was identified in one patient with ET in addition to an MPLW515K mutation identified in one PMF patient. This confirms our hypothesis that BCR/ABL negative and JAK2V617F-negative MPN patients have other mutations besides W515 mutation in MPL exon10 and mutations other than single nucleotide exchange also exist. In addition, MPL mutation was associated with Chinese MPN patients. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Dietary selenomethionine increases exon-specific DNA methylation of the p53 gene in rat liver and colon mucosa.

    Science.gov (United States)

    Zeng, Huawei; Yan, Lin; Cheng, Wen-Hsing; Uthus, Eric O

    2011-08-01

    The regulation of site-specific DNA methylation of tumor suppressor genes has been considered as a leading mechanism by which certain nutrients exert their anticancer property. This study was to investigate whether selenium (Se) affects the methylation of globe genomic DNA and the exon-specific p53 gene. Three groups of rats (n = 6-7/group) were fed the AIN-93G basal diet supplemented with 0 [Se deficient (D)], 0.15 [Se adequate (A)], or 4 mg [Se supranutritional (S)] (Se as l-selenomethionine)/kg diet for 104 d, respectively. Rats fed the A or S diet had greater plasma and liver glutathione peroxidase activity, liver thioredoxin reductase activity, and plasma homocysteine concentration than those fed the D diet. However, compared with the A diet, rats fed the S diet did not further increase these Se-dependent enzyme activities or homocysteine concentration. In contrast, Se concentrations in kidney, liver, gastrocnemius muscle, and plasma were increased in a Se-dose-dependent manner. Interestingly, rats fed the S diet had significantly less global liver genomic DNA methylation than those fed the D diet. However, the S diet significantly increased the methylation of the p53 gene (exons 5-8) but not the β-actin gene (exons 2-3) DNA in liver and colon mucosa compared with those fed the D diet. Taken together, long-term Se consumption not only affects selenoprotein enzyme activities, homocysteine, tissue Se concentrations, and global genomic DNA methylation but also increases exon-specific DNA methylation of the p53 gene in a Se-dose-dependent manner in rat liver and colon mucosa.

  11. Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder.

    Science.gov (United States)

    Poultney, Christopher S; Goldberg, Arthur P; Drapeau, Elodie; Kou, Yan; Harony-Nicolas, Hala; Kajiwara, Yuji; De Rubeis, Silvia; Durand, Simon; Stevens, Christine; Rehnström, Karola; Palotie, Aarno; Daly, Mark J; Ma'ayan, Avi; Fromer, Menachem; Buxbaum, Joseph D

    2013-10-03

    Copy number variation (CNV) is an important determinant of human diversity and plays important roles in susceptibility to disease. Most studies of CNV carried out to date have made use of chromosome microarray and have had a lower size limit for detection of about 30 kilobases (kb). With the emergence of whole-exome sequencing studies, we asked whether such data could be used to reliably call rare exonic CNV in the size range of 1-30 kilobases (kb), making use of the eXome Hidden Markov Model (XHMM) program. By using both transmission information and validation by molecular methods, we confirmed that small CNV encompassing as few as three exons can be reliably called from whole-exome data. We applied this approach to an autism case-control sample (n = 811, mean per-target read depth = 161) and observed a significant increase in the burden of rare (MAF ≤1%) 1-30 kb CNV, 1-30 kb deletions, and 1-10 kb deletions in ASD. CNV in the 1-30 kb range frequently hit just a single gene, and we were therefore able to carry out enrichment and pathway analyses, where we observed enrichment for disruption of genes in cytoskeletal and autophagy pathways in ASD. In summary, our results showed that XHMM provided an effective means to assess small exonic CNV from whole-exome data, indicated that rare 1-30 kb exonic deletions could contribute to risk in up to 7% of individuals with ASD, and implicated a candidate pathway in developmental delay syndromes. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  12. Construction report of the PF slow-positron source. 1

    International Nuclear Information System (INIS)

    Enomoto, Atsushi; Kurihara, Toshikazu; Kobayashi, Hitoshi

    1993-12-01

    The slow positron source utilizing the electron beam of the 2.5 GeV electron beam accelerator which is the synchrotron radiation injector is being constructed. The outline of the project and the present state of construction are reported. As of November, 1993, by injecting the electron beam of about 10 W to the targets for producing positrons, the slow positrons of 4 x 10 4 e + /s has been obtained in the laboratory. Finally, with the electron beam of 30 kW, it is aimed at to obtain the slow positron beam of 2 x 10 9 e + /s. In the slow positron source, the electron beam from the 2.5 GeV linear accelerator is used as the primary beam. This beam is led to the target with electromagnets. Radiation shields were strengthened, and the electrostatic lens system was attached to efficiently extract and send out slow positrons. The conveying system for slow positrons is explained. Primary electron beam, target and moderator for producing slow positrons, the change to continuous current of pulsed slow positron beam and the heightening of luminance of slow positron beam, and the experiment on the utilization of slow positron beam, and the control system for positron conveyance path are reported. (K.I.)

  13. Novel P2 promoter-derived HNF4α isoforms with different N-terminus generated by alternate exon insertion

    International Nuclear Information System (INIS)

    Huang, Jianmin; Levitsky, Lynne L.; Rhoads, David B.

    2009-01-01

    Hepatocyte nuclear factor 4α (HNF4α) is a critical transcription factor for pancreas and liver development and functions in islet β cells to maintain glucose homeostasis. Mutations in the human HNF4A gene lead to maturity onset diabetes of the young (MODY1) and polymorphisms are associated with increased risk for type 2 diabetes mellitus (T2DM). Expression of six HNF4α variants, three each from two developmentally regulated promoters, has been firmly established. We have now detected a new set of HNF4α variants designated HNF4α10-12 expressed from distal promoter P2. These variants, generated by inclusion of previously undetected exon 1E (human = 222 nt, rodent = 136 nt) following exon 1D have an altered N-terminus but identical remaining reading frame. HNF4α10-α12 are expressed in pancreatic islets (and liver) and exhibit transactivation potentials similar to the corresponding α7-α9 isoforms. DNA-binding analyses implied much higher protein levels of HNF4α10-α12 in liver than expected from the RT-PCR data. Our results provide evidence for a more complex expression pattern of HNF4α than previously appreciated. We recommend inclusion of exon 1E and nearby DNA sequences in screening for HNF4α mutations and polymorphisms in genetic analyses of MODY1 and T2DM.

  14. Alternative splicing at exon 2 results in the loss of the catalytic activity of mouse DNA polymerase iota in vitro.

    Science.gov (United States)

    Kazachenko, Konstantin Y; Miropolskaya, Nataliya A; Gening, Leonid V; Tarantul, Vyacheslav Z; Makarova, Alena V

    2017-02-01

    Y-family DNA polymerase iota (Pol ι) possesses both DNA polymerase and dRP lyase activities and was suggested to be involved in DNA translesion synthesis and base excision repair in mammals. The 129 strain of mice and its derivatives have a natural nonsense codon mutation in the second exon of the Pol ι gene resulting in truncation of the Pol ι protein. These mice were widely used as a Pol ι-null model for in vivo studies of the Pol ι function. However whether 129-derived strains of mice are fully deficient in the Pol ι functions was a subject of discussion since Pol ι mRNA undergoes alternative splicing at exon 2. Here we report purification of mouse Pol ι lacking the region encoded by exon 2, which includes several conserved residues involved in catalysis. We show that the deletion abrogates both the DNA polymerase and dRP lyase activities of Pol ι in the presence of either Mg 2+ or Mn 2+ ions. Thus, 129-derived strains of mice express catalytically inactive alternatively spliced Pol ι variant, whose cellular functions, if any exist, remain to be established. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Novel P2 promoter-derived HNF4{alpha} isoforms with different N-terminus generated by alternate exon insertion

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Jianmin, E-mail: jmhuang@partners.org [Pediatric Endocrine Unit, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, 02114-2696 (United States); Levitsky, Lynne L. [Pediatric Endocrine Unit, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, 02114-2696 (United States); Rhoads, David B., E-mail: rhoads@helix.mgh.harvard.edu [Pediatric Endocrine Unit, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, 02114-2696 (United States)

    2009-04-15

    Hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) is a critical transcription factor for pancreas and liver development and functions in islet {beta} cells to maintain glucose homeostasis. Mutations in the human HNF4A gene lead to maturity onset diabetes of the young (MODY1) and polymorphisms are associated with increased risk for type 2 diabetes mellitus (T2DM). Expression of six HNF4{alpha} variants, three each from two developmentally regulated promoters, has been firmly established. We have now detected a new set of HNF4{alpha} variants designated HNF4{alpha}10-12 expressed from distal promoter P2. These variants, generated by inclusion of previously undetected exon 1E (human = 222 nt, rodent = 136 nt) following exon 1D have an altered N-terminus but identical remaining reading frame. HNF4{alpha}10-{alpha}12 are expressed in pancreatic islets (and liver) and exhibit transactivation potentials similar to the corresponding {alpha}7-{alpha}9 isoforms. DNA-binding analyses implied much higher protein levels of HNF4{alpha}10-{alpha}12 in liver than expected from the RT-PCR data. Our results provide evidence for a more complex expression pattern of HNF4{alpha} than previously appreciated. We recommend inclusion of exon 1E and nearby DNA sequences in screening for HNF4{alpha} mutations and polymorphisms in genetic analyses of MODY1 and T2DM.

  16. Long-term Exon Skipping Studies With 2′-O-Methyl Phosphorothioate Antisense Oligonucleotides in Dystrophic Mouse Models

    Directory of Open Access Journals (Sweden)

    Christa L Tanganyika-de Winter

    2012-01-01

    Full Text Available Antisense-mediated exon skipping for Duchenne muscular dystrophy (DMD is currently tested in phase 3 clinical trials. The aim of this approach is to modulate splicing by skipping a specific exon to reframe disrupted dystrophin transcripts, allowing the synthesis of a partly functional dystrophin protein. Studies in animal models allow detailed analysis of the pharmacokinetic and pharmacodynamic profile of antisense oligonucleotides (AONs. Here, we tested the safety and efficacy of subcutaneously administered 2′-O-methyl phosphorothioate AON at 200 mg/kg/week for up to 6 months in mouse models with varying levels of disease severity: mdx mice (mild phenotype and mdx mice with one utrophin allele (mdx/utrn+/−; more severe phenotype. Long-term treatment was well tolerated and exon skipping and dystrophin restoration confirmed for all animals. Notably, in the more severely affected mdx/utrn+/− mice the therapeutic effect was larger: creatine kinase (CK levels were more decreased and rotarod running time was more increased. This suggests that the mdx/utrn+/− model may be a more suitable model to test potential therapies than the regular mdx mouse. Our results also indicate that long-term subcutaneous treatment in dystrophic mouse models with these AONs is safe and beneficial.

  17. Low incidence of germline mutation in BRCA1 Exon 11 among early-onset and familial Filipino breast cancer patients

    International Nuclear Information System (INIS)

    Nato, Alejandro Q. Jr; Deocaris, Custer C.; Sajise, Sheila C.

    2002-01-01

    Breast cancer susceptibility gene, type 1 (BRCA1) has been thought to be responsible for about 45% of families with multiple breast carcinoma cases and for more than 80% of hereditary breast and ovarian cancer (HBOC) families. About 61-75% of the reported distinct alterations that result in truncated protein products have been found in exon 11 which comprises 61% (3427bp) of the coding sequence of BRCA1(5592bp). Protein truncation test (PTT) has become a popular method as an efficient means of screening mutations in a coding sequence that lead to a truncated protein product. In this study, 34 early-onset and/or familial breast cancer (FBC) patients were investigated. Twenty-six patients are early-onset B(o)C cases (diagnosed≤40 years old), 14 of which have familiality of the disease. Among the 8 patients that have been diagnosed above 40 years old, 7 have familial clustering. Through radioactive PTT analysis of the 34 BC cases in a 5-20% denaturing gradient polyacrylamide gel, we found only one mutation in exon 11 having a 29.7 kDa truncated protein product. Our results corroborate the findings of a recently reported study of unselected incident breast cancer cases in the Philippines where the prevalence of BRCA1 mutation is also low. This would, however, be the second documented mutation in BRCA1 exon 11 in a Filipino BC patient since 1998. (author)

  18. Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency.

    Science.gov (United States)

    da Silva, Karina Ribeiro; Fraga, Tatiana Rodrigues; Lucatelli, Juliana Faggion; Grumach, Anete Sevciovic; Isaac, Lourdes

    2016-05-01

    Primary deficiency of complement C3 is rare and usually associated with increased susceptibility to bacterial infections. In this work, we investigated the molecular basis of complete C3 deficiency in a Brazilian 9-year old female patient with a family history of consanguinity. Hemolytic assays revealed complete lack of complement-mediated hemolytic activity in the patient's serum. While levels of the complement regulatory proteins Factor I, Factor H and Factor B were normal in the patient's and family members' sera, complement C3 levels were undetectable in the patient's serum and were reduced by at least 50% in the sera of the patient's parents and brother. Additionally, no C3 could be observed in the patient's plasma and cell culture supernatants by Western blot. We also observed that patient's skin fibroblasts stimulated with Escherichia coli LPS were unable to secrete C3, which might be accumulated within the cells before being intracellularly degraded. Sequencing analysis of the patient's C3 cDNA revealed a genetic mutation responsible for the complete skipping of exon 27, resulting in the loss of 99 nucleotides (3450-3549) located in the TED domain. Sequencing of the intronic region between the exons 26 and 27 of the C3 gene (nucleotides 6690313-6690961) showed a nucleotide exchange (T→C) at position 6690626 located in a splicing donor site, resulting in the complete skipping of exon 27 in the C3 mRNA. Copyright © 2016. Published by Elsevier GmbH.

  19. Lariat sequencing in a unicellular yeast identifies regulated alternative splicing of exons that are evolutionarily conserved with humans.

    Science.gov (United States)

    Awan, Ali R; Manfredo, Amanda; Pleiss, Jeffrey A

    2013-07-30

    Alternative splicing is a potent regulator of gene expression that vastly increases proteomic diversity in multicellular eukaryotes and is associated with organismal complexity. Although alternative splicing is widespread in vertebrates, little is known about the evolutionary origins of this process, in part because of the absence of phylogenetically conserved events that cross major eukaryotic clades. Here we describe a lariat-sequencing approach, which offers high sensitivity for detecting splicing events, and its application to the unicellular fungus, Schizosaccharomyces pombe, an organism that shares many of the hallmarks of alternative splicing in mammalian systems but for which no previous examples of exon-skipping had been demonstrated. Over 200 previously unannotated splicing events were identified, including examples of regulated alternative splicing. Remarkably, an evolutionary analysis of four of the exons identified here as subject to skipping in S. pombe reveals high sequence conservation and perfect length conservation with their homologs in scores of plants, animals, and fungi. Moreover, alternative splicing of two of these exons have been documented in multiple vertebrate organisms, making these the first demonstrations of identical alternative-splicing patterns in species that are separated by over 1 billion y of evolution.

  20. Identification of MSH2 inversion of exons 1-7 in clinical evaluation of families with suspected Lynch syndrome.

    Science.gov (United States)

    Mork, Maureen E; Rodriguez, Andrea; Taggart, Melissa W; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; Bannon, Sarah A; You, Y Nancy; Vilar, Eduardo

    2017-07-01

    Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining.

  1. An ancient duplication of exon 5 in the Snap25 gene is required for complex neuronal development/function.

    Directory of Open Access Journals (Sweden)

    Jenny U Johansson

    2008-11-01

    Full Text Available Alternative splicing is an evolutionary innovation to create functionally diverse proteins from a limited number of genes. SNAP-25 plays a central role in neuroexocytosis by bridging synaptic vesicles to the plasma membrane during regulated exocytosis. The SNAP-25 polypeptide is encoded by a single copy gene, but in higher vertebrates a duplication of exon 5 has resulted in two mutually exclusive splice variants, SNAP-25a and SNAP-25b. To address a potential physiological difference between the two SNAP-25 proteins, we generated gene targeted SNAP-25b deficient mouse mutants by replacing the SNAP-25b specific exon with a second SNAP-25a equivalent. Elimination of SNAP-25b expression resulted in developmental defects, spontaneous seizures, and impaired short-term synaptic plasticity. In adult mutants, morphological changes in hippocampus and drastically altered neuropeptide expression were accompanied by severe impairment of spatial learning. We conclude that the ancient exon duplication in the Snap25 gene provides additional SNAP-25-function required for complex neuronal processes in higher eukaryotes.

  2. The DRD4 exon III VNTR, bupropion, and associations with prospective abstinence.

    Science.gov (United States)

    Bergen, Andrew W; Javitz, Harold S; Su, Li; He, Yungang; Conti, David V; Benowitz, Neal L; Tyndale, Rachel F; Lerman, Caryn; Swan, Gary E

    2013-07-01

    DRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive-behavioral mood management therapy. We used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies. VNTR genotypes were coded with the long allele dominant resulting in 4 analysis categories. Covariates included demographics, dependence measures, depressive symptoms, and genetic ancestry. We also performed genotype-stratified secondary analyses. We observed significant effects of time in longitudinal analyses of both abstinence outcomes, of treatment in individuals with VNTR long allele genotypes for both abstinence outcomes, and of covariates in some analyses. We observed non-significantly larger differences in active versus placebo effect sizes in individuals with VNTR long allele genotypes than in individuals without the VNTR long allele, in the directions previously reported. VNTR by treatment interaction differences between these and previous analyses may be attributable to insufficient size of the replication sample. Analyses of multiple randomized clinical trials will enable identification and validation of factors mediating treatment response.

  3. Upstream ORF affects MYCN translation depending on exon 1b alternative splicing

    International Nuclear Information System (INIS)

    Besançon, Roger; Puisieux, Alain; Valsesia-Wittmann, Sandrine; Locher, Clara; Delloye-Bourgeois, Céline; Furhman, Lydie; Tutrone, Giovani; Bertrand, Christophe; Jallas, Anne-Catherine; Garin, Elisabeth

    2009-01-01

    The MYCN gene is transcribed into two major mRNAs: one full-length (MYCN) and one exon 1b-spliced (MYCN Δ1b ) mRNA. But nothing is known about their respective ability to translate the MYCN protein. Plasmids were prepared to enable translation from the upstream (uORF) and major ORF of the two MYCN transcripts. Translation was studied after transfection in neuroblastoma SH-EP cell line. Impact of the upstream AUG on translation was evaluated after directed mutagenesis. Functional study with the two MYCN mRNAs was conducted by a cell viability assay. Existence of a new protein encoded by the MYCN Δ1b uORF was explored by designing a rabbit polyclonal antibody against a specific epitope of this protein. Both are translated, but higher levels of protein were seen with MYCN Δ1b mRNA. An upstream ORF was shown to have positive cis-regulatory activity on translation from MYCN but not from MYCN Δ1b mRNA. In transfected SH-EP neuroblastoma cells, high MYCN dosage obtained with MYCN Δ1b mRNA translation induces an antiapoptotic effect after serum deprivation that was not observed with low MYCN expression obtained with MYCN mRNA. Here, we showed that MYCNOT: MYCN Overlap Transcript, a new protein of unknown function is translated from the upstream AUG of MYCN Δ1b mRNA. Existence of upstream ORF in MYCN transcripts leads to a new level of MYCN regulation. The resulting MYCN dosage has a weak but significant anti-apoptotic activity after intrinsic apoptosis induction

  4. Binding, internalization and fate of Huntingtin Exon1 fibrillar assemblies in mitotic and nonmitotic neuroblastoma cells.

    Science.gov (United States)

    Ruiz-Arlandis, G; Pieri, L; Bousset, L; Melki, R

    2016-02-01

    The aggregation of Huntingtin (HTT) protein and of its moiety encoded by its Exon1 (HTTExon1) into fibrillar structures inside neurons is the molecular hallmark of Huntington's disease. Prion-like transmission of these aggregates between cells has been demonstrated. The cell-to-cell transmission mechanisms of these protein aggregates and the susceptibility of different kinds of neuronal cells to these toxic assemblies still need assessment. Here, we documented the binding to and internalization by differentiated and undifferentiated neuroblastoma cells of exogenous fibrillar HTTExon1 and polyglutamine (polyQ) polypeptides containing the same number of glutamines. We assessed the contribution of endocytosis to fibrillar HTTExon1 uptake, their intracellular localization and fate. We observed that undifferentiated neuroblastoma cells were more susceptible to fibrillar HTTExon1 and polyQ than their differentiated counterparts. Furthermore, we demonstrated that exogenous HTTExon1 aggregates are mainly taken up by endocytosis and directed to lysosomal compartments in both mitotic and quiescent cells. These data suggest that the rates of endocytic processes that differ in mitotic and quiescent cells strongly impact the uptake of exogenous HTTExon1 and polyQ fibrils. This may be either the consequence of distinct metabolisms or distributions of specific protein partners for amyloid-like assemblies at the surface of highly dividing versus quiescent cells. Our results highlight the importance of endocytic processes in the internalization of exogenous HTTExon1 fibrils and suggest that a proportion of those assemblies reach the cytosol where they can amplify by recruiting the endogenous protein after escaping, by yet an unknown process, from the endo-lysosomal compartments. © 2015 British Neuropathological Society.

  5. Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1.

    Directory of Open Access Journals (Sweden)

    Amber L Southwell

    2011-01-01

    Full Text Available Proteolytic processing of mutant huntingtin (mHtt, the protein that causes Huntington's disease (HD, is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD.We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1 clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V(L12.3, turnover of soluble mHDx-1 in living cells is blocked.These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications.

  6. Exon expression in lymphoblastoid cell lines from subjects with schizophrenia before and after glucose deprivation

    Directory of Open Access Journals (Sweden)

    Martin Maureen V

    2009-09-01

    Full Text Available Abstract Background The purpose of this study was to examine the effects of glucose reduction stress on lymphoblastic cell line (LCL gene expression in subjects with schizophrenia compared to non-psychotic relatives. Methods LCLs were grown under two glucose conditions to measure the effects of glucose reduction stress on exon expression in subjects with schizophrenia compared to unaffected family member controls. A second aim of this project was to identify cis-regulated transcripts associated with diagnosis. Results There were a total of 122 transcripts with significant diagnosis by probeset interaction effects and 328 transcripts with glucose deprivation by probeset interaction probeset effects after corrections for multiple comparisons. There were 8 transcripts with expression significantly affected by the interaction between diagnosis and glucose deprivation and probeset after correction for multiple comparisons. The overall validation rate by qPCR of 13 diagnosis effect genes identified through microarray was 62%, and all genes tested by qPCR showed concordant up- or down-regulation by qPCR and microarray. We assessed brain gene expression of five genes found to be altered by diagnosis and glucose deprivation in LCLs and found a significant decrease in expression of one gene, glutaminase, in the dorsolateral prefrontal cortex (DLPFC. One SNP with previously identified regulation by a 3' UTR SNP was found to influence IRF5 expression in both brain and lymphocytes. The relationship between the 3' UTR rs10954213 genotype and IRF5 expression was significant in LCLs (p = 0.0001, DLPFC (p = 0.007, and anterior cingulate cortex (p = 0.002. Conclusion Experimental manipulation of cells lines from subjects with schizophrenia may be a useful approach to explore stress related gene expression alterations in schizophrenia and to identify SNP variants associated with gene expression.

  7. Missense mutation in exon 2 of SLC36A1 responsible for champagne dilution in horses.

    Directory of Open Access Journals (Sweden)

    Deborah Cook

    2008-09-01

    Full Text Available Champagne coat color in horses is controlled by a single, autosomal-dominant gene (CH. The phenotype produced by this gene is valued by many horse breeders, but can be difficult to distinguish from the effect produced by the Cream coat color dilution gene (CR. Three sires and their families segregating for CH were tested by genome scanning with microsatellite markers. The CH gene was mapped within a 6 cM region on horse chromosome 14 (LOD = 11.74 for theta = 0.00. Four candidate genes were identified within the region, namely SPARC [Secreted protein, acidic, cysteine-rich (osteonectin], SLC36A1 (Solute Carrier 36 family A1, SLC36A2 (Solute Carrier 36 family A2, and SLC36A3 (Solute Carrier 36 family A3. SLC36A3 was not expressed in skin tissue and therefore not considered further. The other three genes were sequenced in homozygotes for CH and homozygotes for the absence of the dilution allele (ch. SLC36A1 had a nucleotide substitution in exon 2 for horses with the champagne phenotype, which resulted in a transition from a threonine amino acid to an arginine amino acid (T63R. The association of the single nucleotide polymorphism (SNP with the champagne dilution phenotype was complete, as determined by the presence of the nucleotide variant among all 85 horses with the champagne dilution phenotype and its absence among all 97 horses without the champagne phenotype. This is the first description of a phenotype associated with the SLC36A1 gene.

  8. Frequent Nuclear/Cytoplasmic Localization of β-Catenin without Exon 3 Mutations in Malignant Melanoma

    Science.gov (United States)

    Rimm, David L.; Caca, Karel; Hu, Gang; Harrison, Frank B.; Fearon, Eric R.

    1999-01-01

    β-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen synthase kinase 3β phosphorylation sites near the β-catenin amino terminus have been found in some cancers and cancer cell lines. The mutations render β-catenin resistant to regulation by a complex containing the glycogen synthase kinase 3β, adenomatous polyposis coli, and axin proteins. As a result, β-catenin accumulates in the cytosol and nucleus and activates T-cell factor/lymphoid enhancing factor transcription factors. Previously, 6 of 27 melanoma cell lines were found to have β-catenin exon 3 mutations affecting the N-terminal phosphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790–1792). To assess the role of β-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequencing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localization of β-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somatic mutation in β-catenin was found in only one case (codon 45 Ser→Pro). Our findings demonstrate that β-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of β-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it may reflect focal and transient activation of the wnt pathway within the tumor. PMID:10027390

  9. Toward standardization of slow earthquake catalog -Development of database website-

    Science.gov (United States)

    Kano, M.; Aso, N.; Annoura, S.; Arai, R.; Ito, Y.; Kamaya, N.; Maury, J.; Nakamura, M.; Nishimura, T.; Obana, K.; Sugioka, H.; Takagi, R.; Takahashi, T.; Takeo, A.; Yamashita, Y.; Matsuzawa, T.; Ide, S.; Obara, K.

    2017-12-01

    Slow earthquakes have now been widely discovered in the world based on the recent development of geodetic and seismic observations. Many researchers detect a wide frequency range of slow earthquakes including low frequency tremors, low frequency earthquakes, very low frequency earthquakes and slow slip events by using various methods. Catalogs of the detected slow earthquakes are open to us in different formats by each referring paper or through a website (e.g., Wech 2010; Idehara et al. 2014). However, we need to download catalogs from different sources, to deal with unformatted catalogs and to understand the characteristics of different catalogs, which may be somewhat complex especially for those who are not familiar with slow earthquakes. In order to standardize slow earthquake catalogs and to make such a complicated work easier, Scientific Research on Innovative Areas "Science of Slow Earthquakes" has been developing a slow earthquake catalog website. In the website, we can plot locations of various slow earthquakes via the Google Maps by compiling a variety of slow earthquake catalogs including slow slip events. This enables us to clearly visualize spatial relations among slow earthquakes at a glance and to compare the regional activities of slow earthquakes or the locations of different catalogs. In addition, we can download catalogs in the unified format and refer the information on each catalog on the single website. Such standardization will make it more convenient for users to utilize the previous achievements and to promote research on slow earthquakes, which eventually leads to collaborations with researchers in various fields and further understanding of the mechanisms, environmental conditions, and underlying physics of slow earthquakes. Furthermore, we expect that the website has a leading role in the international standardization of slow earthquake catalogs. We report the overview of the website and the progress of construction. Acknowledgment: This

  10. Slow positron applications at slow positron facility of institute of materials structure science, KEK

    Science.gov (United States)

    Hyodo, Toshio; Mochizuki, Izumi; Wada, Ken; Toge, Nobukazu; Shidara, Tetsuo

    2018-05-01

    Slow Positron Facility at High Energy Accelerator Research Organization (KEK) is a user dedicated facility with an energy-tunable (0.1 - 35 keV) slow positron beam created by a dedicated ˜ 50 MeV linac. It operates in a short pulse (width 1-12 ns, variable, 5×106 e+/s) and a long pulse (width 1.2 µs, 5×107 e+/s) modes of 50 Hz. High energy positrons from pair creation are moderated by reemission after thermalization in W foils. The reemitted positrons are then electrostatically accelerated to a desired energy up to 35 keV and magnetically transported. A pulse-stretching section (pulse stretcher) is installed in the middle of the beamline. It stretches the slow positron pulse for the experiments where too many positrons annihilating in the sample at the same time has to be avoided. Four experiment stations for TRHEPD (total-reflection high-energy positron diffraction), LEPD (low-energy positron diffraction), Ps- (positronium negative ion), and Ps-TOF (positronium time-of-flight) experiments are connected to the beamline branches, SPF-A3, SPF-A4, SPF-B1 and SPF-B2, respectively. Recent results of these stations are briefly described.

  11. Deciding about fast and slow decisions.

    Science.gov (United States)

    Croskerry, Pat; Petrie, David A; Reilly, James B; Tait, Gordon

    2014-02-01

    Two reports in this issue address the important topic of clinical decision making. Dual process theory has emerged as the dominant model for understanding the complex processes that underlie human decision making. This theory distinguishes between the reflexive, autonomous processes that characterize intuitive decision making and the deliberate reasoning of an analytical approach. In this commentary, the authors address the polarization of viewpoints that has developed around the relative merits of the two systems. Although intuitive processes are typically fast and analytical processes slow, speed alone does not distinguish them. In any event, the majority of decisions in clinical medicine are not dependent on very short response times. What does appear relevant to diagnostic ease and accuracy is the degree to which the symptoms of the disease being diagnosed are characteristic ones. There are also concerns around some methodological issues related to research design in this area of enquiry. Reductionist approaches that attempt to isolate dependent variables may create such artificial experimental conditions that both external and ecological validity are sacrificed. Clinical decision making is a complex process with many independent (and interdependent) variables that need to be separated out in a discrete fashion and then reflected on in real time to preserve the fidelity of clinical practice. With these caveats in mind, the authors believe that research in this area should promote a better understanding of clinical practice and teaching by focusing less on the deficiencies of intuitive and analytical systems and more on their adaptive strengths.

  12. Slow feature analysis: unsupervised learning of invariances.

    Science.gov (United States)

    Wiskott, Laurenz; Sejnowski, Terrence J

    2002-04-01

    Invariant features of temporally varying signals are useful for analysis and classification. Slow feature analysis (SFA) is a new method for learning invariant or slowly varying features from a vectorial input signal. It is based on a nonlinear expansion of the input signal and application of principal component analysis to this expanded signal and its time derivative. It is guaranteed to find the optimal solution within a family of functions directly and can learn to extract a large number of decorrelated features, which are ordered by their degree of invariance. SFA can be applied hierarchically to process high-dimensional input signals and extract complex features. SFA is applied first to complex cell tuning properties based on simple cell output, including disparity and motion. Then more complicated input-output functions are learned by repeated application of SFA. Finally, a hierarchical network of SFA modules is presented as a simple model of the visual system. The same unstructured network can learn translation, size, rotation, contrast, or, to a lesser degree, illumination invariance for one-dimensional objects, depending on only the training stimulus. Surprisingly, only a few training objects suffice to achieve good generalization to new objects. The generated representation is suitable for object recognition. Performance degrades if the network is trained to learn multiple invariances simultaneously.

  13. Range and stopping power for slow particles

    International Nuclear Information System (INIS)

    Bastiano, M.; Fernandez, J. E.; Molinari, V. G.

    1997-01-01

    Generally, the effects of thermal agitation and chemical bonding of the target atoms need to be taken into account to compute properly the range and stopping power of particles. These two effects, however, complicate very much the calculation of the above parameters, and for this reason are usually neglected. In fact, when the energy of the test particles (t.p.) is sufficiently high compared to the thermal or bonding energies, these two effects can be safely disregarded. When the energy of the t.p. is of the same order of the thermal agitation or the chemical bonding, on the other hand, such approximation is not realistic, and to obtain meaningful results one must take into account the velocity distribution of the field particles (f.p.). The aim of this paper is to present a simple model describing the transport of particles (e.g., electrons) in the thermal zone, considering the thermal agitation of f.p. with an arbitrary distribution. It will be shown that in the first part of the slowing down the kinetic energy of t.p. is partially transformed into temperature. In the second part, the temperature tends to reach the equilibrium temperature, while average velocity of t.p. becomes zero. (author)

  14. Mixing, ergodicity and slow relaxation phenomena

    Science.gov (United States)

    Costa, I. V. L.; Vainstein, M. H.; Lapas, L. C.; Batista, A. A.; Oliveira, F. A.

    2006-11-01

    Investigations on diffusion in systems with memory [I.V.L. Costa, R. Morgado, M.V.B.T. Lima, F.A. Oliveira, Europhys. Lett. 63 (2003) 173] have established a hierarchical connection between mixing, ergodicity, and the fluctuation-dissipation theorem (FDT). This hierarchy means that ergodicity is a necessary condition for the validity of the FDT, and mixing is a necessary condition for ergodicity. In this work, we compare those results with recent investigations using the Lee recurrence relations method [M.H. Lee, Phys. Rev. B 26 (1982) 2547; M.H. Lee, Phys. Rev. Lett. 87 (2001) 250601; M.H. Lee, J. Phys. A: Math. Gen. 39 (2006) 4651]. Lee shows that ergodicity is violated in the dynamics of the electron gas [M.H. Lee, J. Phys. A: Math. Gen. 39 (2006) 4651]. This reinforces both works and implies that the results of [I.V.L. Costa, R. Morgado, M.V.B.T. Lima, F.A. Oliveira, Europhys. Lett. 63 (2003) 173] are more general than the framework in which they were obtained. Some applications to slow relaxation phenomena are discussed.

  15. Commodity chemical growth to slow in 1993

    International Nuclear Information System (INIS)

    Plishner, E.S.

    1992-01-01

    In their latest chemical outlook, DRI/McGraw-Hill economists characterize 1992 as a peak year for U.S. commodity chemical demand growth, at 4.2%, tapering off to a compound 2.2% between 1993 and 1995. Just as operating rates begin to reach higher levels in 1995, however, DRI forecasts slowing GNP growth. DRI's Ramunas J. Svarcas expects a decline in exports. Those plastics promising the rosiest consumption outlook include melamine-formaldehyde resin, up 9.9% in 1992, from 155 million lbs in 1991, and projected to grow 8.6%/year through 1995; styrene acrylonitrile resin, up 23% this year, from 58 million lbs last year, and growing 8.2%/year through 1995; and unsaturated polyester, up 11.7% this year, from 1.07 billion lbs in 1991, and increasing at 6.5%/year. Methanol is a bright spot, with consumption growing 4.7%, from 11.2 billion lbs in 1991 and 12%/year thereafter. Ortho-xylene managed an impressive 21% rebound from a depressed 1991 level of 783 million lbs, and is expected to continue its recovery at 7.7%/year

  16. Molten fuel behaviour during slow overpower transients

    International Nuclear Information System (INIS)

    Guerin, Y.; Boidron, M.

    1985-01-01

    In large commercial reactors as Super-Phenix, if we take into account all the uncertainties on the pins and on the core, it is no longer possible to guarantee the absence of fuel melting during incidental events such as slow overpower transients. We have then to explain what happens in the pins when fuel melting occurs and to demonstrate that a limited amount of molten fuel generates no risk of clad failure. For that purpose, we may use the results of a great number of experiments (about 40) that have been performed at C.E.A., most of them in thermal reactor, but some experiments have also been performed in Rapsodie, especially during the last run of this reactor. In a great part of these experiments, fuel melting occurred at beginning of life, but we have also some results at different burnups up to 5 at %. It is not the aim of this paper to describe all these experiments and the results of their post irradiation examination, but to summarize the main conclusions that have been set out of them and that have enabled us to determine the main characteristics of fuel element behaviour when fuel melting occurs

  17. Origin of Pseudotachylites during slow creep experiments

    Science.gov (United States)

    Peč, M.; Stünitz, H.; Heilbronner, R.; Drury, M.; De Capitani, C.

    2012-04-01

    Pseudotachylites are interpreted as solidified friction induced melts which form exclusively during seismic or impact events and are thus accepted as 'unequivocal evidence' of paleo-earthquakes on exhumed faults. However, we found in experiments that pseudotachylites can form under clearly aseismic conditions at confining pressures and temperatures typical of mid crustal levels (Pc = 500 MPa, T = 300° C). The starting material consists of granitoid powder crushed to a size of ≤ 200 μm in diameter. This material (0.1 g), with 0.2 wt% water added, is placed between alumina forcing blocks pre-cut at 45° , weld-sealed in platinum jackets with an inner nickel foil insert and deformed in a solid medium deformation apparatus (modified Griggs rig). We applied displacement rates of (10-8 ms-1 precursor material and is in general more ferromagnesian and basic compared to the bulk rock indicating preferred melting of biotite. The calculated temperature increase due to shear heating is at the most 5°C. High stresses cause pervasive comminution: the smallest crystalline fragments within the bubbly melt have a grain diameter of 10 nm. Nanomaterials exhibit a 'melting point depression' (dependence of melting point on grain size) which allows melting well below bulk melting temperatures. Thus, it seems that melting is a continuation of the comminution once the rock has reached small enough grain size. We therefore suggest that pseudotachylites may also form as 'mechanical melts' at slow displacement rates without the necessity of reaching high temperatures.

  18. A new slow positron beam facility using a compact cyclotron

    International Nuclear Information System (INIS)

    Hirose, Masafumi

    1998-01-01

    In 1993, Sumitomo Heavy Industries became the first in the world to successfully produce a slow positron beam using a compact cyclotron. Slow positron beam production using an accelerator had mainly consisted of using an electron linear accelerator (LINAC). However, the newly developed system that uses a compact cyclotron enabled cost reduction, downsizing of equipment, production of a DC slow positron beam, a polarized slow positron beam, and other benefits. After that, a genuine slow positron beam facility was developed with the construction of compact cyclotron No.2, and beam production in the new facility has already been started. The features of this new slow positron beam facility are explained below. 1) It is the world's first compact slow positron beam facility using a compact cyclotron. 2) It is the only genuine slow positron beam facility in the world which incorporates the production and use of a slow positron beam in the design stage of the cyclotron. To use a slow positron beam for non-destructive detection of lattice defects in semiconductor material, it is necessary to convert the beam into ultra-short pulses of several hundreds of pico-seconds. Sumitomo Heavy Industries has devised a new short-pulsing method (i.e. an induction bunching method) that enables the conversion of a slow positron beam into short pulses with an optimum pulsing electric field change, and succeeded in converting a slow positron beam into short pulses using this method for the first time in the world. Non-destructive detection of lattice defects in semiconductor material using this equipment has already been started, and some information about the depth distribution, size, density, etc. of lattice defects has already been obtained. (J.P.N.)

  19. Fast wave current drive above the slow wave density limit

    International Nuclear Information System (INIS)

    McWilliams, R.; Sheehan, D.P.; Wolf, N.S.; Edrich, D.

    1989-01-01

    Fast wave and slow wave current drive near the mean gyrofrequency were compared in the Irvine Torus using distinct phased array antennae of similar principal wavelengths, frequencies, and input powers. The slow wave current drive density limit was measured for 50ω ci ≤ω≤500ω ci and found to agree with trends in tokamaks. Fast wave current drive was observed at densities up to the operating limit of the torus, demonstrably above the slow wave density limit

  20. PRINCIPLES OF SLOW TRAVEL APPLIED TO TOURIST LEISURE CONTEMPORARY

    OpenAIRE

    Bauer, Rafael Chequer; Netto, Alexandre Panosso

    2014-01-01

    The article shows the concept of Slow Travel, a travel’s modality based in a new perspective of touristic use considering a slowdown style. In this way, the paper analyses the context of growing and development about Slow Travel, including its ideological matrix based in industrial revolution’s contestation, specially about the acceleration noted at contemporary society and its application inside the leisure and travel universes. At least, shows the main characteristics of Slow Travel, and it...

  1. Occipital horn syndrome and classical Menkes syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon

    DEFF Research Database (Denmark)

    Yasmeen, Saiqa; Lund, Katrine; De Paepe, Anne

    2014-01-01

    Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9% of the patients exhibit a milder form of Menkes disease. The mildest form is called occipital horn syndrome (OHS). Mutations...... patients: two patients with OHS and one patient with classical Menkes disease. The pseudo-exons were inserted between exons 10 and 11, between exons 16 and 17 and between exons 14 and 15 in the three patients, as a result of deep intronic mutations. This is the first time the activation of pseudo...... mechanism, which has hitherto been overlooked.European Journal of Human Genetics advance online publication, 4 September 2013; doi:10.1038/ejhg.2013.191....

  2. Threshold Characteristics of Slow-Light Photonic Crystal Lasers

    DEFF Research Database (Denmark)

    Xue, Weiqi; Yu, Yi; Ottaviano, Luisa

    2016-01-01

    The threshold properties of photonic crystal quantum dot lasers operating in the slow-light regime are investigated experimentally and theoretically. Measurements show that, in contrast to conventional lasers, the threshold gain attains a minimum value for a specific cavity length. The experimental...... results are explained by an analytical theory for the laser threshold that takes into account the effects of slow light and random disorder due to unavoidable fabrication imperfections. Longer lasers are found to operate deeper into the slow-light region, leading to a trade-off between slow-light induced...

  3. Application of Planar Broadband Slow-Wave Systems

    Directory of Open Access Journals (Sweden)

    Edvardas Metlevskis

    2012-04-01

    Full Text Available Different types of planar broadband slow-wave systems are used for designing microwave devices. The papers published by Lithuanian scientists analyze and investigate the models of helical and meander slow-wave systems. The article carefully examines the applications of meander slow-wave systems and presents the areas where similar systems, e.g. mobile devices, RFID, wireless technologies are used and reviewed nowadays. The paper also focuses on the examples of the papers discussing antennas, filters and couplers that contain designed and fabricated meander slow-wave systems.Article in Lithuanian

  4. Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.

    Science.gov (United States)

    Antonescu, Cristina R; Sommer, Gunhild; Sarran, Lisa; Tschernyavsky, Sylvia J; Riedel, Elyn; Woodruff, James M; Robson, Mark; Maki, Robert; Brennan, Murray F; Ladanyi, Marc; DeMatteo, Ronald P; Besmer, Peter

    2003-08-15

    Activating mutations of the KIT juxtamembrane region are the most common genetic events in gastrointestinal stromal tumors (GISTs) and have been noted as independent prognostic factors. The impact of KIT mutation in other regions, such as the extracellular or kinase domains, is not well-defined and fewer than 30 cases have been published to date. One hundred twenty GISTs, confirmed by KIT immunoreactivity, were evaluated for the presence of KIT exon 9, 11, 13, and 17 mutations. The relation between the presence/type of KIT mutation and clinicopathological factors was analyzed using Fisher's exact test and log-rank test. Forty-four % of the tumors were located in the stomach, 47% in the small bowel, 6% in the rectum, and 3% in the retroperitoneum. Overall, KIT mutations were detected in 78% of patients as follows: 67% in exon 11, 11% in exon 9, and none in exon 13 or 17. The types of KIT exon 11 mutations were heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11. Seven % of cases showed internal tandem duplications (ITD) at the 3' end of exon 11, in a region that we designate as a second hot spot for KIT mutations. Interestingly, these cases were associated with: female predominance, stomach location, occurrence in older patients, and favorable outcome. There were significant associations between exon 9 mutations and large tumor size (P < 0.001) and extragastric location (P = 0.02). Ten of these 13 patients with more than 1-year follow-up have developed recurrent disease. Most KIT-expressing GISTs show KIT mutations that are preferentially located within the classic hot spot of exon 11. In addition, we found an association between a second hot spot at the 3'end of exon 11, characterized by ITDs, and a subgroup of clinically indolent gastric GISTs in older females. KIT exon 9 mutations seem to define a distinct subset of GISTs, located predominantly in the small bowel and associated with an unfavorable clinical course.

  5. Anorexia nervosa: slow regain of bone mass.

    Science.gov (United States)

    Valla, A; Groenning, I L; Syversen, U; Hoeiseth, A

    2000-01-01

    In a retrospective study of women aged 18-30 years, aimed at assessing factors associated with peak bone mass (PBM), 13 of 239 study cases reported having had anorexia nervosa. The mean total femoral and lumbar bone mineral density (BMD) values were not significantly lower in women who had had anorexia than in the pooled group (mean Z-scores of -0.60 and -0.48). Cases with less than 6 years since the anorexia had on average a present weight 5.7 kg less than their premorbid weights, while cases with more than 6 years since the eating disorder had an average weight 22.5 kg above their pre-morbid weights. The cases who had not regained their weight had BMD values significantly lower than the pooled material (mean Z-scores -1.15 and -0.9 in the lumbar spine and total femur respectively). Those who had regained their weight had BMD values as predicted from their present anthropometric data, while those who had not regained their weight had BMD values that were substantially below that predicted from their present weight. Anorexia nervosa seems to be associated with a low BMD which is even lower than that which can be predicted from the weight loss alone. This suggests that weight loss and other factors, such as menstrual dysfunction and estrogen deficiency, are independent and thus additive causes of bone loss in anorexia nervosa. Recovery of BMD seems slow, but the BMD may become as predicted from the anthropometric data after restoration of body weight and menses. The potential for recovery of BMD seems intact for several years after menarche.

  6. [Exon-dependent Subgroup-analysis of the Non-interventional REASON-Study: PFS and OS in EGFR-mutated NSCLC Patients Treated with Gefitinib or Chemotherapy].

    Science.gov (United States)

    Schuette, W; Dietel, M; Thomas, M; Eberhardt, W; Griesinger, F; Zirrgiebel, U; Radke, S; Schirmacher, P

    2016-08-01

    To analyze the influence of the localization of mutations in the epidermal growth factor receptor (EGFR) gene on progression-free (PFS) and overall survival (OS) in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with gefitinib (gef) or chemotherapy (CT) under real world conditions within the REASON study. Subgroups of pts with mutations in exon 19 (n = 141), 18/20 (n = 43), and 21 (n = 104) were analyzed for PFS and OS according to gef or CT treatment and compared using the log-rank test. Pts with mutations in exon 19 and 18/20 treated with gef as first line therapy showed increased PFS and OS compared to CT. This increase was statistically significant in pts with exon 19 mutation (11.3 vs. 6.5 months), but was not found in pts with exon 21 mutation (9.1 vs. 9.3 months). Also, OS was significantly increased in patients with mutation in exon 19 treated with gef ever over all treatment lines compared to CT (21.8 vs. 10.6 months), whereas this was not found in pts with mutation in exon 21 (14.1 vs. 13.9 months). Localization and nature of EGFR mutations influences gefitinib treatment outcomes under routine conditions and should therefore be analyzed in detail. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Long-Term Efficacy of Systemic Multiexon Skipping Targeting Dystrophin Exons 45–55 With a Cocktail of Vivo-Morpholinos in Mdx52 Mice

    Directory of Open Access Journals (Sweden)

    Yusuke Echigoya

    2015-01-01

    Full Text Available Antisense-mediated exon skipping, which can restore the reading frame, is a most promising therapeutic approach for Duchenne muscular dystrophy. Remaining challenges include the limited applicability to patients and unclear function of truncated dystrophin proteins. Multiexon skipping targeting exons 45–55 at the mutation hotspot of the dystrophin gene could overcome both of these challenges. Previously, we described the feasibility of exons 45–55 skipping with a cocktail of Vivo-Morpholinos in vivo; however, the long-term efficacy and safety of Vivo-Morpholinos remains to be determined. In this study, we examined the efficacy and toxicity of exons 45–55 skipping by intravenous injections of 6 mg/kg 10-Vivo-Morpholino cocktail (0.6 mg/kg each vPMO every 2 weeks for 18 weeks to dystrophic exon-52 knockout (mdx52 mice. Systemic skipping of the entire exons 45–55 region was induced, and the Western blot analysis exhibited the restoration of 5–27% of normal levels of dystrophin protein in skeletal muscles, accompanied by improvements in histopathology and muscle strength. No obvious immune response and renal and hepatic toxicity were detected at the end-point of the treatment. We demonstrate our new regimen with the 10-Vivo-Morpholino cocktail is effective and safe for long-term repeated systemic administration in the dystrophic mouse model.

  8. Single base mutation in the proα2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in-frame proα2(I) chain

    International Nuclear Information System (INIS)

    Tromp, G.; Prockop, D.J.

    1988-01-01

    Previous observations demonstrated that a lethal variant of osteogenesis imperfecta had two altered alleles for proα2(I) chains of type I procollagen. One mutation produced a nonfunctioning allele in that there was synthesis of mRNA but no detectable synthesis of proα2(I) chains from the allele. The mutation in the other allele caused synthesis of shortened proα2(I) chains that lacked most or all of the 18 amino acids encoded by exon 28. Subclones of the proα2(I) gene were prepared from the proband's DNA and the DNA sequence was determined for a 582-base-pair (bp) region that extended from the last 30 bp of intervening sequence 26 to the first 26 bp of intervening sequence 29. Data from six independent subclones demonstrated that all had the same sequence as a previously isolated normal clone for the proα2(I) gene except that four subclones had a single base mutation at the 3' end of intervening sequence 27. The mutation was a substitution of guanine for adenine that changed the universal consensus sequence for the 3' splicing site of RNA from -AG- to -GG-. S1 nuclease experiments demonstrated that about half the proα2(I) mRNA in the proband's fibroblasts was abnormally spliced and that the major species of abnormal proα2(I) mRNA was completely spliced from the last codon of exon 27 to the first codon of exon 29. The mutation is apparently unique among RNA splicing mutations of mammalian systems in producing a shortened polypeptide chain that is in-frame in terms of coding sequences, that is used in the subunit assembly of a protein, and that contributes to a lethal phenotype

  9. Experimental determination of the slow-neutron wavelength distribution

    DEFF Research Database (Denmark)

    Lebech, Bente; Mikke, K.; Sledziewska-Blocka, D.

    1970-01-01

    Different experiments for determining the slow-neutron wavelength distribution in the region 227-3 meV have been carried out, and the results compared. It is concluded that the slow-neutron wave-length distribution can be determined accurately by elastic scattering on a pure incoherent or a pure...

  10. The Localizing Value Of Focal Delta Slowing In Temporal Lobe ...

    African Journals Online (AJOL)

    Slow wave EEG had a higher marginal probability than neuropsychological assessment of predicting the focus, and was equally effective as other investigative methods. Conclusion These results suggest that focal temporal delta slowing is useful in the localization of epileptogenic foci. There was no discordance with the ...

  11. On the reasons for bombarding uranium with slow neutrons

    International Nuclear Information System (INIS)

    Xu Diyu

    1997-01-01

    Form the concepts of slow neutrons, the binding energy and the excitation energy of complex nuclei, and the activation energy in nuclear fission, the four reasons for bombarding uranium with slow neutrons are summed up. Not only the reasons for uranium fission are brought in light, but also the micromechanism is dealt with

  12. Slow Light at High Frequencies in an Amplifying Semiconductor Waveguide

    DEFF Research Database (Denmark)

    Öhman, Filip; Yvind, Kresten; Mørk, Jesper

    2006-01-01

    We demonstrate slow-down of a modulated light signal in a semiconductor waveguide. Concatenated amplifying and absorbing sections simultaneously achieve both amplification and a controllable time delay at 15 GHz.......We demonstrate slow-down of a modulated light signal in a semiconductor waveguide. Concatenated amplifying and absorbing sections simultaneously achieve both amplification and a controllable time delay at 15 GHz....

  13. Spacetime Dynamics and Slow Neutrino Background

    Science.gov (United States)

    Zhang, Tianxi

    2018-06-01

    Space is a form of existence of matter, while time is a measure of change of the matter in the space. Issac Newton suggested that the space and time are absolute, not affected by matter and its motion. His first law of motion or the law of inertia says that, without net force acts on it, an object in motion remains the motion in a straight line at a constant speed. Ernest Mach proposed that the inertia of a body results from the gravitational interaction on the body by the rest of the entire universe. As mass is a measure of inertia, Mach’s principle can be simply stated as mass here is affected by matter there. On the basis of Mach’s principle, Albert Einstein considered the space and time to be relative and developed two theories of relativities. One called special relativity describes the effect of motion on spacetime and the other called general relativity describes the effect of matter on spacetime. Recently, the author has further considered reactions of the influenced spacetime on the moving objects, including photons. A moving object including a photon, because of its continuously keeping on displacement, disturbs the rest of the entire universe or distorts/curves the spacetime. The distorted or curved spacetime then generates an effective gravitational force to act back on the moving object or photon, so that reduces the object inertia or photon frequency. Considering the disturbance of spacetime by a photon is extremely weak, the author has modelled the effective gravitational force to be Newtonian and derived a new redshift-distance relation that not only perfectly explained the redshift-distance measurement of distant type Ia supernovae but also inherently obtained Hubble’s law as an approximate at small redshift. In this study, we will further analyse the reaction of the influenced spacetime on moving neutrinos and demonstrate the creation of slow neutrino (or tired neutrino) background that may be gravitationally orbiting around clusters

  14. CELF family RNA-binding protein UNC-75 regulates two sets of mutually exclusive exons of the unc-32 gene in neuron-specific manners in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Hidehito Kuroyanagi

    Full Text Available An enormous number of alternative pre-mRNA splicing patterns in multicellular organisms are coordinately defined by a limited number of regulatory proteins and cis elements. Mutually exclusive alternative splicing should be strictly regulated and is a challenging model for elucidating regulation mechanisms. Here we provide models of the regulation of two sets of mutually exclusive exons, 4a-4c and 7a-7b, of the Caenorhabditis elegans uncoordinated (unc-32 gene, encoding the a subunit of V0 complex of vacuolar-type H(+-ATPases. We visualize selection patterns of exon 4 and exon 7 in vivo by utilizing a trio and a pair of symmetric fluorescence splicing reporter minigenes, respectively, to demonstrate that they are regulated in tissue-specific manners. Genetic analyses reveal that RBFOX family RNA-binding proteins ASD-1 and FOX-1 and a UGCAUG stretch in intron 7b are involved in the neuron-specific selection of exon 7a. Through further forward genetic screening, we identify UNC-75, a neuron-specific CELF family RNA-binding protein of unknown function, as an essential regulator for the exon 7a selection. Electrophoretic mobility shift assays specify a short fragment in intron 7a as the recognition site for UNC-75 and demonstrate that UNC-75 specifically binds via its three RNA recognition motifs to the element including a UUGUUGUGUUGU stretch. The UUGUUGUGUUGU stretch in the reporter minigenes is actually required for the selection of exon 7a in the nervous system. We compare the amounts of partially spliced RNAs in the wild-type and unc-75 mutant backgrounds and raise a model for the mutually exclusive selection of unc-32 exon 7 by the RBFOX family and UNC-75. The neuron-specific selection of unc-32 exon 4b is also regulated by UNC-75 and the unc-75 mutation suppresses the Unc phenotype of the exon-4b-specific allele of unc-32 mutants. Taken together, UNC-75 is the neuron-specific splicing factor and regulates both sets of the mutually exclusive

  15. On Kinetic Slow Modes, Fluid Slow Modes, and Pressure-balanced Structures in the Solar Wind

    Energy Technology Data Exchange (ETDEWEB)

    Verscharen, Daniel [Space Science Center and Department of Physics, University of New Hampshire, Durham, NH 03824 (United States); Chen, Christopher H. K. [Department of Physics, Imperial College London, London SW7 2AZ (United Kingdom); Wicks, Robert T., E-mail: daniel.verscharen@unh.edu, E-mail: christopher.chen@imperial.ac.uk, E-mail: r.wicks@ucl.ac.uk [Mullard Space Science Laboratory, University College London, London WC1E 6BT (United Kingdom)

    2017-05-10

    Observations in the solar wind suggest that the compressive component of inertial-range solar-wind turbulence is dominated by slow modes. The low collisionality of the solar wind allows for nonthermal features to survive, which suggests the requirement of a kinetic plasma description. The least-damped kinetic slow mode is associated with the ion-acoustic (IA) wave and a nonpropagating (NP) mode. We derive analytical expressions for the IA-wave dispersion relation in an anisotropic plasma in the framework of gyrokinetics and then compare them to fully kinetic numerical calculations, results from two-fluid theory, and magnetohydrodynamics (MHD). This comparison shows major discrepancies in the predicted wave phase speeds from MHD and kinetic theory at moderate to high β . MHD and kinetic theory also dictate that all plasma normal modes exhibit a unique signature in terms of their polarization. We quantify the relative amplitude of fluctuations in the three lowest particle velocity moments associated with IA and NP modes in the gyrokinetic limit and compare these predictions with MHD results and in situ observations of the solar-wind turbulence. The agreement between the observations of the wave polarization and our MHD predictions is better than the kinetic predictions, which suggests that the plasma behaves more like a fluid in the solar wind than expected.

  16. Slow Money for Soft Energy: Lessons for Energy Finance from the Slow Money Movement

    Energy Technology Data Exchange (ETDEWEB)

    Kock, Beaudry E. [Environmental Change Institute, University of Oxford, Oxford (United Kingdom)], e-mail: beaudry.kock@ouce.ox.ac.uk

    2012-12-15

    Energy infrastructure is decarbonizing, shifting from dirty coal to cleaner gas- and emissions-free renewables. This is an important and necessary change that unfortunately risks preserving many problematic technical and institutional properties of the old energy system: in particular, the large scales, high aggregation, and excessive centralization of renewable energy infrastructure and, importantly, its financing. Large-scale renewables carry environmental, social and political risks that cannot be ignored, and more importantly they may not alone accomplish the necessary decarbonization of the power sector. We need to revive a different approach to clean energy infrastructure: a 'softer' (Lovins 1978), more distributed, decentralized, local-scale strategy. To achieve this, we need a fundamentally different approach to the financing of clean energy infrastructure. I propose we learn from the 'Slow Money' approach being pioneered in sustainable agriculture (Tasch 2010), emphasizing a better connection to place, smaller scales, and a focus on quality over quantity. This 'slow money, soft energy' vision is not a repudiation of big-scale renewables, since there are some societal needs, which can only be met by big, centralized power. But we do not need the level of concentration in control and finance epitomized by the current trends in the global renewables sector: this can and must change.

  17. On Kinetic Slow Modes, Fluid Slow Modes, and Pressure-balanced Structures in the Solar Wind

    International Nuclear Information System (INIS)

    Verscharen, Daniel; Chen, Christopher H. K.; Wicks, Robert T.

    2017-01-01

    Observations in the solar wind suggest that the compressive component of inertial-range solar-wind turbulence is dominated by slow modes. The low collisionality of the solar wind allows for nonthermal features to survive, which suggests the requirement of a kinetic plasma description. The least-damped kinetic slow mode is associated with the ion-acoustic (IA) wave and a nonpropagating (NP) mode. We derive analytical expressions for the IA-wave dispersion relation in an anisotropic plasma in the framework of gyrokinetics and then compare them to fully kinetic numerical calculations, results from two-fluid theory, and magnetohydrodynamics (MHD). This comparison shows major discrepancies in the predicted wave phase speeds from MHD and kinetic theory at moderate to high β . MHD and kinetic theory also dictate that all plasma normal modes exhibit a unique signature in terms of their polarization. We quantify the relative amplitude of fluctuations in the three lowest particle velocity moments associated with IA and NP modes in the gyrokinetic limit and compare these predictions with MHD results and in situ observations of the solar-wind turbulence. The agreement between the observations of the wave polarization and our MHD predictions is better than the kinetic predictions, which suggests that the plasma behaves more like a fluid in the solar wind than expected.

  18. Enhancement of sleep slow waves: underlying mechanisms and practical consequences.

    Directory of Open Access Journals (Sweden)

    Michele eBellesi

    2014-10-01

    Full Text Available Even modest sleep restriction, especially the loss of sleep slow wave activity, is invariably associated with slower EEG activity during wake, the occurrence of local sleep in an otherwise awake brain, and impaired performance due to cognitive and memory deficits. Recent studies not only confirm the beneficial role of sleep in memory consolidation, but also point to a specific role for sleep slow waves. Thus, the implementation of methods to enhance sleep slow waves without unwanted arousals or lightening of sleep could have significant practical implications. Here we first review the evidence that it is possible to enhance sleep slow waves in humans using transcranial direct-current stimulation and transcranial magnetic stimulation. Since these methods are currently impractical and their safety is questionable, especially for chronic long-term exposure, we then discuss novel data suggesting that it is possible to enhance slow waves using sensory stimuli. We consider the physiology of the K-complex, a peripheral evoked slow wave, and show that, among different sensory modalities, acoustic stimulation is the most effective in increasing the magnitude of slow waves, likely through the activation of non-lemniscal ascending pathways to the thalamo-cortical system. In addition, we discuss how intensity and frequency of the acoustic stimuli, as well as exact timing and pattern of stimulation, affect sleep enhancement. Finally, we discuss automated algorithms that read the EEG and, in real-time, adjust the stimulation parameters in a closed-loop manner to obtain an increase in sleep slow waves and avoid undesirable arousals. In conclusion, while discussing the mechanisms that underlie the generation of sleep slow waves, we review the converging evidence showing that acoustic stimulation is safe and represents an ideal tool for slow wave sleep enhancement.

  19. Dynamics of co-transcriptional pre-mRNA folding influences the induction of dystrophin exon skipping by antisense oligonucleotides.

    Directory of Open Access Journals (Sweden)

    Keng Boon Wee

    Full Text Available Antisense oligonucleotides (AONs mediated exon skipping offers potential therapy for Duchenne muscular dystrophy. However, the identification of effective AON target sites remains unsatisfactory for lack of a precise method to predict their binding accessibility. This study demonstrates the importance of co-transcriptional pre-mRNA folding in determining the accessibility of AON target sites for AON induction of selective exon skipping in DMD. Because transcription and splicing occur in tandem, AONs must bind to their target sites before splicing factors. Furthermore, co-transcriptional pre-mRNA folding forms transient secondary structures, which redistributes accessible binding sites. In our analysis, to approximate transcription elongation, a "window of analysis" that included the entire targeted exon was shifted one nucleotide at a time along the pre-mRNA. Possible co-transcriptional secondary structures were predicted using the sequence in each step of transcriptional analysis. A nucleotide was considered "engaged" if it formed a complementary base pairing in all predicted secondary structures of a particular step. Correlation of frequency and localisation of engaged nucleotides in AON target sites accounted for the performance (efficacy and efficiency of 94% of 176 previously reported AONs. Four novel insights are inferred: (1 the lowest frequencies of engaged nucleotides are associated with the most efficient AONs; (2 engaged nucleotides at 3' or 5' ends of the target site attenuate AON performance more than at other sites; (3 the performance of longer AONs is less attenuated by engaged nucleotides at 3' or 5' ends of the target site compared to shorter AONs; (4 engaged nucleotides at 3' end of a short target site attenuates AON efficiency more than at 5' end.

  20. Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: a case report

    International Nuclear Information System (INIS)

    Escobar, Guillermo A; Robinson, William A; Nydam, Trevor L; Heiple, Drew C; Weiss, Glen J; Buckley, Linda; Gonzalez, Rene; McCarter, Martin D

    2007-01-01

    Non-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it. A thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm × 25 cm × 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, 'big' insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT. Optimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11–20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established

  1. Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19.

    Science.gov (United States)

    Park, Min Ju; Shen, Hailian; Spaeth, Jason M; Tolvanen, Jaana H; Failor, Courtney; Knudtson, Jennifer F; McLaughlin, Jessica; Halder, Sunil K; Yang, Qiwei; Bulun, Serdar E; Al-Hendy, Ayman; Schenken, Robert S; Aaltonen, Lauri A; Boyer, Thomas G

    2018-03-30

    Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of MED12 mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs. © 2018 Park et al.

  2. Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression

    Science.gov (United States)

    Lowther, Chelsea; Speevak, Marsha; Armour, Christine M.; Goh, Elaine S.; Graham, Gail E.; Li, Chumei; Zeesman, Susan; Nowaczyk, Malgorzata J.M.; Schultz, Lee-Anne; Morra, Antonella; Nicolson, Rob; Bikangaga, Peter; Samdup, Dawa; Zaazou, Mostafa; Boyd, Kerry; Jung, Jack H.; Siu, Victoria; Rajguru, Manjulata; Goobie, Sharan; Tarnopolsky, Mark A.; Prasad, Chitra; Dick, Paul T.; Hussain, Asmaa S.; Walinga, Margreet; Reijenga, Renske G.; Gazzellone, Matthew; Lionel, Anath C.; Marshall, Christian R.; Scherer, Stephen W.; Stavropoulos, Dimitri J.; McCready, Elizabeth; Bassett, Anne S.

    2016-01-01

    Purpose The purpose of the current study was to assess the penetrance of NRXN1 deletions. Methods We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant CNVs was used as a proxy to estimate the relative penetrance of NRXN1 deletions. Results We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability, significantly greater than in controls [OR=8.14 (95% CI 2.91–22.72), p< 0.0001)]. Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3′ end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5′ NRXN1 deletion [OR=7.47 (95% CI 2.36–23.61), p=0.0006]. The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (p=0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV, a two-fold greater prevalence than for exonic NRXN1 deletion cases (p=0.0035). Conclusions The results support the importance of exons near the 5′ end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes. PMID:27195815

  3. Polymorphism in exons of the myostatin gene and its relationship with body weight traits in the Bian chicken.

    Science.gov (United States)

    Zhang, Genxi; Ding, Fuxiang; Wang, Jinyu; Dai, Guojun; Xie, Kaizhou; Zhang, Lijun; Wang, Wei; Zhou, Shenghua

    2011-02-01

    In our research, single nucleotide polymorphisms (SNPs) of exon regions of the myostatin gene were detected by PCR-SSCP in the Bian chicken and three reference chicken populations (Jinghai, Youxi, and Arbor Acre). Four novel SNPs (G2283A, C7552T, C7638T, and T7661A) were detected. The findings from the least square means showed that Bian chickens with EE and DE genotypes had significantly higher body weight, at 6-18 weeks of age, than those of the DD genotype (P chicken.

  4. A synonymous polymorphic variation in ACADM exon 11 affects splicing efficiency and may affect fatty acid oxidation

    DEFF Research Database (Denmark)

    Bruun, Gitte Hoffmann; Doktor, Thomas Koed; Andresen, Brage Storstein

    2013-01-01

    beta-oxidation of medium-chain fatty acids. We examined the functional basis for this association and identified linkage between rs211718 and the intragenic synonymous polymorphic variant c.1161A>G in ACADM exon 11 (rs1061337). Employing minigene studies we show that the c.1161A allele is associated......, perhaps due to improved splicing. This study is a proof of principle that synonymous SNPs are not neutral. By changing the binding sites for splicing regulatory proteins they can have significant effects on pre-mRNA splicing and thus protein function. In addition, this study shows that for a sequence...

  5. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA

    DEFF Research Database (Denmark)

    Andersen, Christian Brix Folsted; Ballut, Lionel; Johansen, Jesper Sanderhoff

    2006-01-01

    exon junction core complex containing the DEAD-box adenosine triphosphatase (ATPase) eukaryotic initiation factor 4AIII (eIF4AIII) bound to an ATP analog, MAGOH, Y14, a fragment of MLN51, and a polyuracil mRNA mimic. eIF4AIII interacts with the phosphate-ribose backbone of six consecutive nucleotides...... and prevents part of the bound RNA from being double stranded. The MAGOH and Y14 subunits lock eIF4AIII in a prehydrolysis state, and activation of the ATPase probably requires only modest conformational changes in eIF4AIII motif I....

  6. A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping.

    Directory of Open Access Journals (Sweden)

    Gemma L Walmsley

    2010-01-01

    Full Text Available Duchenne muscular dystrophy (DMD, which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot".Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD. The dogs harbour a missense mutation in the 5' donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression.Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD.

  7. Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay.

    Science.gov (United States)

    Levit, A; Nutman, D; Osher, E; Kamhi, E; Navon, R

    2010-06-01

    We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G (p.Asn399Asp) in exon 11, has been previously characterized as a common polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, transfected with HEXA cDNA constructs bearing these mutations, was unaltered from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR products revealed three aberrant transcripts in the patient, one where exon 8 was absent, one where exon 11 was absent and a third lacking both exons 10 and 11. All three novel transcripts contain frameshifts resulting in premature termination codons (PTCs). Transfection of mini-gene constructs carrying the c.814G>A and c.1305C>T mutations proved that the two mutations result in exon skipping. mRNAs that harbor a PTC are detected and degraded by the nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal proteins. However, although NMD is functional in the patient's fibroblasts, aberrant transcripts are still present. We suggest that the level of correctly spliced transcripts as well as the efficiency in which NMD degrade the PTC-containing transcripts, apparently plays an important role in the phenotype severity of the unique patient and thus should be considered as a potential target for drug therapy.

  8. Identification of a novel first exon in the human dystrophin gene and of a new promoter located more than 500 kb upstream of the nearest known promoter

    Energy Technology Data Exchange (ETDEWEB)

    Yanagawa, H.; Nishio, H.; Takeshima, Y. [Kobe Univ. School of Medicine (Japan)] [and others

    1994-09-01

    The dystrophin gene, which is muted in patients with Duchenne and Becker muscular dystrophies, is the largest known human gene. Five alternative promoters have been characterized until now. Here we show that a novel dystrophin isoform with a different first exon can be produced through transcription initiation at a previously-unidentified alternative promoter. The case study presented is that of patient with Duchenne muscular dystrophy who had a deletion extending from 5{prime} end of the dystrophin gene to exon 2, including all promoters previously mapped in the 5{prime} part of the gene. Transcripts from lymphoblastoid cells were found to contain sequences corresponding to exon 3, indicating the presence of new promoter upstream of this exon. The nucleotide sequence of amplified cDNA corresponding to the 5{prime} end of the new transcript indicated that the 5{prime} end of exon 3 was extended by 9 codons, only the last (most 3{prime}) of which codes for methionine. The genomic nucleotide sequence upstream from the new exon, as determined using inverse polymerase chain reaction, revealed the presence of sequences similar to a TATA box, an octamer motif and an MEF-2 element. The identified promoter/exon did not map to intron 2, as might have been expected, but to a position more than 500 kb upstream of the most 5{prime} of the previously-identified promoters, thereby adding 500 kb to the dystrophin gene. The sequence of part of the new promoter region is very similar to that of certain medium reiteration frequency repetitive sequences. These findings may help us understand the molecular evolution of the dystrophin gene.

  9. Identifying factors contributing to slow growth in pigs.

    Science.gov (United States)

    He, Y; Deen, J; Shurson, G C; Wang, L; Chen, C; Keisler, D H; Li, Y Z

    2016-05-01

    Pigs that grow slower than their contemporaries can cause complications for animal welfare and profitability. This study was conducted to investigate factors that may contribute to slow growth of pigs. Pigs ( = 440) farrowed by 65 sows were monitored from birth to market. Pigs were categorized as slow, average, and fast growers based on market weight adjusted to 170 d of age (slow growers were 125 kg). Blood samples were collected from 48 focal pigs at 9 and 21 wk of age and analyzed for hormone and free AA concentrations. Data were analyzed using the Mixed and Logistic procedures of SAS. Slow-growing pigs accounted for 10% of pigs marketed, average growers accounted for 49% of pigs marketed, and fast growers accounted for 41% of pigs marketed. Compared with fast growers, slow growers were lighter at birth ( ratio = 2.17, 95% confidence interval = 1.19 to 3.96, = 0.01). Litter size and parity of the pigs' dam were not associated with slow growth. These results suggest that low concentrations of IGF-1, insulin, leptin, and AA may contribute to or be associated with slow growth in pigs.

  10. Azimuthal asymmetry of slow particles in high energy nuclear interaction

    International Nuclear Information System (INIS)

    Sarkar, Subir; Goswami, T.D.

    2002-01-01

    An asymmetry in the angular distribution of slow particles in the azimuthal plane has been observed during high energy nuclear disintegration of photo emulsion nuclei exposed to 1.8 GeV/c k - and 20 GeV/c protons. The mechanism of disintegration is not in accordance with the cascade-evaporation model, which is based on isotropic emission of slow particles. Deviation from isotropy indicates that some of the slow particles might be emitted well before the thermal equilibrium is reached in the disintegrating system. (author)

  11. Theory of neutron slowing down in nuclear reactors

    CERN Document Server

    Ferziger, Joel H; Dunworth, J V

    2013-01-01

    The Theory of Neutron Slowing Down in Nuclear Reactors focuses on one facet of nuclear reactor design: the slowing down (or moderation) of neutrons from the high energies with which they are born in fission to the energies at which they are ultimately absorbed. In conjunction with the study of neutron moderation, calculations of reactor criticality are presented. A mathematical description of the slowing-down process is given, with particular emphasis on the problems encountered in the design of thermal reactors. This volume is comprised of four chapters and begins by considering the problems

  12. Slow Food: por um alimento bom, limpo e justo

    OpenAIRE

    Porazzi, Fabiele

    2012-01-01

    REVIEW:PETRINI, Carlo. Slow Food: princípios da nova gastronomia. Trad. de Renata Lúcia Botina. São Paulo: Editora Senac, 2009. 245 p. RESEÑA:PETRINI, Carlo. Slow Food: princípios da nova gastronomia. Trad. de Renata Lúcia Botina. São Paulo: Editora Senac, 2009. 245 p. http://dx.doi.org/10.5007/1807-1384.2012v9n1p384 RESENHA:PETRINI, Carlo. Slow Food: princípios da nova gastronomia. Trad. de Renata Lúcia Botina. São Paulo: Editora Senac, 2009. 245 p.

  13. Face recognition using slow feature analysis and contourlet transform

    Science.gov (United States)

    Wang, Yuehao; Peng, Lingling; Zhe, Fuchuan

    2018-04-01

    In this paper we propose a novel face recognition approach based on slow feature analysis (SFA) in contourlet transform domain. This method firstly use contourlet transform to decompose the face image into low frequency and high frequency part, and then takes technological advantages of slow feature analysis for facial feature extraction. We named the new method combining the slow feature analysis and contourlet transform as CT-SFA. The experimental results on international standard face database demonstrate that the new face recognition method is effective and competitive.

  14. Slow light invisibility, teleportation, and other mysteries of light

    CERN Document Server

    Perkowitz, Sidney

    2011-01-01

    Slow Light is a popular treatment of today's astonishing breakthroughs in the science of light. Even though we don't understand light's quantum mysteries, we can slow it to a stop and speed it up beyond its Einsteinian speed limit, 186,000 miles/sec; use it for quantum telecommunications; teleport it; manipulate it to create invisibility; and perhaps generate hydrogen fusion power with it. All this is lucidly presented for non-scientists who wonder about teleportation, Harry Potter invisibility cloaks, and other fantastic outcomes. Slow Light shows how the real science and the fantasy inspire

  15. Slow extraction from the IHEP accelerator by internal target scattering

    International Nuclear Information System (INIS)

    Maksimov, A.V.

    1994-01-01

    The existing slow extraction system is not able to satisfy the required quality of the beam time structure in the intensity region 10 10 - 10 11 ppp. Calculations on simulation of slow extraction by internal target scattering are presented. Two regime of slow extraction are analysed: nonresonant and resonant extraction by target scattering. Resonant extraction by target scattering is able to ensure intensity of extracted beam up to 10 11 . The agreement between calculations and experimental data is good enough. The calculation of extraction possibility by thin W-target scattering are also presented. In this case the extraction efficiency is about 85%. 15 refs., 6 figs

  16. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene.

    Science.gov (United States)

    Gonçalves, Ana; Oliveira, Jorge; Coelho, Teresa; Taipa, Ricardo; Melo-Pires, Manuel; Sousa, Mário; Santos, Rosário

    2017-10-03

    A broad mutational spectrum in the dystrophin ( DMD ) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD , adding to the diversity of mutational events that give rise to D/BMD.

  17. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.

    Science.gov (United States)

    Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Rouleau, Guy A

    2008-07-01

    Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

  18. Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

    Science.gov (United States)

    Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G.; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Rouleau, Guy A.

    2008-01-01

    Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system–specific exon of the with-no-lysine(K)–1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII. PMID:18521183

  19. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene

    Science.gov (United States)

    Gonçalves, Ana; Coelho, Teresa; Melo-Pires, Manuel; Sousa, Mário

    2017-01-01

    A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD. PMID:28972564

  20. Use of intron-exonic marker in assessment of genetic diversity of two subspecies of Thymus daenensis

    Directory of Open Access Journals (Sweden)

    Ahmad Ismaili

    2013-11-01

    Full Text Available Study of genetic diversity in medicinal plant is very important for improvement and evolutionary variations. In this study, assessment of genetic diversity in two subspecies of Thymus daenensis was evaluated, using intron-exonic markers. Thirty primers produced 633 polymorphic bands (98% polymorphism. The highest polymorphic information content (PIC included ISJ5 and ISJ9 primers and the lowest PIC also included IT15-32 primer. The highest marker index (MI produced by IT10-6 primer. Results of Analysis of Molecular Variance (AMOVA showed that intra-sub specific variation was more than inter-sub specific variation. Dendrogram obtained from Cluster analysis, using NTSYS-pc software and UPGMA method based on Dice's similarity matrix, divided accessions into 4 groups. The maximum range of genetic similarity was observed between two accessions of sub-species daenensis. Two accessions of Fars and Semnan formed a separate group. Results showed that clustering based on molecular data and principal coordinate analysis had a medium alignment. Grouping based on cluster analysis also could separate two subspecies of Thymus daenensis. Results obtained from this study showed that intron-exonic markers had an effective potential in assessment of genetic relationships between the two sub-species of daenensis.

  1. Identification of Exonic Nucleotide Variants of the Gene Associated with Carcass Traits and Fatty Acid Composition in Korean Cattle

    Directory of Open Access Journals (Sweden)

    Dong-yep Oh

    2014-10-01

    Full Text Available The thyroid hormone responsive protein (THRSP gene is a functional gene that can be used to indicate the fatty acid compositions. This study investigates the relationships of exonic single nucleotide polymorphisms (SNPs in the THRSP gene and fatty acid composition of muscle fat and marbling score in the 612 Korean cattle. The relationships between fatty acid composition and eight SNPs in the THRSP gene (g.78 G>A, g.173 C>T, g.184 C>T, g.190 C>A, g.194 C>T, g.277 C>G, g.283 T>G and g.290 T>G were investigated, and according to the results, two SNPs (g.78 G>A and g.184 C>T in exon 1 were associated with fatty acid composition. The GG and CC genotypes of g.78 G>A and g.184 C>T had higher unsaturated fatty acid (UFA and monounsaturated fatty acid (MUFA content (pA and g.184 C>T had significantly relationships with UFAs and MUFAs. Two SNPs in the THRSP gene affected fatty acid composition, suggesting that GG and CC genotypes and the ht1*ht1 group (Val/Ala haplotype can be markers to genetically improve the quality and flavor of beef.

  2. An Enhancer Near ISL1 and an Ultraconserved Exon of PCBP2 areDerived from a Retroposon

    Energy Technology Data Exchange (ETDEWEB)

    Bejerano, Gill; Lowe, Craig; Ahituv, Nadav; King, Bryan; Siepel,Adam; Salama, Sofie; Rubin, Edward M.; Kent, W. James; Haussler, David

    2005-11-27

    Hundreds of highly conserved distal cis-regulatory elementshave been characterized to date in vertebrate genomes1. Many thousandsmore are predicted based on comparative genomics2,3. Yet, in starkcontrast to the genes they regulate, virtually none of these regions canbe traced using sequence similarity in invertebrates, leaving theirevolutionary origin obscure. Here we show that a class of conserved,primarily non-coding regions in tetrapods originated from a novel shortinterspersed repetitive element (SINE) retroposon family that was activein Sarcopterygii (lobe-finned fishes and terrestrial vertebrates) in theSilurian at least 410 Mya4, and, remarkably, appears to be recentlyactive in the "living fossil" Indonesian coelacanth, Latimeriamenadoensis. We show that one copy is a distal enhancer, located 500kbfrom the neuro-developmental gene ISL1. Several others represent new,possibly regulatory, alternatively spliced exons in the middle ofpre-existing Sarcopterygian genes. One of these is the>200bpultraconserved region5, 100 percent identical in mammals, and 80 percentidentical to the coelacanth SINE, that contains a 31aa alternativelyspliced exon of the mRNA processing gene PCBP26. These add to a growinglist of examples7 in which relics of transposable elements have acquireda function that serves their host, a process termed "exaptation"8, andprovide an origin for at least some of the highly-conservedvertebrate-specific genomic sequences recently discovered usingcomparative genomics.

  3. CELF1 preferentially binds to exon-intron boundary and regulates alternative splicing in HeLa cells.

    Science.gov (United States)

    Xia, Heng; Chen, Dong; Wu, Qijia; Wu, Gang; Zhou, Yanhong; Zhang, Yi; Zhang, Libin

    2017-09-01

    The current RIP-seq approach has been developed for the identification of genome-wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3'UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5' and 3' splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Analysis of ELA-DQB exon 2 polymorphism in Argentine Creole horses by PCR-RFLP and PCR-SSCP.

    Science.gov (United States)

    Villegas-Castagnasso, E E; Díaz, S; Giovambattista, G; Dulout, F N; Peral-García, P

    2003-08-01

    The second exon of equine leucocyte antigen (ELA)-DQB genes was amplified from genomic DNA of 32 Argentine Creole horses by PCR. Amplified DNA was analysed by PCR-restriction fragment length polymorphism (RFLP) and PCR-single-strand conformation polymorphism (SSCP). The PCR-RFLP analysis revealed two HaeIII patterns, four RsaI patterns, five MspI patterns and two HinfI patterns. EcoRI showed no variation in the analysed sample. Additional patterns that did not account for known exon 2 DNA sequences were observed, suggesting the existence of novel ELA-DQB alleles. PCR-SSCP analysis exhibited seven different band patterns, and the number of bands per animal ranged from four to nine. Both methods indicated that at least two DQB genes are present. The presence of more than two alleles in each animal showed that the primers employed in this work are not specific for a unique DQB locus. The improvement of this PCR-RFLP method should provide a simple and rapid technique for an accurate definition of ELA-DQB typing in horses.

  5. A case report of reversible generalized seizures in a patient with Waardenburg syndrome associated with a novel nonsense mutation in the penultimate exon of SOX10.

    Science.gov (United States)

    Suzuki, Noriomi; Mutai, Hideki; Miya, Fuyuki; Tsunoda, Tatsuhiko; Terashima, Hiroshi; Morimoto, Noriko; Matsunaga, Tatsuo

    2018-05-23

    Waardenburg syndrome type 1 (WS1) can be distinguished from Waardenburg syndrome type 2 (WS2) by the presence of dystopia canthorum. About 96% of WS1 are due to PAX3 mutations, and SOX10 mutations have been reported in 15% of WS2. This report describes a patient with WS1 who harbored a novel SOX10 nonsense mutation (c.652G > T, p.G218*) in exon 3 which is the penultimate exon. The patient had mild prodromal neurological symptoms that were followed by severe attacks of generalized seizures associated with delayed myelination of the brain. The immature myelination recovered later and the neurological symptoms could be improved. This is the first truncating mutation in exon 3 of SOX10 that is associated with neurological symptoms in Waardenburg syndrome. Previous studies reported that the neurological symptoms that associate with WS are congenital and irreversible. These findings suggest that the reversible neurological phenotype may be associated with the nonsense mutation in exon 3 of SOX10. When patients of WS show mild prodromal neurological symptoms, the clinician should be aware of the possibility that severe attacks of generalized seizures may follow, which may be associated with the truncating mutation in exon 3 of SOX10.

  6. A novel point mutation within the EDA gene causes an exon dropping in mature RNA in Holstein Friesian cattle breed affected by X-linked anhidrotic ectodermal dysplasia

    Directory of Open Access Journals (Sweden)

    Pariset Lorraine

    2011-07-01

    Full Text Available Abstract Background X-linked anhidrotic ectodermal dysplasia is a disorder characterized by abnormal development of tissues and organs of ectodermal origin caused by mutations in the EDA gene. The bovine EDA gene encodes the ectodysplasin A, a membrane protein expressed in keratinocytes, hair follicles and sweat glands, which is involved in the interactions between cell and cell and/or cell and matrix. Four mutations causing ectodermal dysplasia in cattle have been described so far. Results We identified a new single nucleotide polymorphism (SNP at the 9th base of exon 8 in the EDA gene in two calves of Holstein Friesian cattle breed affected by ectodermal dysplasia. This SNP is located in the exonic splicing enhancer (ESEs recognized by SRp40 protein. As a consequence, the spliceosome machinery is no longer able to recognize the sequence as exonic and causes exon skipping. The mutation determines the deletion of the entire exon (131 bp in the RNA processing, causing a severe alteration of the protein structure and thus the disease. Conclusion We identified a mutation, never described before, that changes the regulation of alternative splicing in the EDA gene and causes ectodermal dysplasia in cattle. The analysis of the SNP allows the identification of carriers that can transmit the disease to the offspring. This mutation can thus be exploited for a rational and efficient selection of unequivocally healthy cows for breeding.

  7. Identification of polymorphism in exons 7 and 12 of lactoferrin gene and its association with incidence of clinical mastitis in Murrah buffalo.

    Science.gov (United States)

    Dinesh, Krishanender; Verma, Archana; Das Gupta, Ishwar; Thakur, Yash Pal; Verma, Nishant; Arya, Ashwani

    2015-04-01

    Lactoferrin gene is one of the important candidate genes for mastitis resistance. The gene is located on chromosome BTA 22 and consists of 17 exons spanning over 34.5 kb of genomic DNA. The present study was undertaken with the objectives to identify allelic variants in exons 7 and 12 of lactoferrin gene and to analyze association between its genetic variants and incidence of clinical mastitis in Murrah buffalo. The amplification of exons 7 and 12 of lactoferrin gene yielded amplicons of 232- and 461-bp sizes. PCR-restriction fragment length polymorphism (RFLP) analysis of 232-bp amplicon using BccI restriction enzyme revealed three genotypes (AA, AB, and BB) with frequencies of 0.62, 0.22, and 0.16, respectively. The frequencies of two alleles, A and B, were estimated as 0.73 and 0.27. Hpy188I-RFLP for 461-bp amplicon revealed polymorphism with three genotypes, CC, CD, and DD, with respective frequencies of 0.06, 0.39, and 0.56, whereas frequencies for C and D alleles were 0.25 and 0.75. The chi-square (χ(2)) analysis revealed a significant association between incidence of clinical mastitis and genetic variants of exon 7, and animals of AA genotype of exon 7 were found to be least susceptible to mastitis. The findings indicate potential scope for incorporation of lactoferrin gene in selection and breeding of Murrah buffaloes for improved genetic resistance to mastitis.

  8. Association of Exon 10A and 10B inactivating mutation of follicle stimulating hormone receptor gene (FSHR) and Polycystic Ovarian Syndrome in Vellore cohort

    Science.gov (United States)

    Sekar, Nishu; Kulkarni, Rucha; Ozalkar, Sharvari; Prabhu, Yogamaya D.; Renu, Kaviyarasi; Ramgir, Shalaka S.; Abilash, V. G.

    2017-11-01

    Polycystic ovarian syndrome is the most common heterogenous endocrine disorder in women. Follicle stimulating hormone receptor is associated with normal development as well as maturation of follicles and triggers estrogen production in granulosa cells of the ovary. Inactivating mutation in FSHR gene correlated with reduction of ovarian function in women is due to damage to receptor function. This study aims to investigate whether inactivating mutations, in follicle stimulating hormone receptor gene is related to polycystic ovarian morphology in women with PCOS. Genomic DNA isolated from 15 subjects from Sandhya Hospital, Vellore (10 patients with PCOS and 5 healthy controls) was taken for this study. Patient data included a clinical report, hormonal levels, and ovarian morphological details. DNA isolation was followed by DNA amplification by polymerase chain reaction using Exon 10 A and Exon 10 B primers. The PCR-RFLP analysis was performed using Dde1 restriction enzyme. Here we discuss inactivating mutation found in Exon 10 of FSHR gene in patients with PCOS.The absence of inactivating mutation was observed through PCR-RFLP study on Exon 10A and Exon 10B.

  9. Slow light enhancement and limitations in periodic media

    DEFF Research Database (Denmark)

    Grgic, Jure

    in the vicinity of the band edge. The minimum attainable group velocity will depend on the amount of imperfections. Since imperfections are inherited as part of any periodic structure it is necessary to take them into account when we are interested in slow light applications. Slowly propagating light gives rise......Properties of periodic dielectric media have attracted a big interest in the last two decades due to numerous exciting physical phenomena that cannot occur in homogeneous media. Due to their strong dispersive properties, the speed of light can be significantly slowed down in periodic structures....... When light velocity is much smaller than the speed of light in a vacuum, we describe this phenomena as slow light. In this thesis, we analyze important properties of slow light enhancement and limitations in periodic structures. We analyze quantitatively and qualitatively different technologies...

  10. Critical slowing down and error analysis in lattice QCD simulations

    Energy Technology Data Exchange (ETDEWEB)

    Schaefer, Stefan [Humboldt-Universitaet, Berlin (Germany). Inst. fuer Physik; Sommer, Rainer; Virotta, Francesco [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). John von Neumann-Inst. fuer Computing NIC

    2010-09-15

    We study the critical slowing down towards the continuum limit of lattice QCD simulations with Hybrid Monte Carlo type algorithms. In particular for the squared topological charge we find it to be very severe with an effective dynamical critical exponent of about 5 in pure gauge theory. We also consider Wilson loops which we can demonstrate to decouple from the modes which slow down the topological charge. Quenched observables are studied and a comparison to simulations of full QCD is made. In order to deal with the slow modes in the simulation, we propose a method to incorporate the information from slow observables into the error analysis of physical observables and arrive at safer error estimates. (orig.)

  11. Preparation and characterization of Slow Release Formulations of ...

    African Journals Online (AJOL)

    alginate beads and characterize the resulting slow release formulations (SRFs) using scanning electron microscopy (SEM), and Fourier Transform infrared spectroscopy (FTIR). Two sets of formulations were made by extrusion into 0.25 M calcium ...

  12. Critical slowing down and error analysis in lattice QCD simulations

    International Nuclear Information System (INIS)

    Schaefer, Stefan; Sommer, Rainer; Virotta, Francesco

    2010-09-01

    We study the critical slowing down towards the continuum limit of lattice QCD simulations with Hybrid Monte Carlo type algorithms. In particular for the squared topological charge we find it to be very severe with an effective dynamical critical exponent of about 5 in pure gauge theory. We also consider Wilson loops which we can demonstrate to decouple from the modes which slow down the topological charge. Quenched observables are studied and a comparison to simulations of full QCD is made. In order to deal with the slow modes in the simulation, we propose a method to incorporate the information from slow observables into the error analysis of physical observables and arrive at safer error estimates. (orig.)

  13. Very Slow Speed Axial Motion Reluctance Motor | Agu | Nigerian ...

    African Journals Online (AJOL)

    Abstract. This paper presents the scheme for a very slow speed linear machine which uses conventional laminations and with which speeds of the same low order as that of the screw-thread motor can be obtained.

  14. Structural slow light can enhance Beer-Lambert absorption

    OpenAIRE

    Dicaire Isabelle; Chin Sanghoon; Thévenaz Luc

    2011-01-01

    We experimentally demonstrate that structural slow light can enhance Beer-Lambert absorption. A 4-fold reduction of the group velocity induced by mere cavity effects has caused an increase of molecular absorption by 130%.

  15. Techniques for slow positron beam generation and the applications

    International Nuclear Information System (INIS)

    Okada, Sohei

    1994-01-01

    Slow positron beams have been expected to be a powerful tool for observation of nature in wide range of research fields from materials science to basic physics, chemistry and biology. In this paper, at first, the beam technology is reviewed, which includes the positron generation, the transformation to slow positron beams and the beam manipulation such as beam stretching, bunching and brightness enhancement. Next, the present status of the slow positron beam applications to a variety of fields is demonstrated in terms of special characteristics of positron, that is, depth controllability, surface sensitivity, unique ionization channels and elemental anti-particle properties. Finally, prospects to produce intense slow positron beams are described. (author) 65 refs

  16. Electron heating and current drive by mode converted slow waves

    International Nuclear Information System (INIS)

    Majeski, R.; Phillips, C.K.; Wilson, J.R.

    1994-01-01

    An approach to obtaining efficient single pass mode conversion at high parallel wave number from the fast magnetosonic wave to the slow ion Bernstein wave, in a two-ion species tokamak plasma, is described. The intent is to produce localized electron heating or current drive via the mode converted slow wave. In particular, this technique can be adapted to off-axis current drive for current profile control. Modeling for the case of deuterium-tritium plasmas in TFTR is presented

  17. Slow-light enhancement of Beer-Lambert-Bouguer absorption

    DEFF Research Database (Denmark)

    Mortensen, Asger; Xiao, Sanshui

    2007-01-01

    We theoretically show how slow light in an optofluidic environment facilitates enhanced light-matter interactions, by orders of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized chemical absorbance cells for Beer-Lambert-Bouguer absorption measureme......We theoretically show how slow light in an optofluidic environment facilitates enhanced light-matter interactions, by orders of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized chemical absorbance cells for Beer-Lambert-Bouguer absorption...

  18. Exploring carrier dynamics in semiconductors for slow light

    DEFF Research Database (Denmark)

    Mørk, Jesper; Xue, Weiqi; Chen, Yaohui

    2009-01-01

    We give an overview of recent results on slow and fast light in active semiconductor waveguides. The cases of coherent population oscillations as well as electromagnetically induced transparency are covered, emphasizing the physics and fundamental limitations.......We give an overview of recent results on slow and fast light in active semiconductor waveguides. The cases of coherent population oscillations as well as electromagnetically induced transparency are covered, emphasizing the physics and fundamental limitations....

  19. Neutron slowing-down time in finite water systems

    International Nuclear Information System (INIS)

    Hirschberg, S.

    1981-11-01

    The influence of the size of a moderator system on the neutron slowing-down time has been investigated. The experimental part of the study was performed on six cubes of water with side lengths from 8 to 30 cm. Neutrons generated in pulses of about 1 ns width were slowed down from 14 MeV to 1.457 eV. The detection method used was based on registration of gamma radiation from the main capture resonance of indium. The most probable slowing-down times were found to be 778 +- 23 ns and 898 +- 25 ns for the smallest and for the largest cubes, respectively. The corresponding mean slowing-down times were 1205 +- 42 ns and 1311 +- 42 ns. In a separate measurement series the space dependence of the slowing-down time close to the source was studied. These experiments were supplemented by a theoretical calculation which gave an indication of the space dependence of the slowingdown time in finite systems. The experimental results were compared to the slowing-down times obtained from various theoretical approaches and from Monte Carlo calculations. All the methods show a decrease of the slowing-down time with decreasing size of the moderator. This effect was least pronounced in the experimental results, which can be explained by the fact the measurements are spatially dependent. The agreement between the Monte Carlo results and those obtained using the diffusion approximation or the age-diffusion theory is surprisingly good, especially for large systems. The P1 approximation, on the other hand, leads to an overestimation of the effect of the finite size on the slowing-down time. (author)

  20. Perceptions of the Slow Food Cultural Trend among the Youth

    OpenAIRE

    Lelia Voinea; Anca Atanase; Ion Schileru

    2016-01-01

    As they become increasingly aware of the importance of healthy eating and of the serious food imbalance caused by the overconsumption of industrial, ultra-processed and superorganoleptic food, consumers are now beginning to turn their attention to food choices guaranteeing both individual health and also of the environment . Thus, in recent years we are witnessing the rise of a cultural trend ‒ Slow Food. Slow Food has become an international movement that advocates for satisfying culinary pl...

  1. Development of slow pyrolysis business operations in Finland - Hidaspyro

    Energy Technology Data Exchange (ETDEWEB)

    Fagernas, L. [VTT Technical Research Centre of Finland, Espoo (Finland)], email: leena.fagernas@vtt.fi

    2012-07-01

    Birch distillate, a by-product in slow pyrolysis process of charcoal production, was found to be a promising source for biological pesticides. However, product commercialization was problematic, for EU registration is costly, and composition, active ingredients and ecotoxicological properties were not known. In addition, constant quality and process optimisation were needed. More collaboration between SMEs and research institutes was required. The primary aim was to support and develop slow pyrolysis business operations of SMEs in Finland by generating knowledge that was needed.

  2. The space charge effects on the slow extraction process

    International Nuclear Information System (INIS)

    Ohmori, Chihiro.

    1992-06-01

    The calculation of the slow extraction which includes the space charge effects has been performed for the Compressor/Stretcher Ring (CSR) of the proposed Japanese Hadron Project. We have investigated the slow extraction of 1 GeV proton beam with an average current of 100μA. Calculation shows not only the emittance growth of the extracted beam but also decrease of the extraction efficiency and discontinuity of beam spill. (author)

  3. Electron heating and current drive by mode converted slow waves

    International Nuclear Information System (INIS)

    Majeski, R.; Phillips, C.K.; Wilson, J.R.

    1994-08-01

    An approach to obtaining efficient single pass mode conversion at high parallel wavenumber from the fast magnetosonic wave to the slow ion Bernstein wave, in a two ion species tokamak plasma, is described. The intent is to produce localized electron heating or current drive via the mode converted slow wave. In particular, this technique can be adapted to off-axis current drive for current profile control. Modelling for the case of deuterium-tritium plasmas in TFTR is presented

  4. Slow light in semiconductor waveguides: Theory and experiment

    DEFF Research Database (Denmark)

    Mørk, Jesper; Öhman, Filip; Poel, Mike van der

    2007-01-01

    Slow light in multi-section quantum well waveguide structure is realized using either coherent population oscillations (CPO) and electromagnetically induced transparency (EIT) is studied. The properties of the two schemes are compared and discussed.......Slow light in multi-section quantum well waveguide structure is realized using either coherent population oscillations (CPO) and electromagnetically induced transparency (EIT) is studied. The properties of the two schemes are compared and discussed....

  5. Slow wave maturation on a visual working memory task.

    Science.gov (United States)

    Barriga-Paulino, Catarina I; Rodríguez-Martínez, Elena I; Rojas-Benjumea, Ma Ángeles; Gómez, Carlos M

    2014-07-01

    The purpose of the present study is to analyze how the Slow Wave develops in the retention period on a visual Delayed Match-to-Sample task performed by 170 subjects between 6 and 26 years old, divided into 5 age groups. In addition, a neuropsychological test (Working Memory Test Battery for Children) was correlated with this Event Related Potential (ERP) in order to observe possible relationships between Slow Wave maturation and the components of Baddeley and Hitch's Working Memory model. The results showed a slow negativity during the retention period in the posterior region in all the age groups, possibly resulting from sustained neural activity related to the visual item presented. In the anterior region, a positive slow wave was observed in the youngest subjects. Dipole analysis suggests that this fronto-central positivity in children (6-13 years old) consists of the positive side of the posterior negativity, once these subjects only needed two posterior dipoles to explain almost all the neural activity. Negative correlations were shown between the Slow Wave and the Working Memory Test Battery for Children, indicating a commonality in assessing Working Memory with the Slow Wave and the neuropsychological testing. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Beneficial Effects of Slow Steaming in Bulk Freight Markets

    Directory of Open Access Journals (Sweden)

    Sarah Boone

    2017-12-01

    Full Text Available Slow steaming has recently been adopted into normal practice by many maritime shipping companies for the fuel and monetary savings it offers. The practice also offers savings in Greenhouse Gas (GHG emissions. With regulations coming into play such as the 2020 sulfur cap, slow steaming may be the least costly option for some maritime companies to adjust their operations. While some have accepted the new practice, there are still companies and vessels that see this exercise as a loss of revenue due to the extra time it takes to deliver goods to their destination. This paper reviews how the method of rating ships by their GHG emissions per nautical mile can be directly related to slow steaming. We propose that ships with poor ratings (E, F, G find mandatory regulations to slow steam or improve their CO2 output in some way. Those with superior ratings (A, B, C, D would benefit from incentives packages tied to their implementation of slow steaming practices. It will also examine how slow steaming benefits maritime businesses both economically and environmentally to find ways to lower their emissions and discusses the possible chain reaction that may occur if these eco-friendly shipping practices are observed.

  7. Implications of the Deep Minimum for Slow Solar Wind Origin

    Science.gov (United States)

    Antiochos, S. K.; Mikic, Z.; Lionello, R.; Titov, V. S.; Linker, J. A.

    2009-12-01

    The origin of the slow solar wind has long been one of the most important problems in solar/heliospheric physics. Two observational constraints make this problem especially challenging. First, the slow wind has the composition of the closed-field corona, unlike the fast wind that originates on open field lines. Second, the slow wind has substantial angular extent, of order 30 degrees, which is much larger than the widths observed for streamer stalks or the widths expected theoretically for a dynamic heliospheric current sheet. We propose that the slow wind originates from an intricate network of narrow (possibly singular) open-field corridors that emanate from the polar coronal hole regions. Using topological arguments, we show that these corridors must be ubiquitous in the solar corona. The total solar eclipse in August 2008, near the lowest point of the Deep Minimum, affords an ideal opportunity to test this theory by using the ultra-high resolution Predictive Science's (PSI) eclipse model for the corona and wind. Analysis of the PSI eclipse model demonstrates that the extent and scales of the open-field corridors can account for both the angular width of the slow wind and its closed-field composition. We discuss the implications of our slow wind theory for the structure of the corona and heliosphere at the Deep Minimum and describe further observational and theoretical tests. This work has been supported by the NASA HTP, SR&T, and LWS programs.

  8. Slowness and sparseness have diverging effects on complex cell learning.

    Directory of Open Access Journals (Sweden)

    Jörn-Philipp Lies

    2014-03-01

    Full Text Available Following earlier studies which showed that a sparse coding principle may explain the receptive field properties of complex cells in primary visual cortex, it has been concluded that the same properties may be equally derived from a slowness principle. In contrast to this claim, we here show that slowness and sparsity drive the representations towards substantially different receptive field properties. To do so, we present complete sets of basis functions learned with slow subspace analysis (SSA in case of natural movies as well as translations, rotations, and scalings of natural images. SSA directly parallels independent subspace analysis (ISA with the only difference that SSA maximizes slowness instead of sparsity. We find a large discrepancy between the filter shapes learned with SSA and ISA. We argue that SSA can be understood as a generalization of the Fourier transform where the power spectrum corresponds to the maximally slow subspace energies in SSA. Finally, we investigate the trade-off between slowness and sparseness when combined in one objective function.

  9. Use of a Fluorescent Aptamer RNA as an Exonic Sequence to Analyze Self-Splicing Ability of a Group I Intron from Structured RNAs

    Directory of Open Access Journals (Sweden)

    Airi Furukawa

    2016-11-01

    Full Text Available Group I self-splicing intron constitutes an important class of functional RNA molecules that can promote chemical transformation. Although the fundamental mechanism of the auto-excision from its precursor RNA has been established, convenient assay systems for its splicing activity are still useful for a further understanding of its detailed mechanism and of its application. Because some host RNA sequences, to which group I introns inserted form stable three-dimensional (3D structures, the effects of the 3D structures of exonic elements on the splicing efficiency of group I introns are important but not a fully investigated issue. We developed an assay system for group I intron self-splicing by employing a fluorescent aptamer RNA (spinach RNA as a model exonic sequence inserted by the Tetrahymena group I intron. We investigated self-splicing of the intron from spinach RNA, serving as a model exonic sequence with a 3D structure.

  10. MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.

    Science.gov (United States)

    Togashi, Yosuke; Mizuuchi, Hiroshi; Tomida, Shuta; Terashima, Masato; Hayashi, Hidetoshi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-12-01

    MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3% of all lung adenocarcinomas. Patients with lung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported. The CRISPR/Cas9 system is a recently developed genome-engineering tool that can easily and rapidly cause small insertions or deletions. We created an in vitro model for MET exon 14 deletion using the CRISPR/Cas9 system and the HEK293 cell line. The phenotype, which included MET inhibitor sensitivity, was then investigated in vitro. Additionally, MET splice site mutations were analyzed in several cancers included in The Cancer Genome Atlas (TCGA) dataset. An HEK293 cell line with a MET exon 14 deletion was easily and rapidly created; this cell line had a higher MET protein expression level, enhanced MET phosphorylation, and prolonged MET activation. In addition, a direct comparison of phenotypes using this system demonstrated enhanced cellular growth, colony formation, and MET inhibitor sensitivity. In the TCGA dataset, lung adenocarcinomas had the highest incidence of MET exon 14 deletions, while other cancers rarely carried such mutations. Approximately 10% of the lung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion. These findings suggested that this system may be useful for experiments requiring the creation of specific mutations, and the present experimental findings encourage the development of MET-targeted therapy against lung cancer carrying the MET exon 14 deletion. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17.

    Science.gov (United States)

    Yeh, Chun-Nan; Chen, Ming-Huang; Chen, Yen-Yang; Yang, Ching-Yao; Yen, Chueh-Chuan; Tzen, Chin-Yuan; Chen, Li-Tzong; Chen, Jen-Shi

    2017-07-04

    Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%-90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1-21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.

  12. A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A.

    Science.gov (United States)

    Bethanis, Sotirios; Koutsodontis, George; Palouka, Theodosia; Avgoustis, Christos; Yannoukakos, Drakoulis; Bei, Thalia; Papadopoulos, Savas; Linos, Dimitrios; Tsagarakis, Stylianos

    2007-01-01

    Multiple endocrine neoplasia type 2A (MEN2A) is a syndrome of familial neoplasias characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperplasia of the parathyroid glands. RET protooncogene mutations are responsible for MEN 2A. Mutations in exons 10 or 11 have been identified in more than 96% of patients with MEN 2A. We herein report for the first time a patient with MEN 2A harboring a mutation (Gly(533)Cys) in exon 8. A 66-year old male patient was referred to our department for bilateral adrenal nodules. The patient's family history was remarkable in that his mother had pheochromocytoma. Biochemical evaluation and findings of the magnetic resonance imaging of the adrenals were compatible with the diagnosis of bilateral pheochromocytomas. The patient underwent laparoscopic bilateral adrenalectomy and histological examination confirmed the preoperative diagnosis of pheochromocytoma. Absence of phenotypic characteristics of VHL or NF1 and elevated calcitonin levels both basal and post pentagastrin stimulation, raised the possibility of MEN 2A syndrome. Total thyroidectomy was performed and histological examination showed the presence of MTC. Direct sequencing of exon 8 from the patient's genomic DNA revealed the mutation c.1,597G-->T (Gly533Cys). Although this missense point mutation has been associated with familial MTC (FMTC), to the best of our knowledge mutations in exon 8 have not previously been identified in patients with MEN 2A. In conclusion, in patients with clinical suspicion of MEN 2A syndrome, analysis of RET exon 8 should be considered when the routine evaluation of MEN 2A-associated mutations is negative. Furthermore, patients with FMTC and exon 8 mutations should also be screened for pheochromocytoma.

  13. Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction.

    Directory of Open Access Journals (Sweden)

    Barbara Wappenschmidt

    Full Text Available Screening for pathogenic mutations in breast and ovarian cancer genes such as BRCA1/2, CHEK2 and RAD51C is common practice for individuals from high-risk families. However, test results may be ambiguous due to the presence of unclassified variants (UCV in the concurrent absence of clearly cancer-predisposing mutations. Especially the presence of intronic or exonic variants within these genes that possibly affect proper pre-mRNA processing poses a challenge as their functional implications are not immediately apparent. Therefore, it appears necessary to characterize potential splicing UCV and to develop appropriate classification tools. We investigated 30 distinct BRCA1 variants, both intronic and exonic, regarding their spliceogenic potential by commonly used in silico prediction algorithms (HSF, MaxEntScan along with in vitro transcript analyses. A total of 25 variants were identified spliceogenic, either causing/enhancing exon skipping or activation of cryptic splice sites, or both. Except from a single intronic variant causing minor effects on BRCA1 pre-mRNA processing in our analyses, 23 out of 24 intronic variants were correctly predicted by MaxEntScan, while HSF was less accurate in this cohort. Among the 6 exonic variants analyzed, 4 severely impair correct pre-mRNA processing, while the remaining two have partial effects. In contrast to the intronic alterations investigated, only half of the spliceogenic exonic variants were correctly predicted by HSF and/or MaxEntScan. These data support the idea that exonic splicing mutations are commonly disease-causing and concurrently prone to escape in silico prediction, hence necessitating experimental in vitro splicing analysis.

  14. The old and the new in prekallikrein deficiency: historical context and a family from Argentina with PK deficiency due to a new mutation (Arg541Gln) in exon 14 associated with a common polymorphysm (Asn124Ser) in exon 5.

    Science.gov (United States)

    Girolami, Antonio; Vidal, Josè; Sabagh, Marcela; Salagh, Marcela; Gervan, Nora; Parody, Maria; Peroni, Edoardo; Sambado, Luisa; Guglielmone, Hugo

    2014-07-01

    Prekallikrein (PK) is one of the clotting factors involved in the contact phase of blood. PK has an important historical role as its deficiency state represents the second instance of a clotting defect without bleeding manifestations, the first one being factor XII deficiency. PK deficiency is a rare clotting disorder. Moreover, only 11 patients have been investigated so far by molecular biology techniques. In this article, we briefly review some of the history around PK and also present some recent data on a newly identified family from Argentina suffering from PK deficiency. Two patients are homozygous whereas other family members are heterozygous. PK activity and antigen are 1% of normal in the homozygotes and around 60 to 70% of normal in the heterozygotes. As expected, all patients are asymptomatic of bleeding or thrombosis presentations. However, the two homozygotes showed essential hypertension. The PK deficiency in this family is due to a new mutation (Arg541Gln) in exon 14. The defect segregates together with a known polymorphism, Asn124Ser, in exon 5. The significance of the presence of hypertension in the two homozygotes is discussed in view of the extra coagulation effects of PK on vasodilation, vessel permeability, and the control of blood pressure. Structure function analysis indicates that the substitution of Arg with Gln probably impedes the transmembrane diffusion of the molecule, which therefore cannot be secreted in the homozygotes. The presence of hypertension in patients with PK deficiency has been previously reported in some but not all patients. Future research activities will probably concentrate on the effect of PK and other contact phase factors on the vascular system. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  15. Estimating the Nucleotide Diversity in Ceratodon purpureus (Ditrichaceae from 218 Conserved Exon-Primed, Intron-Spanning Nuclear Loci

    Directory of Open Access Journals (Sweden)

    Stuart F. McDaniel

    2013-04-01

    Full Text Available Premise of the study: We developed and tested primers for 218 nuclear loci for studying population genetics, phylogeography, and genome evolution in bryophytes. Methods and Results: We aligned expressed sequence tags (ESTs from Ceratodon purpureus to the Physcomitrella patens genome sequence, and designed primers that are homologous to conserved exons but span introns in the P. patens genome. We tested these primers on four isolates from New York, USA; Otavalo, Ecuador; and two laboratory isolates from Austria (WT4 and GG1. The median genome-wide nucleotide diversity was 0.008 substitutions/site, but the range was large (0–0.14, illustrating the among-locus heterogeneity in the species. Conclusions: These loci provide a valuable resource for finely resolved, genome-wide population genetic and species-level phylogenetic analyses of C. purpureus and its relatives.

  16. KRAS exon 2 mutations influence activity of regorafenib in an SW48-based disease model of colorectal cancer.

    Science.gov (United States)

    Camaj, Peter; Primo, Stefano; Wang, Yan; Heinemann, Volker; Zhao, Yue; Laubender, Ruediger Paul; Stintzing, Sebastian; Giessen-Jung, Clemens; Jung, Andreas; Gamba, Sebastian; Bruns, Christiane Josephine; Modest, Dominik Paul

    2015-01-01

    To investigate the impact of KRAS mutation variants on the activity of regorafenib in SW48 colorectal cancer cells. Activity of regorafenib was evaluated in isogenic SW48 KRAS wild-type (WT) and mutant cells. Subcutaneous xenografts (KRAS WT and G12C mutant variants) in NOD/SCID mice were analyzed to elucidate the effect of regorafenib treatment in vivo. Compared with KRAS WT cells, all mutant variants seemed associated with some degree of resistance to regorafenib-treatment in vitro. In vivo, activation of apoptosis (TUNEL) and reduction of proliferation (Ki67) after treatment with regorafenib were more pronounced in KRAS WT tumors as compared with G12C variants. In SW48 cells, exon 2 mutations of the KRAS gene may influence antitumor effects of regorafenib.

  17. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene

    International Nuclear Information System (INIS)

    Lichter-Konecki, U.; Konecki, D.S.; DiLella, A.G.; Brayton, K.; Marvit, J.; Hahn, T.M.; Trefz, E.K.; Woo, S.L.C.

    1988-01-01

    A novel restriction fragment length polymorphism in the phenylalanine hydroxylase (PAH) locus generated by the restriction endonuclease MspI was observed in a German phenylketonuria (PKU) patient. Molecular cloning and DNA sequence analyses revealed that the MspI polymorphism was created by a T to C transition in exon 9 of the human PAH gene, which also resulted in the conversion of a leucine codon to proline codon. The effect of the amino acid substitution was investigated by creating a corresponding mutation in a full-length human PAD cDNA by site-directed mutagenesis followed by expression analysis in cultured mammalian cells. Results demonstrate that the mutation in the gene causes the synthesis of an unstable protein in the cell corresponding to a CRM - phenotype. Together with the other mutations recently reported in the PAH gene,the data support previous biochemical and clinical observations that PKU is a heterogeneous disorder at the gene level

  18. Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene

    Energy Technology Data Exchange (ETDEWEB)

    Lichter-Konecki, U.; Konecki, D.S.; DiLella, A.G.; Brayton, K.; Marvit, J.; Hahn, T.M.; Trefz, E.K.; Woo, S.L.C.

    1988-04-19

    A novel restriction fragment length polymorphism in the phenylalanine hydroxylase (PAH) locus generated by the restriction endonuclease MspI was observed in a German phenylketonuria (PKU) patient. Molecular cloning and DNA sequence analyses revealed that the MspI polymorphism was created by a T to C transition in exon 9 of the human PAH gene, which also resulted in the conversion of a leucine codon to proline codon. The effect of the amino acid substitution was investigated by creating a corresponding mutation in a full-length human PAD cDNA by site-directed mutagenesis followed by expression analysis in cultured mammalian cells. Results demonstrate that the mutation in the gene causes the synthesis of an unstable protein in the cell corresponding to a CRM/sup -/ phenotype. Together with the other mutations recently reported in the PAH gene,the data support previous biochemical and clinical observations that PKU is a heterogeneous disorder at the gene level.

  19. Developing Exon-Primed Intron-Crossing (EPIC) markers for population genetic studies in three Aedes disease vectors.

    Science.gov (United States)

    White, Vanessa Linley; Endersby, Nancy Margaret; Chan, Janice; Hoffmann, Ary Anthony; Weeks, Andrew Raymond

    2015-03-01

    Aedes aegypti, Aedes notoscriptus, and Aedes albopictus are important vectors of many arboviruses implicated in human disease such as dengue fever. Genetic markers applied across vector species can provide important information on population structure, gene flow, insecticide resistance, and taxonomy, however, robust microsatellite markers have proven difficult to develop in these species and mosquitoes generally. Here we consider the utility and transferability of 15 Ribosome protein (Rp) Exon-Primed Intron-Crossing (EPIC) markers for population genetic studies in these 3 Aedes species. Rp EPIC markers designed for Ae. aegypti also successfully amplified populations of the sister species, Ae. albopictus, as well as the distantly related species, Ae. notoscriptus. High SNP and good indel diversity in sequenced alleles plus support for amplification of the same regions across populations and species were additional benefits of these markers. These findings point to the general value of EPIC markers in mosquito population studies. © 2014 Institute of Zoology, Chinese Academy of Sciences.

  20. Molecular genetic analysis of cereal β-amylase genes using exon-primed intron-crossing (EPIC PCR

    Directory of Open Access Journals (Sweden)

    Stratula Olga

    2014-01-01

    Full Text Available The proteins encoded by cereal β-amylase genes Bamy1 and Bamy2 genes play an important role in seedling germination and in the brewing process. Here, we use exon-primed intron-crossing (EPIC to analyse Bamy1 and Bamy2 genetic diversity among 38 accessions belonging to six Poaceae tribes. DNA sequence alignment of multiple Poaceae species β-amylase sequences allowed design of EPIC primers that simultaneously amplify Bamy1 and Bamy2 in all the cereal species investigated. The genetic variation observed in the samples investigated is analysed and discussed, and illustrates the effectiveness of this approach for intra- and interspecific analysis in plant species.

  1. Clinical implications of cytosine deletion of exon 5 of P53 gene in non small cell lung cancer patients

    Directory of Open Access Journals (Sweden)

    Rashid Mir

    2016-01-01

    Full Text Available Aim: Lung cancer is considered to be the most common cancer in the world. In humans, about 50% or more cancers have a mutated tumor suppressor p53 gene thereby resulting in accumulation of p53 protein and losing its function to activate the target genes that regulate the cell cycle and apoptosis. Extensive research conducted in murine cancer models with activated p53, loss of p53, or p53 missense mutations have facilitated researchers to understand the role of this key protein. Our study was aimed to evaluate the frequency of cytosine deletion in nonsmall cell lung cancer (NSCLC patients. Methods: One hundred NSCLC patients were genotyped for P53 (exon5, codon168 cytosine deletion leading to loss of its function and activate the target genes by allele-specific polymerase chain reaction. The P53 cytosine deletion was correlated with all the clinicopathological parameters of the patients. Results and Analysis: 59% cases were carrying P53 cytosine deletion. Similarly, the significantly higher incidence of cytosine deletion was reported in current smokers (75% in comparison to exsmoker and nonsmoker. Significantly higher frequency of cytosine deletion was reported in adenocarcinoma (68.08% than squamous cell carcinoma (52.83%. Also, a significant difference was reported between p53 cytosine deletion and metastasis (64.28%. Further, the majority of the cases assessed for response carrying P53 cytosine deletion were found to show faster disease progression. Conclusion: The data suggests that there is a significant association of the P53 exon 5 deletion of cytosine in codon 168 with metastasis and staging of the disease.

  2. Role of accelerated segment switch in exons to alter targeting (ASSET in the molecular evolution of snake venom proteins

    Directory of Open Access Journals (Sweden)

    Kini R Manjunatha

    2009-06-01

    Full Text Available Abstract Background Snake venom toxins evolve more rapidly than other proteins through accelerated changes in the protein coding regions. Previously we have shown that accelerated segment switch in exons to alter targeting (ASSET might play an important role in its functional evolution of viperid three-finger toxins. In this phenomenon, short sequences in exons are radically changed to unrelated sequences and hence affect the folding and functional properties of the toxins. Results Here we analyzed other snake venom protein families to elucidate the role of ASSET in their functional evolution. ASSET appears to be involved in the functional evolution of three-finger toxins to a greater extent than in several other venom protein families. ASSET leads to replacement of some of the critical amino acid residues that affect the biological function in three-finger toxins as well as change the conformation of the loop that is involved in binding to specific target sites. Conclusion ASSET could lead to novel functions in snake venom proteins. Among snake venom serine proteases, ASSET contributes to changes in three surface segments. One of these segments near the substrate binding region is known to affect substrate specificity, and its exchange may have significant implications for differences in isoform catalytic activity on specific target protein substrates. ASSET therefore plays an important role in functional diversification of snake venom proteins, in addition to accelerated point mutations in the protein coding regions. Accelerated point mutations lead to fine-tuning of target specificity, whereas ASSET leads to large-scale replacement of multiple functionally important residues, resulting in change or gain of functions.

  3. Novel and known MYOC exon 3 mutations in an admixed Peruvian primary open-angle glaucoma population.

    Science.gov (United States)

    Mendoza-Reinoso, Veronica; Patil, Teja S; Guevara-Fujita, Maria L; Fernández, Silvia; Vargas, Enrique; Castillo-Herrera, Wilder; Perez-Grossmann, Rodolfo; Lizaraso-Caparó, Frank; Richards, Julia E; Fujita, Ricardo

    2012-01-01

    The aim of this study was to characterize a representative sample of the Peruvian population suffering open-angle glaucoma (OAG) with respect to the myocilin gene (MYOC) mutations, glaucoma phenotype, and ancestry for future glaucoma risk assessment. DNA samples from 414 unrelated Peruvian subjects, including 205 open-angle glaucoma cases (10 juvenile glaucoma [JOAG], 19 normal-tension glaucoma [NTG], and 176 POAG) and 209 randomly sampled controls, were screened for nucleotide changes in MYOC exon 3 by conformational sensitive gel electrophoresis (CSGE) and mutation screening. We identified a probable causative novel MYOC missense mutation, Gly326Ser, in one POAG case and found a consistent genotype-phenotype correlation in eight of his relatives. We also found the known causative MYOC mutation Trp286Arg in one JOAG case and one POAG case. A known causative single base MYOC deletion, T1357, was found in one POAG case. Two previously reported silent polymorphisms, Thr325Thr and Tyr347Tyr, were found in both the case and the control populations. A novel missense variant, Met476Arg, was identified in two unrelated controls. The screening of exon 3 of MYOC in a representative sample of 205 independent POAG patients from Peru and 209 matched controls identified novel and previously reported mutations (both pathogenic and nonpathogenic) from other global regions. These results reflect the complex admixture of Amerindian and Old World ancestry in urban populations of Latin America, in general, and in Peru, in particular. It will be important to gather information about the ancestral origin of MYOC and other POAG gene mutations to develop screening panels and risk assessment for POAG in Peru.

  4. Expression and new exon mutations of the human Beta defensins and their association on colon cancer development.

    Directory of Open Access Journals (Sweden)

    Abdelhabib Semlali

    Full Text Available The development of cancer involves genetic predisposition and a variety of environmental exposures. Genome-wide linkage analyses provide evidence for the significant linkage of many diseases to susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Human β-defensins (hBDs are important molecules of innate immunity. This study was designed to analyze the expression and genetic variations in hBDs (hBD-1, hBD-2, hBD-3 and hBD-4 and their putative association with colon cancer. hBD gene expression and relative protein expression were evaluated by Real-Time polymerase chain reaction (qPCR and immunohistochemistry, respectively, from 40 normal patients and 40 age-matched patients with colon cancer in Saudi Arabia. In addition, hBD polymorphisms were genotyped by exon sequencing and by promoter methylation. hBD-1, hBD-2, hBD-3 and hBD-4 basal messenger RNA expression was significantly lower in tumor tissues compared with normal tissues. Several insertion mutations were detected in different exons of the analyzed hBDs. However, no methylation in any hBDs promoters was detected because of the limited number of CpG islands in these regions. We demonstrated for the first time a link between hBD expression and colon cancer. This suggests that there is a significant link between innate immunity deregulation through disruption of cationic peptides (hBDs and the potential development of colon cancer.

  5. Prevalence of endothelial nitric oxide synthase (eNOS) gene exon 7 Glu298Asp variant in North Eastern India

    Science.gov (United States)

    Shankarishan, Priyanka; Borah, Prasanta Kumar; Ahmed, Giasuddin; Mahanta, Jagadish

    2011-01-01

    Background & objectives Endothelial nitric oxide is a potent vasodilator and impairment of its generation brought about by gene polymorphism is considered a major predictor for several diseases. A single nucleotide polymorphism G894T within exon 7 of endothelial nitric oxide synthase (eNOS-7) gene, resulting in a replacement of glutamic acid by aspartic acid, has been studied as a putative candidate gene for cardiovascular diseases. The pattern of eNOS-7 Glu298Asp variant in the Indian population is poorly known. The present study was planned to determine the prevalence of the variant of this gene among tea garden community in Assam, North-East India with high prevalence of hypertension. Methods Study participants of both sex aged ≥18 yr were recruited randomly from temporary field clinics established in tea gardens of Dibrugarh, Assam. Genomic DNA was extracted from 409 subjects by the conventional phenol-chloroform method. The prevalence of the eNOS exon 7 Glu298Asp variant was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Results The study population was in Hardy-Weinberg Equilibrium. The frequency of the eNOS GG, GT and TT genotypes was found to be 75, 22 and 3 per cent respectively and did not show any significant difference in gender wise analysis. Interpretation & conclusions Our results showed that the prevalence of the homozygous GG genotype was high (75%) and the rare mutant genotype (homozygous, TT) was 3 per cent in a population at risk with cardiovascular disease. Such population-based data on various polymorphisms can ultimately be exploited in pharmacogenomics. PMID:21623032

  6. [Using exon combined target region capture sequencing chip to detect the disease-causing genes of retinitis pigmentosa].

    Science.gov (United States)

    Rong, Weining; Chen, Xuejuan; Li, Huiping; Liu, Yani; Sheng, Xunlun

    2014-06-01

    To detect the disease-causing genes of 10 retinitis pigmentosa pedigrees by using exon combined target region capture sequencing chip. Pedigree investigation study. From October 2010 to December 2013, 10 RP pedigrees were recruited for this study in Ningxia Eye Hospital. All the patients and family members received complete ophthalmic examinations. DNA was abstracted from patients, family members and controls. Using exon combined target region capture sequencing chip to screen the candidate disease-causing mutations. Polymerase chain reaction (PCR) and direct sequencing were used to confirm the disease-causing mutations. Seventy patients and 23 normal family members were recruited from 10 pedigrees. Among 10 RP pedigrees, 1 was autosomal dominant pedigrees and 9 were autosomal recessive pedigrees. 7 mutations related to 5 genes of 5 pedigrees were detected. A frameshift mutation on BBS7 gene was detected in No.2 pedigree, the patients of this pedigree combined with central obesity, polydactyly and mental handicap. No.2 pedigree was diagnosed as Bardet-Biedl syndrome finally. A missense mutation was detected in No.7 and No.10 pedigrees respectively. Because the patients suffered deafness meanwhile, the final diagnosis was Usher syndrome. A missense mutation on C3 gene related to age-related macular degeneration was also detected in No. 7 pedigrees. A nonsense mutation and a missense mutation on CRB1 gene were detected in No. 1 pedigree and a splicesite mutation on PROM1 gene was detected in No. 5 pedigree. Retinitis pigmentosa is a kind of genetic eye disease with diversity clinical phenotypes. Rapid and effective genetic diagnosis technology combined with clinical characteristics analysis is helpful to improve the level of clinical diagnosis of RP.

  7. Growth hormone receptor exon 3 isoforms may have no importance in the clinical setting of multiethnic Brazilian acromegaly patients.

    Science.gov (United States)

    de Oliveira Machado, Evelyn; Lima, Carlos Henrique Azeredo; Ogino, Liana Lumi; Kasuki, Leandro; Gadelha, Mônica R

    2016-08-01

    Acromegaly is associated with significant morbidity and increased mortality, but has a variable severity phenotype. The presence of the exon 3-deleted isoform of the growth hormone receptor (d3-GHR) may influence the disease phenotype and treatment outcomes, including the frequency of biochemical discordance after medical treatment. The objective of this study was to analyze the influence of the d3-GHR isoform on clinical and biochemical characteristics and in the treatment outcomes of Brazilian multiethnic acromegaly patients. We retrospectively analyzed our acromegaly outpatient clinic databank and collected demographic, clinical, biochemical and treatment outcome data from those patients who agreed to participate in the study. A blood sample was collected from all patients, the DNA was extracted and the GHR isoforms were evaluated by PCR, with the full length (fl)-GHR represented by a 935-bp fragment and the d3-GHR represented by a 532-bp fragment. A total of 121 patients were included. Fifty-six patients (46.3 %) were full-length homozygous (fl/fl), 48 (39.7 %) were heterozygous (fl/d3) and 17 (14.0 %) were d3-GHR homozygous (d3/d3). There was no difference between patients homozygous for the fl isoform and those harboring at least one d3-GHR allele in the demographic, clinical and biochemical data or in the treatment outcomes, including somatostatin receptor ligands (SRL) monotherapy, combination therapy with SRL and cabergoline and pegvisomant treatment. There was also no difference between the groups for the frequency of GH and IGF-I discordance after medical treatment. GHR exon 3 genotyping appears to have no clinical significance, at least in Brazilian acromegaly patients.

  8. Diversity of Plasmodium falciparum chloroquine resistance transporter (pfcrt exon 2 haplotypes in the Pacific from 1959 to 1979.

    Directory of Open Access Journals (Sweden)

    Chim W Chan

    Full Text Available Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of falciparum malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the pfcrt exon 2 from 771 P. falciparum-infected individuals to explore the spatial and temporal variation in falciparum malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of P. falciparum varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of P. falciparum in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique pfcrt haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two pfcrt mutations (N75D and K76T implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in pfcrt exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in P. falciparum.

  9. Perceptions of the Slow Food Cultural Trend among the Youth

    Directory of Open Access Journals (Sweden)

    Lelia Voinea

    2016-11-01

    Full Text Available As they become increasingly aware of the importance of healthy eating and of the serious food imbalance caused by the overconsumption of industrial, ultra-processed and superorganoleptic food, consumers are now beginning to turn their attention to food choices guaranteeing both individual health and also of the environment . Thus, in recent years we are witnessing the rise of a cultural trend ‒ Slow Food. Slow Food has become an international movement that advocates for satisfying culinary pleasure, protects biological and cultural diversity, spread taste education, links "green" producers to consumers and believes that gastronomy intersects with politics, agriculture and ecology. Slow Food proposes a holistic approach to food problem, where the economic, sociocultural and environmental aspects are interlinked, being pursued as part of an overall strategy. In order to highlight the manner in which the principles of this cultural trend are perceived by the representatives of the new generation of consumers in Romania, exploratory research marketing was conducted among the students in the second year of the master’s program Quality Management, Expertise and Consumer Protection, from the Faculty of Business and Tourism from the Buchares t University of Economic Studies . The results of this research have shown an insufficient knowledge of Slow Food phenomenon and, especially, the Slow Food network activity in Romania. To show that the Slow Food type of food is a healthier option towards which the future consumer demand should be guided, especially those belonging to the younger generation, an antithetical comparative analysis of the nutritional value of two menus was performed: a suggestive one for the Slow Food feeding style and other one, specific to the fast food style. Slow Food style was considered antithetical to the fast food because many previous studies have shown a preference of the young for the fast-food type products, despite the

  10. A taste of ethical consumption at a slow food festival.

    Science.gov (United States)

    Williams, Lauren T; Germov, John; Fuller, Sascha; Freij, Maria

    2015-08-01

    This paper examines the motives and experiences of attendees at a Slow Food festival to gain an understanding of how people engage with ethical consumer projects. Slow Food is a global social movement aimed at promoting food that is regionally, ethically, and sustainably produced, and convivially consumed. The movement uses culinary tourist events, such as food festivals and farmers' markets, to promote its philosophy and attract new members. There have been no empirical studies of ethical consumption using a Slow Food event as a case study. This study uses an ethnographic approach and a framework of virtue ethics to explore the views of people attending a major Slow Food festival in the city of Melbourne, Australia. Semi-structured interviews were conducted in situ with 33 participants (19 consumers and 14 stallholders) to discover their rationales for attending the festival, and their perspectives on ethical consumption. Transcripts were coded and thematically analysed, resulting in three themes reflecting varying degrees of public virtues (altruistic motivations) and private virtues (personal wellbeing): the quest for virtuous lifestyles through ethical consumption, the importance of co-production, and the challenges of putting ethical consumer projects like Slow Food into daily practice. The findings reveal the manner in which virtue ethics affects foodways and highlights the contingent and challenging nature of practising ethical eating. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Human skeletal muscle: transition between fast and slow fibre types.

    Science.gov (United States)

    Neunhäuserer, Daniel; Zebedin, Michaela; Obermoser, Magdalena; Moser, Gerhard; Tauber, Mark; Niebauer, Josef; Resch, Herbert; Galler, Stefan

    2011-05-01

    Human skeletal muscles consist of different fibre types: slow fibres (slow twitch or type I) containing the myosin heavy chain isoform (MHC)-I and fast fibres (fast twitch or type II) containing MHC-IIa (type IIA) or MHC-IId (type IID). The following order of decreasing kinetics is known: type IID > type IIA > type I. This order is especially based on the kinetics of stretch activation, which is the most discriminative property among fibre types. In this study we tested if hybrid fibres containing both MHC-IIa and MHC-I (type C fibres) provide a transition in kinetics between fast (type IIA) and slow fibres (type I). Our data of stretch activation kinetics suggest that type C fibres, with different ratios of MHC-IIa and MHC-I, do not provide a continuous transition. Instead, a specialized group of slow fibres, which we called "transition fibres", seems to provide a transition. Apart of their kinetics of stretch activation, which is most close to that of type IIA, the transition fibres are characterized by large cross-sectional areas and low maximal tensions. The molecular cause for the mechanical properties of the transition fibres is unknown. It is possible that the transition fibres contain an unknown slow MHC isoform, which cannot be separated by biochemical methods. Alternatively, or in addition, isoforms of myofibrillar proteins, other than MHC, and posttranslational modifications of myofibrillar proteins could play a role regarding the characteristics of the transition fibres.

  12. Fast and slow myosins as markers of muscle injury.

    Science.gov (United States)

    Guerrero, M; Guiu-Comadevall, M; Cadefau, J A; Parra, J; Balius, R; Estruch, A; Rodas, G; Bedini, J L; Cussó, R

    2008-07-01

    The diagnosis of muscular lesions suffered by athletes is usually made by clinical criteria combined with imaging of the lesion (ultrasonography and/or magnetic resonance) and blood tests to detect the presence of non-specific muscle markers. This study was undertaken to evaluate injury to fast and slow-twitch fibres using specific muscle markers for these fibres. Blood samples were obtained from 51 non-sports people and 38 sportsmen with skeletal muscle injury. Western blood analysis was performed to determine fast and slow myosin and creatine kinase (CK) levels. Skeletal muscle damage was diagnosed by physical examination, ultrasonography and magnetic resonance and biochemical markers. The imaging tests were found to be excellent for detecting and confirming grade II and III lesions. However, grade I lesions were often unconfirmed by these techniques. Grade I lesions have higher levels of fast myosin than slow myosin with a very small increase in CK levels. Grade II and III lesions have high values of both fast and slow myosin. The evaluation of fast and slow myosin in the blood 48 h after the lesion occurs is a useful aid for the detection of type I lesions in particular, since fast myosin is an exclusive skeletal muscle marker. The correct diagnosis of grade I lesions can prevent progression of the injury in athletes undergoing continual training sessions and competitions, thus aiding sports physicians in their decision making.

  13. Slow extraction control system of HIRFL-CSR

    International Nuclear Information System (INIS)

    Liu Wufeng; Qiao Weimin; Yuan Youjin; Mao Ruishi; Zhao Tiecheng

    2013-01-01

    For heavy-ion radiotherapy, HIRFL-CSR (Heavy Ion Research Facility in Lanzhou-Cooler Storage Ring) needs a long term uniform ion beam extraction from HIRFL-CSR main ring to high energy beam transport line to meet the requirement of heavy-ion radiotherapy's ion beam. Slow extraction control system uses the synchronous signal of HIRFL-CSR control system's timing system to realize process control. When the synchronous event data of HIRFL-CSR control system's timing system trigger controlling and changing data (frequency value, tune value, voltage value), the waveform generator will generate waveform by frequency value, tune value and voltage value, and will amplify the generated waveform by power amplifier to electrostatic deflector to achieve RF-KO slow extraction. The synchronous event receiver of slow extraction system is designed by using FPGA and optical fiber interface to keep high transmission speed and anti-jamming. HIRFL-CSR's running for heavy-ion radiotherapy and ten thousand seconds long period slow extraction experiments show that slow extraction control system is workable and can meet the requirement of heavy-ion radiotherapy's ion beam. (authors)

  14. Late-type components of slow novae and symbiotic stars

    Energy Technology Data Exchange (ETDEWEB)

    Allen, D A [Anglo-Australian Observatory, Epping (Australia); Royal Observatory, Edinburgh (UK))

    1980-08-01

    It is argued that the various types of symbiotic stars and the slow novae are the same phenomena exhibiting a range of associated time-scales, the slow novae being of intermediate speed. Evidence is summarized showing that both types of object contain normal M giants or mira variables. This fact is at odds with currently fashionable single-star models for slow novae, according to which the M star is totally disrupted before the outburst. Spectral types of the late-type components are presented for nearly 80 symbiotic stars and slow novae, derived from 2 ..mu..m spectroscopy. It is found that both the intensity of the emission spectrum and the electron density of the gas are functions of the spectral type of the late-type star. Explanations for these correlations are given. On the assumption that the late-type components are normal giants, spectroscopic parallaxes are determined; credible distances are derived which indicate that the known symbiotic stars have been sampled as far afield as the Galactic Centre. Hydrogen shell flashes on a white dwarf accreting gas from the late-type components offer an attractive explanation of the phenomena of slow novae and symbiotic stars, and such models are discussed in the concluding section.

  15. Optimizing detection and analysis of slow waves in sleep EEG.

    Science.gov (United States)

    Mensen, Armand; Riedner, Brady; Tononi, Giulio

    2016-12-01

    Analysis of individual slow waves in EEG recording during sleep provides both greater sensitivity and specificity compared to spectral power measures. However, parameters for detection and analysis have not been widely explored and validated. We present a new, open-source, Matlab based, toolbox for the automatic detection and analysis of slow waves; with adjustable parameter settings, as well as manual correction and exploration of the results using a multi-faceted visualization tool. We explore a large search space of parameter settings for slow wave detection and measure their effects on a selection of outcome parameters. Every choice of parameter setting had some effect on at least one outcome parameter. In general, the largest effect sizes were found when choosing the EEG reference, type of canonical waveform, and amplitude thresholding. Previously published methods accurately detect large, global waves but are conservative and miss the detection of smaller amplitude, local slow waves. The toolbox has additional benefits in terms of speed, user-interface, and visualization options to compare and contrast slow waves. The exploration of parameter settings in the toolbox highlights the importance of careful selection of detection METHODS: The sensitivity and specificity of the automated detection can be improved by manually adding or deleting entire waves and or specific channels using the toolbox visualization functions. The toolbox standardizes the detection procedure, sets the stage for reliable results and comparisons and is easy to use without previous programming experience. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Simplified slow anti-coincidence circuit for Compton suppression systems

    International Nuclear Information System (INIS)

    Al-Azmi, Darwish

    2008-01-01

    Slow coincidence circuits for the anti-coincidence measurements have been considered for use in Compton suppression technique. The simplified version of the slow circuit has been found to be fast enough, satisfactory and allows an easy system setup, particularly with the advantage of the automatic threshold setting of the low-level discrimination. A well-type NaI detector as the main detector surrounded by plastic guard detector has been arranged to investigate the performance of the Compton suppression spectrometer using the simplified slow circuit. The system has been tested to observe the improvement in the energy spectra for medium to high-energy gamma-ray photons from terrestrial and environmental samples

  17. Role of biological membranes in slow-wave sleep.

    Science.gov (United States)

    Karnovsky, M L

    1991-02-01

    Two involvements of cellular membranes in slow-wave sleep (SWS) are discussed. In the first the endoplasmic reticulum (ER) is focussed upon, and in the second, the plasmalemma, where specific binding sites (receptors?) for promoters of slow-wave sleep are believed to be located. The study concerning the ER focuses on an enzyme in the brain, glucose-6-phosphatase, which, although present at low levels, manifests greatly increased activity during SWS compared to the waking state. The work on the plasmalemma has to do with the specific binding of muramyl peptides, inducers of slow-wave sleep, to various cells, and membrane preparations of various sorts, including those from brain tissue. Such cells as macrophages from mice, B-lymphocytes from human blood, and cells from a cell line (C-6 glioma) have been examined in this context.

  18. Modeling fast and slow earthquakes at various scales.

    Science.gov (United States)

    Ide, Satoshi

    2014-01-01

    Earthquake sources represent dynamic rupture within rocky materials at depth and often can be modeled as propagating shear slip controlled by friction laws. These laws provide boundary conditions on fault planes embedded in elastic media. Recent developments in observation networks, laboratory experiments, and methods of data analysis have expanded our knowledge of the physics of earthquakes. Newly discovered slow earthquakes are qualitatively different phenomena from ordinary fast earthquakes and provide independent information on slow deformation at depth. Many numerical simulations have been carried out to model both fast and slow earthquakes, but problems remain, especially with scaling laws. Some mechanisms are required to explain the power-law nature of earthquake rupture and the lack of characteristic length. Conceptual models that include a hierarchical structure over a wide range of scales would be helpful for characterizing diverse behavior in different seismic regions and for improving probabilistic forecasts of earthquakes.

  19. Enhancing physics demos using iPhone slow motion

    Science.gov (United States)

    Lincoln, James

    2017-12-01

    Slow motion video enhances our ability to perceive and experience the physical world. This can help students and teachers especially in cases of fast moving objects or detailed events that happen too quickly for the eye to follow. As often as possible, demonstrations should be performed by the students themselves and luckily many of them will already have this technology in their pockets. The "S" series of iPhone has the slow motion video feature standard, which also includes simultaneous sound recording (somewhat unusual among slow motion cameras). In this article I share some of my experiences using this feature and provide advice on how to successfully use this technology in the classroom.

  20. The condition for classical slow rolling in new inflation

    International Nuclear Information System (INIS)

    Sasaki, Misao; Nambu, Yasusada; Nakao, Ken-ichi.

    1988-02-01

    By means of the stochastic description of inflation, we investigate the dynamics of a fixed comoving domain in a continuously inflating universe on the global scale, both analytically and numerically. A particular attention is paid to the condition for a domain to enter the classical slow rolling phase. New inflationary universe models with the potential form, V(φ) ∼ V 0 - cφ 2n at φ ∼ 0 are considered. The critical value of the scalar field beyond which the field slowly rolls down the potential hill is estimated. We find, for all models under consideration, the condition for classical slow rolling is a sufficient condition for the expected amplitude of density perturbations to be smaller than unity. In other words, the density perturbation amplitude at the later Friedmann stage is always smaller than unity if the universe experienced the classical slow roll-over phase. (author)

  1. Study of Dynamic Characteristics of Slow-Changing Process

    Directory of Open Access Journals (Sweden)

    Yinong Li

    2000-01-01

    Full Text Available A vibration system with slow-changing parameters is a typical nonlinear system. Such systems often occur in the working and controlled process of some intelligent structures when vibration and deformation exist synchronously. In this paper, a system with slow-changing stiffness, damping and mass is analyzed in an intelligent structure. The relationship between the amplitude and the frequency of the system is studied, and its dynamic characteristic is also discussed. Finally, a piecewise linear method is developed on the basis of the asymptotic method. The simulation and the experiment show that a suitable slow-changing stiffness can restrain the amplitude of the system when the system passes through the resonant region.

  2. Table incremental slow injection CE-CT in lung cancer

    International Nuclear Information System (INIS)

    Yoshida, Shoji; Maeda, Tomoho; Morita, Masaru

    1988-01-01

    The purpose of this study is to evaluate tumor enhancement in lung cancer under the table incremental study with slow injection of contrast media. The early serial 8 sliced images during the slow injection (1.5 ml/sec) of contrant media were obtained. Following the early images, delayed 8 same sliced images were taken in 2 minutes later. Chacteristic enhanced patterns of the primary cancer and metastatic mediastinal lymphnode were recognized in this study. Enhancement of the primary lesion was classified in 4 patterns, irregular geographic pattern, heterogeneous pattern, homogeneous pattern and rim-enhanced pattern. In mediastinal metastatic lymphadenopathy, three enhanced patterns were obtained, heterogeneous, homogeneous and ring enhanced pattern. Some characteristic enhancement patterns according to the histopathological finding of the lung cancer were obtained. With using this incremental slow injection CE-CT, precise information about the relationship between lung cancer and adjacent mediastinal structure, and obvious staining patterns of the tumor and mediastinal lymphnode were recognized. (author)

  3. The condition for classical slow rolling in new inflation

    International Nuclear Information System (INIS)

    Sasaki, Misao; Nambu, Yasusada; Nakao, Ken-ichi

    1988-01-01

    By means of the stochastic description of inflation we investigate the dynamics of a fixed comoving domain in a continuously inflating universe on a global scale, both analytically and numerically. Particular attention is paid to the condition for a domain to enter the classical slow rolling phase. New inflationary universe models with the potential form V(φ) ≅ V 0 -cφ 2n at φ ≅ 0 are considered. The critical value of the scalar field beyond which the field slowly rolls down the potential hill is estimated. We find that for all models under consideration, the condition for classical slow rolling is a sufficient condition for the expected amplitude of density perturbations to be smaller than unity. In other words, the density perturbation amplitude at the later Friedmann stage is always smaller than unity if the universe experienced the classical slow roll-over phase. (orig.)

  4. Slow dynamics in translation-invariant quantum lattice models

    Science.gov (United States)

    Michailidis, Alexios A.; Žnidarič, Marko; Medvedyeva, Mariya; Abanin, Dmitry A.; Prosen, Tomaž; Papić, Z.

    2018-03-01

    Many-body quantum systems typically display fast dynamics and ballistic spreading of information. Here we address the open problem of how slow the dynamics can be after a generic breaking of integrability by local interactions. We develop a method based on degenerate perturbation theory that reveals slow dynamical regimes and delocalization processes in general translation invariant models, along with accurate estimates of their delocalization time scales. Our results shed light on the fundamental questions of the robustness of quantum integrable systems and the possibility of many-body localization without disorder. As an example, we construct a large class of one-dimensional lattice models where, despite the absence of asymptotic localization, the transient dynamics is exceptionally slow, i.e., the dynamics is indistinguishable from that of many-body localized systems for the system sizes and time scales accessible in experiments and numerical simulations.

  5. Neurogenetics of slow axonal transport: from cells to animals.

    Science.gov (United States)

    Sadananda, Aparna; Ray, Krishanu

    2012-09-01

    Slow axonal transport is a multivariate phenomenon implicated in several neurodegenerative disorders. Recent reports have unraveled the molecular basis of the transport of certain slow component proteins, such as the neurofilament subunits, tubulin, and certain soluble enzymes such as Ca(2+)/calmodulin-dependent protein kinase IIa (CaM kinase IIa), etc., in tissue cultured neurons. In addition, genetic analyses also implicate microtubule-dependent motors and other housekeeping proteins in this process. However, the biological relevance of this phenomenon is not so well understood. Here, the authors have discussed the possibility of adopting neurogenetic analyses in multiple model organisms to correlate molecular level measurements of the slow transport phenomenon to animal behavior, thus facilitating the investigation of its biological efficacy.

  6. The Slow Control System of the Auger Fluorescence Detectors

    Science.gov (United States)

    Barenthien, N.; Bethge, C.; Daumiller, K.; Gemmeke, H.; Kampert, K.-H.; Wiebusch, C.

    2003-07-01

    The fluorescence detector (FD) of the Pierre Auger experiment [1] comprises 24 telescopes that will be situated in 4 remote buildings in the Pampa Amarilla. It is planned to run the fluorescence detectors in absence of operators on site. Therefore, the main task of the Slow Control System (SCS) is to ensure a secure remote operation of the FD system. The Slow Control System works autonomously and continuously monitors those parameters which may disturb a secure operation. Commands from the data-acquisition system or the remote operator are accepted only if they do not violate safety rules that depend on the actual experimental conditions (e.g. high-voltage, wind-sp eed, light, etc.). In case of malfunctions (power failure, communication breakdown, ...) the SCS performs an orderly shutdown and subsequent startup of the fluorescence detector system. The concept and the implementation of the Slow Control System are presented.

  7. Mutually-modulated cross-gain modulation and slow light

    International Nuclear Information System (INIS)

    Sternklar, Shmuel; Sarid, Eyal; Wart, Maxim; Granot, Er'el

    2010-01-01

    The interaction of pump and Stokes light in a Brillouin medium, where both beams are modulated, can be utilized for controlling the group velocity of the amplified Stokes (or depleted pump). The dependence of the group velocity for this mutually-modulated cross-gain modulation (MMXGM) technique on the Brillouin gain parameter is studied. A sharp transition to slow light occurs in the G 1 α/β≈1 regime, where G 1 is the Brillouin gain parameter, and α and β are the pump and Stokes modulation indices, respectively. A comparison of MMXGM slow light to the Brillouin dispersion-based slow-light technique reveals the fundamental differences between them. The formation of higher harmonics of the modulation frequency is also discussed. The theoretical predictions are experimentally corroborated and potential applications in fiber-based sensing and interferometry are discussed

  8. Slow Orbit Feedback at the ALS Using Matlab

    International Nuclear Information System (INIS)

    Portmann, G.

    1999-01-01

    The third generation Advanced Light Source (ALS) produces extremely bright and finely focused photon beams using undulatory, wigglers, and bend magnets. In order to position the photon beams accurately, a slow global orbit feedback system has been developed. The dominant causes of orbit motion at the ALS are temperature variation and insertion device motion. This type of motion can be removed using slow global orbit feedback with a data rate of a few Hertz. The remaining orbit motion in the ALS is only 1-3 micron rms. Slow orbit feedback does not require high computational throughput. At the ALS, the global orbit feedback algorithm, based on the singular valued decomposition method, is coded in MATLAB and runs on a control room workstation. Using the MATLAB environment to develop, test, and run the storage ring control algorithms has proven to be a fast and efficient way to operate the ALS

  9. Computation of saddle-type slow manifolds using iterative methods

    DEFF Research Database (Denmark)

    Kristiansen, Kristian Uldall

    2015-01-01

    with respect to , appropriate estimates are directly attainable using the method of this paper. The method is applied to several examples, including a model for a pair of neurons coupled by reciprocal inhibition with two slow and two fast variables, and the computation of homoclinic connections in the Fitz......This paper presents an alternative approach for the computation of trajectory segments on slow manifolds of saddle type. This approach is based on iterative methods rather than collocation-type methods. Compared to collocation methods, which require mesh refinements to ensure uniform convergence...

  10. Experimental studies of heavy-ion slowing down in matter

    International Nuclear Information System (INIS)

    Geissel, H.; Weick, H.; Scheidenberger, C.; Bimbot, R.; Gardes, D.

    2002-08-01

    Measurements of heavy-ion slowing down in matter differ in many aspects from experiments with light particles like protons and α-particles. An overview of the special experimental requirements, methods, data analysis and interpretation is presented for heavy-ion stopping powers, energy- and angular-straggling and ranges in the energy domain from keV/u up to GeV/u. Characteristic experimental results are presented and compared with theory and semiempirical predictions. New applications are outlined, which represent a challenge to continuously improve the knowledge of heavy-ion slowing down. (orig.)

  11. Low, slow, small target recognition based on spatial vision network

    Science.gov (United States)

    Cheng, Zhao; Guo, Pei; Qi, Xin

    2018-03-01

    Traditional photoelectric monitoring is monitored using a large number of identical cameras. In order to ensure the full coverage of the monitoring area, this monitoring method uses more cameras, which leads to more monitoring and repetition areas, and higher costs, resulting in more waste. In order to reduce the monitoring cost and solve the difficult problem of finding, identifying and tracking a low altitude, slow speed and small target, this paper presents spatial vision network for low-slow-small targets recognition. Based on camera imaging principle and monitoring model, spatial vision network is modeled and optimized. Simulation experiment results demonstrate that the proposed method has good performance.

  12. Pulsed neutron method for diffusion, slowing down, and reactivity measurements

    International Nuclear Information System (INIS)

    Sjoestrand, N.G.

    1985-01-01

    An outline is given on the principles of the pulsed neutron method for the determination of thermal neutron diffusion parameters, for slowing-down time measurements, and for reactivity determinations. The historical development is sketched from the breakthrough in the middle of the nineteen fifties and the usefulness and limitations of the method are discussed. The importance for the present understanding of neutron slowing-down, thermalization and diffusion are point out. Examples are given of its recent use for e.g. absorption cross section measurements and for the study of the properties of heterogeneous systems

  13. Solution of neutron slowing down equation including multiple inelastic scattering

    International Nuclear Information System (INIS)

    El-Wakil, S.A.; Saad, A.E.

    1977-01-01

    The present work is devoted the presentation of an analytical method for the calculation of elastically and inelastically slowed down neutrons in an infinite non absorbing homogeneous medium. On the basis of the Central limit theory (CLT) and the integral transform technique the slowing down equation including inelastic scattering in terms of the Green function of elastic scattering is solved. The Green function is decomposed according to the number of collisions. A formula for the flux at any lethargy O (u) after any number of collisions is derived. An equation for the asymptotic flux is also obtained

  14. Wide-band slow-wave systems simulation and applications

    CERN Document Server

    Staras, Stanislovas

    2012-01-01

    The field of electromagnetics has seen considerable advances in recent years, based on the wide applications of numerical methods for investigating electromagnetic fields, microwaves, and other devices. Wide-Band Slow-Wave Systems: Simulation and Applications presents new technical solutions and research results for the analysis, synthesis, and design of slow-wave structures for modern electronic devices with super-wide pass-bands. It makes available, for the first time in English, significant research from the past 20 years that was previously published only in Russian and Lithuanian. The aut

  15. Efficiency evaluation of slow extraction from the synchrotron

    International Nuclear Information System (INIS)

    Kazarinov, N.Yu.; Mikhajlov, V.A.

    1986-01-01

    Analytical calculation of slow extraction of the beam out of the JINR synchrotron is made. The formulae for evaluation of the sextupole amplitudes and phases, quadrupole lens gradient range are obtained, the connection with circulated and extracted beam parameters is shown. The formulae for calculating optimal position of the septum-magnet or electrostatic septum are presented. On this basis the formula for estimating the efficiency of beam slow extraction out of the synchrotron is obtained under assumption that in the septum region during the extraction a quasistationary distribution of the beam density occurs

  16. Consumption of polyphenol plants may slow aging and associated diseases.

    Science.gov (United States)

    Uysal, Utku; Seremet, Sila; Lamping, Jeffrey W; Adams, Jerome M; Liu, Deede Y; Swerdlow, Russell H; Aires, Daniel J

    2013-01-01

    Slowing aging is a widely shared goal. Plant-derived polyphenols, which are found in commonly consumed food plants such as tea, cocoa, blueberry and grape, have been proposed to have many health benefits, including slowing aging. In-vivo studies have demonstrated the lifespan-extending ability of six polyphenol-containing plants. These include five widely consumed foods (tea, blueberry, cocoa, apple, pomegranate) and a flower commonly used as a folk medicine (betony). These and multiple other plant polyphenols have been shown to have beneficial effects on aging-associated changes across a variety of organisms from worm and fly to rodent and human.

  17. On the role of the second coding exon of the HIV-1 Tat protein in virus replication and MHC class I downregulation

    NARCIS (Netherlands)

    Verhoef, K.; Bauer, M.; Meyerhans, A.; Berkhout, B.

    1998-01-01

    Tat is an essential protein of human immunodeficiency virus type 1 (HIV-1) and activates transcription from the viral long terminal repeat (LTR) promoter. The tat gene is composed of two coding exons of which the first, corresponding to the N-terminal 72 amino acid residues, has been reported to be

  18. Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease

    Directory of Open Access Journals (Sweden)

    Erik van der Wal

    2017-06-01

    Full Text Available The most common variant causing Pompe disease is c.-32-13T>G (IVS1 in the acid α-glucosidase (GAA gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA-based AONs. This resulted in the identification of a splicing regulatory element in GAA intron 1. We designed phosphorodiamidate morpholino oligomer-based AONs to this element, and these promoted exon 2 inclusion and enhanced GAA enzyme activity to levels above the disease threshold. These results indicate that the common IVS1 GAA splicing variant in Pompe disease is subject to negative regulation, and inhibition of a splicing regulatory element using AONs is able to restore canonical GAA splicing and endogenous GAA enzyme activity.

  19. JAK2 V617F, MPL W515L and JAK2 Exon 12 Mutations in Chinese Patients with Primary Myelofibrosis.

    Science.gov (United States)

    Xia, Jun; Lu, Mi-Ze; Jiang, Yuan-Qiang; Yang, Guo-Hua; Zhuang, Yun; Sun, Hong-Li; Shen, Yun-Feng

    2012-03-01

    JAK2 V617F, MPL W515L and JAK2 exon 12 mutations are novel acquired mutations that induce constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD). The discovery of these mutations provides novel mechanism for activation of signal transduction in hematopoietic malignancies. This research was to investigate their prevalence in Chinese patients with primary myelofibrosis (PMF). We introduced allele-specific PCR (AS-PCR) combined with sequence analysis to simultaneously screen JAK2 V617F, MPL W515L and JAK2 exon 12 mutations in 30 patients with PMF. Fifteen PMF patients (50.0%) carried JAK2 V617F mutation, and only two JAK2 V617F-negative patients (6.7%) harbored MPL W515L mutation. None had JAK2 exon 12 mutations. Furthermore, these three mutations were not detected in 50 healthy controls. MPL W515L and JAK2 V617F mutations existed in PMF patients but JAK2 exon 12 mutations not. JAK2 V617F and MPL W515L and mutations might contribute to the primary molecular pathogenesis in patients with PMF.

  20. Brief report: Afatinib and cetuximab in four patients with EGFR exon 20 insertion positive advanced non-small-cell lung cancer.

    Science.gov (United States)

    van Veggel, Bianca; de Langen, Adrianus J; Hashemi, Sayed; Monkhorst, Kim; Heideman, Daniëlle A M; Thunnissen, Erik; Smit, Egbert F

    2018-04-24

    Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-9% of EGFR mutated non-small-cell lung cancer (NSCLC). Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. Four patients with EGFR exon 20 insertion positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250-500 mg/m 2 every two weeks. All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n=4) and EGFR TKI (n=2). Three out of four patients showed a partial response according to RECIST 1.1. Median progression-free survival was 5.4 months (95% confidence interval 0.0 - 14.2 months; range 2.7 - 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients. Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion positive NSCLC. Copyright © 2018. Published by Elsevier Inc.

  1. Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome.

    Science.gov (United States)

    Krawitz, Peter M; Schiska, Daniela; Krüger, Ulrike; Appelt, Sandra; Heinrich, Verena; Parkhomchuk, Dmitri; Timmermann, Bernd; Millan, Jose M; Robinson, Peter N; Mundlos, Stefan; Hecht, Jochen; Gross, Manfred

    2014-09-01

    Usher syndrome is an autosomal recessive disorder characterized both by deafness and blindness. For the three clinical subtypes of Usher syndrome causal mutations in altogether 12 genes and a modifier gene have been identified. Due to the genetic heterogeneity of Usher syndrome, the molecular analysis is predestined for a comprehensive and parallelized analysis of all known genes by next-generation sequencing (NGS) approaches. We describe here the targeted enrichment and deep sequencing for exons of Usher genes and compare the costs and workload of this approach compared to Sanger sequencing. We also present a bioinformatics analysis pipeline that allows us to detect single-nucleotide variants, short insertions and deletions, as well as copy number variations of one or more exons on the same sequence data. Additionally, we present a flexible in silico gene panel for the analysis of sequence variants, in which newly identified genes can easily be included. We applied this approach to a cohort of 44 Usher patients and detected biallelic pathogenic mutations in 35 individuals and monoallelic mutations in eight individuals of our cohort. Thirty-nine of the sequence variants, including two heterozygous deletions comprising several exons of USH2A, have not been reported so far. Our NGS-based approach allowed us to assess single-nucleotide variants, small indels, and whole exon deletions in a single test. The described diagnostic approach is fast and cost-effective with a high molecular diagnostic yield.

  2. Alzheimer's disease presenilin-1 exon 9 deletion and L250S mutations sensitize SH-SY5Y neuroblastoma cells to hyperosmotic stress-induced apoptosis

    DEFF Research Database (Denmark)

    Tanii, H; Ankarcrona, M; Flood, F

    2000-01-01

    . In the present study, we determined whether PS1 mutations also sensitize cells to hyperosmotic stress-induced apoptosis. For this, we established SH-SY5Y neuroblastoma cell lines stably transfected with wild-type PS1 or either the PS1 exon 9 deletion (deltaE9) or PS1 L250S mutants. Cultured cells were exposed...

  3. Evolution of EF-hand calcium-modulated proteins. IV. Exon shuffling did not determine the domain compositions of EF-hand proteins

    Science.gov (United States)

    Kretsinger, R. H.; Nakayama, S.

    1993-01-01

    In the previous three reports in this series we demonstrated that the EF-hand family of proteins evolved by a complex pattern of gene duplication, transposition, and splicing. The dendrograms based on exon sequences are nearly identical to those based on protein sequences for troponin C, the essential light chain myosin, the regulatory light chain, and calpain. This validates both the computational methods and the dendrograms for these subfamilies. The proposal of congruence for calmodulin, troponin C, essential light chain, and regulatory light chain was confirmed. There are, however, significant differences in the calmodulin dendrograms computed from DNA and from protein sequences. In this study we find that introns are distributed throughout the EF-hand domain and the interdomain regions. Further, dendrograms based on intron type and distribution bear little resemblance to those based on protein or on DNA sequences. We conclude that introns are inserted, and probably deleted, with relatively high frequency. Further, in the EF-hand family exons do not correspond to structural domains and exon shuffling played little if any role in the evolution of this widely distributed homolog family. Calmodulin has had a turbulent evolution. Its dendrograms based on protein sequence, exon sequence, 3'-tail sequence, intron sequences, and intron positions all show significant differences.

  4. Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins.

    Science.gov (United States)

    Adato, A; Weil, D; Kalinski, H; Pel-Or, Y; Ayadi, H; Petit, C; Korostishevsky, M; Bonne-Tamir, B

    1997-10-01

    Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.

  5. Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non-small-cell lung cancer harboring EGFR exon 20 mutations

    Directory of Open Access Journals (Sweden)

    Chen D

    2016-07-01

    Full Text Available Dan Chen,1 Zhengbo Song,2 Guoping Cheng3 1Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 2Department of Chemotherapy, 3Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China Purpose: Subsets of non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR mutations carry uncommon subtypes. We evaluated the efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, and icotinib in patients with non-small-cell lung cancer carrying insertions and T790M and S768I mutations in EGFR exon 20. Patients and methods: Patients carrying EGFR exon 20 insertion/T790M/S768I mutations and treated with EGFR-TKIs were evaluated from 2005 to 2014 in Zhejiang Cancer Hospital. The efficacy was evaluated using the Kaplan–Meier method and compared with the log-rank test. Results: Sixty-two patients with exon 20 insertion/T790M/S768I mutations were enrolled. Mutations including exon 20 insertions and T790M and S768I mutations were observed in 29, 23, and ten patients, respectively. In total, the response rate and median progression-free survival (PFS were 8.1% and 2.1 months, respectively. Patients with S768I mutation manifested the longest median PFS (2.7 months, followed by those with T790M (2.4 months and exon 20 insertions (1.9 months; P=0.022. Patients with complex mutations show a better PFS than those with single mutations (2.7 months vs 1.9 months; P=0.034. Conclusion: First-generation EGFR-TKIs are less effective in patients with exon 20 uncommon mutations than in those with common mutations. Patients with complex mutations benefited more from first-generation EGFR-TKIs than those with single mutations. Keywords: non-small cell lung cancer, epidermal growth factor receptor, EGFR mutations, exon 20, tyrosine kinase inhibitor

  6. Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Bahram Jafar-Mohammadi

    2009-08-01

    Full Text Available There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8-10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY than mutations in exons 1-7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8-10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D.We performed targeted capillary resequencing of HNF1A exons 8-10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis ( or =1 affected sibling. PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9-24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected.We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.

  7. EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.

    Science.gov (United States)

    Kobayashi, Yoshihisa; Togashi, Yosuke; Yatabe, Yasushi; Mizuuchi, Hiroshi; Jangchul, Park; Kondo, Chiaki; Shimoji, Masaki; Sato, Katsuaki; Suda, Kenichi; Tomizawa, Kenji; Takemoto, Toshiki; Hida, Toyoaki; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-12-01

    Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined. Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature. Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. ©2015 American Association for Cancer Research.

  8. The molecular analysis of mutations in exons 4, 11 and 21 of the cystic fibrosis transmembrane conductance regulator (CFTR gene in cystic fibrosis patients in Kermanshah, Iran

    Directory of Open Access Journals (Sweden)

    Nasibe Karimi

    2017-03-01

    Full Text Available Introduction: Cystic fibrosis (CF is a common genetic disorder in white populations with an autosomal recessive pattern, caused by mutations in the CFTR gene. The frequency of more than 1950 various mutations reported in the CFTR gene significantly varies in different populations. ∆F508 is a common mutation in exon 10, which is first addressed in the molecular analysis of the disease. Other exons are required to be investigated owing to failing to identify mutations in the patients. The present study was conducted to investigate mutations in exons 4, 11 and 21 of the CFTR gene using the sequencing method in CF patients in Kermanshah province, Iran. Methods: The present descriptive study was conducted on all patients with CF presenting to the medical genetics center in Kermanshah in 2010-2011. After taking blood samples and extracting DNA using saturated NaCl solution, sequences of exons were amplified using PCR and sequenced for identifying mutations. Results: The frequency of mutations was found to be respectively 0, 0 and 5.5% in exon 11, 21 and 4. The D110H mutation was found to be homozygous in one subject and heterozygous in another. Moreover, the 4029A>G polymorphism (12.9% was found to be homozygous in two subjects and heterozygous in three others. Conclusion: The D110H mutation is recommended to be included in the screening programs of the study population. The results obtained support the effects of ethnic and geographical factors on the distribution of CF mutations.

  9. The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a JAK2 Exon 12 Mutation.

    Science.gov (United States)

    Ikeda, Kazuhiko; Ueda, Koki; Sano, Takahiro; Ogawa, Kazuei; Ikezoe, Takayuki; Hashimoto, Yuko; Morishita, Soji; Komatsu, Norio; Ohto, Hitoshi; Takeishi, Yasuchika

    2017-01-01

    Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L). This case suggests that ruxolitinib is a treatment option for post-PV MF in patients with thrombocytopenia or JAK2 exon 12 mutations.

  10. Observing and modeling the spectrum of a slow slip event: Constraints on the scaling of slow slip and tremor

    Science.gov (United States)

    Hawthorne, J. C.; Bartlow, N. M.; Ghosh, A.

    2017-12-01

    We estimate the normalized moment rate spectrum of a slow slip event in Cascadia and then attempt to reproduce it. Our goal is to further assess whether a single physical mechanism could govern slow slip and tremor events, with durations that span 6 orders of magnitude, so we construct the spectrum by parameterizing a large slow slip event as the sum of a number of subevents with various durations. The spectrum estimate uses data from three sources: the GPS-based slip inversion of Bartlow et al (2011), PBO borehole strain measurements, and beamforming-based tremor moment estimates of Ghosh et al (2009). We find that at periods shorter than 1 day, the moment rate power spectrum decays as frequencyn, where n is between 0.7 and 1.4 when measured from strain and between 1.2 and 1.4 when inferred from tremor. The spectrum appears roughly flat at periods of 1 to 10 days, as both the 1-day-period strain and tremor data and the 6-day-period slip inversion data imply a moment rate power of 0.02 times the the total moment squared. We demonstrate one way to reproduce this spectrum: by constructing the large-scale slow slip event as the sum of a series of subevents. The shortest of these subevents could be interpreted as VLFEs or even LFEs, while longer subevents might represent the aseismic slip that drives rapid tremor reverals, streaks, or rapid tremor migrations. We pick the subevent magnitudes from a Gutenberg-Richter distribution and place the events randomly throughout a 30-day interval. Then we assign each subevent a duration that scales with its moment to a specified power. Finally, we create a moment rate function for each subevent and sum all of the moment rates. We compute the summed slow slip moment rate spectra with two approaches: a time-domain numerical computation and a frequency-domain analytical summation. Several sets of subevent parameters can allow the constructed slow slip event to match the observed spectrum. One allowable set of parameters is of

  11. Textile slow-release systems with medical applications

    NARCIS (Netherlands)

    ten Breteler, M.R.; Nierstrasz, Vincent; Warmoeskerken, Marinus

    2002-01-01

    In the development of medical drug delivery systems, attention has been increasingly focused on slow- or controlled delivery systems in order to achieve an optimal therapeutic effect. Since the administration of drugs often requires a defined or minimum effective dosage in the human body, more

  12. Delineating psychomotor slowing from reduced processing speed in schizophrenia

    NARCIS (Netherlands)

    Morrens, M.; Hulstijn, W.; Matton, C.; Madani, Y.; Bouwel, L. van; Peuskens, J.; Sabbe, B.G.C.

    2008-01-01

    Introduction. Psychomotor slowing is an intrinsic feature of schizophrenia that is poorly delineated from generally reduced processing speed. Although the Symbol Digit Substitution Test (SDST) is widely used to assess psychomotor speed, the task also taps several higher-order cognitive processes.

  13. Investigating the critical slowing down of QCD simulations

    International Nuclear Information System (INIS)

    Schaefer, Stefan

    2009-12-01

    Simulations of QCD are known to suffer from serious critical slowing down towards the continuum limit. This is particularly prominent in the topological charge. We investigate the severeness of the problem in the range of lattice spacings used in contemporary simulations and propose a method to give more reliable error estimates. (orig.)

  14. Passive integrated circuits utilizing slow light in photonic crystal waveguides

    DEFF Research Database (Denmark)

    Lavrinenko, Andrei; Têtu, Amélie; Yang, Lirong

    2006-01-01

    We report thorough investigations of photonic crystal waveguide properties in the slow light regime. The transmission and the group index near the cutoff wavelengths oscillate in phase in close analogy with the ID photonic crystal behavior. The influence of having a finite number of periods...

  15. Slow Light by Two-Dimensional Photonic Crystal Waveguides

    International Nuclear Information System (INIS)

    Chao, Zhang; Yan, Huang; Xiao-Yu, Mao; Kai-Yu, Cui; Yi-Dong, Huang; Wei, Zhang; Jiang-De, Peng

    2009-01-01

    A simple and effective way to measure the group velocity of photonic crystal waveguides (PCWGs) is developed by using a fiber Mach–Zehnder interferometer. A PCWG with perfect air-bridge structure is fabricated and slow light with group velocity slower than c/80 is demonstrated. (fundamental areas of phenomenology (including applications))

  16. Reduction in slow intercompartmental clearance of urea during dialysis

    International Nuclear Information System (INIS)

    Bowsher, D.J.; Krejcie, T.C.; Avram, M.J.; Chow, M.J.; Del Greco, F.; Atkinson, A.J. Jr.

    1985-01-01

    The kinetics of urea and inulin were analyzed in five anesthetized dogs during sequential 2-hour periods before, during, and after hemodialysis. The distribution of both compounds after simultaneous intravenous injection was characterized by three-compartment models, and the total volumes of urea (0.66 +/- 0.05 L/kg) and inulin (0.19 +/- 0.01 L/kg) distribution were similar to expected values for total body water and extravascular space, respectively. Intercompartmental clearances calculated before dialysis were used to estimate blood flows to the fast and slow equilibrating compartments. In agreement with previous results, the sum of these flows was similar to cardiac output, averaging 101% of cardiac output measured before dialysis (range 72% to 135%). Dialysis was accompanied by reductions in the slow intercompartmental clearances of urea (81%) and inulin (47%), which reflected a 90% attenuation in blood flow supplying the slow equilibrating compartments. This was estimated to result in a 10% average reduction in the efficiency with which urea was removed by dialysis (range 2.0% to 16.4%). Mean arterial pressure fell by less than 5% during dialysis, but total peripheral resistance increased by 47% and cardiac output fell by 35%. In the postdialysis period, total peripheral resistance and cardiac output returned toward predialysis values, but blood flow to the slow equilibrating peripheral compartment was still reduced by 80%. These changes parallel activation of the renin-angiotensin system, but further studies are required to establish causality

  17. Spatial ability of slow learners based on Hubert Maier theory

    Science.gov (United States)

    Permatasari, I.; Pramudya, I.; Kusmayadi, T. A.

    2018-03-01

    Slow learners are children who have low learning achievement (under the average of normal children) in one or all of the academic field, but they are not classified as a mentally retarded children. Spatial ability developed according to age and level of knowledge possessed, both from the neighborhood and formal education. Analyzing the spatial ability of students is important for teachers, as an effort to improve the quality of learning for slow learners. Especially on the implementation of inclusion school which is developing in Indonesia. This research used a qualitative method and involved slow learner students as the subject. Based on the data analysis it was found the spatial ability of slow learners, there were: spatial perception, students were able to describe the other shape of object when its position changed; spatial visualisation, students were able to describe the materials that construct an object; mental rotation, students cannot describe the object being rotated; spatial relation, students cannot describe the relations of same objects; spatial orientation, students were able to describe object from the others perspective.

  18. Optical signal processing using slow and fast light technologies

    DEFF Research Database (Denmark)

    Capmany, J.; Sales, Salvador; Xue, Weiqi

    2009-01-01

    We review the theory of slow and fat light effects due to coherent population oscillations in semiconductor waveguides, which can be potentially applied in microwave photonic systems as a RF phase shifters. In order to satisfy the application requirement of 360 degrees RF phase shift at different...

  19. First Observation of the Slow Dragonet Callionymus aagilis Fricke ...

    African Journals Online (AJOL)

    The slow dragonet is a rare marine species of the family Callionymidae, and is endemic to Reunion and Mauritius and possibly the other Mascarene Islands. It is grey in colour with small round white spots aligned on the flanks and a honeycomb pattern on the cheeks and the snout (Fig. 1a-c). The apices of the first dorsal ...

  20. One Size Fits All? Slow Cortical Potentials Neurofeedback: A Review

    Science.gov (United States)

    Mayer, Kerstin; Wyckoff, Sarah N.; Strehl, Ute

    2013-01-01

    Objective: The intent of this manuscript was to review all published studies on slow cortical potentials (SCP) neurofeedback for the treatment of ADHD, with emphasis on neurophysiological rationale, study design, protocol, outcomes, and limitations. Method: For review, PubMed, MEDLINE, ERIC, and Google Scholar searches identified six studies and…