WorldWideScience

Sample records for antisense-induced exon skipping

  1. 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.

  2. Targeted exon skipping to correct exon duplications in the dystrophin gene

    National Research Council Canada - National Science Library

    Greer, Kane L; Lochmüller, Hanns; Flanigan, Kevin; Fletcher, Susan; Wilton, Steve D

    2014-01-01

    .... 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...

  3. 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 pr...... oligonucleotides (2'-O-methyl phosphorothioate (2OME-PS), phosphorodiamidate morpholino oligomer (PMO)) and peptide nucleic acid (PNA)....

  4. 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 int

  5. Therapeutic effects of exon skipping and losartan on skeletal muscle of mdx mice.

    Science.gov (United States)

    Lee, Eun-Joo; Kim, Ah-Young; Lee, Eun-Mi; Lee, Myeong-Mi; Min, Chang-Woo; Kang, Kyung-Ku; Park, Jin-Kyu; Hwang, Meeyul; Kwon, Soon-Hak; Tremblay, Jacques P; Jeong, Kyu-Shik

    2014-08-01

    Various attempts have been made to find treatments for Duchenne muscular dystrophy (DMD) patients. Exon skipping is one of the promising technologies for DMD treatment by restoring dystropin protein, which is one of the muscle components. It is well known that losartan, an angiotensin II type1 receptor blocker, promotes muscle regeneration and differentiation by lowering the level of transforming growth factor-beta1 signaling. In this study, we illustrated the combined effects of exon skipping and losartan on skeletal muscle of mdx mice. We supplied mdx mice with losartan for 2 weeks before exon skipping treatment. The losartan with the exon skipping group showed less expression of myf5 than the losartan treated group. Also the losartan with exon skipping group recovered normal muscle architecture, in contrast to the losartan group which still showed many central nuclei. However, the exon skipping efficiency and the restoration of dystrophin protein were lower in the losartan with exon skipping group compared to the exon skipping group. We reveal that losartan promotes muscle regeneration and shortens the time taken to restore normal muscle structure when combined with exon skipping. However, combined treatment of exon skipping and losartan decreases the restoration of dystrophin protein meaning decrease of exon skipping efficiency.

  6. Antisense-mediated exon skipping to reframe transcripts.

    Science.gov (United States)

    Turczynski, Sandrina; Titeux, Matthias; Pironon, Nathalie; Hovnanian, Alain

    2012-01-01

    Numerous genetic disorders are caused by loss-of-function mutations that disrupt the open reading frame of the gene either by nonsense or by frameshift (insertion, deletion, indel, or splicing) mutations. Most of the time, the result is the absence of functional protein synthesis due to mRNA degradation by nonsense-mediated mRNA decay, or rapid degradation of a truncated protein. Antisense-based splicing modulation is a powerful tool that has the potential to treat genetic disorders by restoring the open reading frame through selective removal of the mutated exon, or by restoring correct splicing.We have developed this approach for a severe genetic skin disorder, recessive dystrophic epidermolysis bullosa, caused by mutations in the COL7A1 gene encoding type VII collagen. This gene is particularly suited for exon-skipping approaches due to its unique genomic structure. It is composed of 118 exons, 83 of which are in frame. Moreover, these exons encode a single repetitive collagenous domain.Using this gene as an example, we describe general methods that demonstrate the feasibility and efficacy of the antisense-mediated exon-skipping strategy to reframe transcripts.

  7. Variants affecting exon skipping contribute to complex traits.

    Directory of Open Access Journals (Sweden)

    Younghee Lee

    Full Text Available DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1 experimentally validate our in silico predictions of skipped exons and 2 characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

  8. Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy.

    Science.gov (United States)

    Miskew Nichols, Bailey; Aoki, Yoshitsugu; Kuraoka, Mutsuki; Lee, Joshua J A; Takeda, Shin'ichi; Yokota, Toshifumi

    2016-05-24

    Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic diseases worldwide, caused by mutations in the dystrophin (DMD) gene. Exon skipping employs short DNA/RNA-like molecules called antisense oligonucleotides (AONs) that restore the reading frame and produce shorter but functional proteins. However, exon skipping therapy faces two major hurdles: limited applicability (up to only 13% of patients can be treated with a single AON drug), and uncertain function of truncated proteins. These issues were addressed with a cocktail AON approach. While approximately 70% of DMD patients can be treated by single exon skipping (all exons combined), one could potentially treat more than 90% of DMD patients if multiple exon skipping using cocktail antisense drugs can be realized. The canine X-linked muscular dystrophy (CXMD) dog model, whose phenotype is more similar to human DMD patients, was used to test the systemic efficacy and safety of multi-exon skipping of exons 6 and 8. The CXMD dog model harbors a splice site mutation in intron 6, leading to a lack of exon 7 in dystrophin mRNA. To restore the reading frame in CXMD requires multi-exon skipping of exons 6 and 8; therefore, CXMD is a good middle-sized animal model for testing the efficacy and safety of multi-exon skipping. In the current study, a cocktail of antisense morpholinos targeting exon 6 and exon 8 was designed and it restored dystrophin expression in body-wide skeletal muscles. Methods for transfection/injection of cocktail oligos and evaluation of the efficacy and safety of multi-exon skipping in the CXMD dog model are presented.

  9. Antisense oligonucleotide induced exon skipping and the dystrophin gene transcript: cocktails and chemistries

    Directory of Open Access Journals (Sweden)

    Fletcher Sue

    2007-07-01

    Full Text Available Abstract Background Antisense oligonucleotides (AOs can interfere with exon recognition and intron removal during pre-mRNA processing, and induce excision of a targeted exon from the mature gene transcript. AOs have been used in vitro and in vivo to redirect dystrophin pre-mRNA processing in human and animal cells. Targeted exon skipping of selected exons in the dystrophin gene transcript can remove nonsense or frame-shifting mutations that would otherwise have lead to Duchenne Muscular Dystrophy, the most common childhood form of muscle wasting. Results Although many dystrophin exons can be excised using a single AO, several exons require two motifs to be masked for efficient or specific exon skipping. Some AOs were inactive when applied individually, yet pronounced exon excision was induced in transfected cells when the AOs were used in select combinations, clearly indicating synergistic rather than cumulative effects on splicing. The necessity for AO cocktails to induce efficient exon removal was observed with 2 different chemistries, 2'-O-methyl modified bases on a phosphorothioate backbone and phosphorodiamidate morpholino oligomers. Similarly, other trends in exon skipping, as a consequence of 2'-O-methyl AO action, such as removal of additional flanking exons or variations in exon skipping efficiency with overlapping AOs, were also seen when the corresponding sequences were prepared as phosphorodiamidate morpholino oligomers. Conclusion The combination of 2 AOs, directed at appropriate motifs in target exons was found to induce very efficient targeted exon skipping during processing of the dystrophin pre-mRNA. This combinatorial effect is clearly synergistic and is not influenced by the chemistry of the AOs used to induce exon excision. A hierarchy in exon skipping efficiency, observed with overlapping AOs composed of 2'-O-methyl modified bases, was also observed when these same sequences were evaluated as phosphorodiamidate morpholino

  10. Evidence for association of multi-exon skipping events with tumors

    Institute of Scientific and Technical Information of China (English)

    Jianning BI; Tao PENG; Yanda LI

    2008-01-01

    Alternative splicing(AS)has been shown to be frequently present in human tumors.Specifically,it has been observed in some experimental studies that multi-exon skipping(MES)events often appear in tumorous tissues.Prompted by this observation,we conducted a genomewide analysis of MES events to investigate their association with tumors.The results show that MES events are more likely associated with tumors than single-exon skipping (SES) and the degree of association increases with the number of skipped exons.Furthermore,MES events are found to be less conserved than their SES counterparts,which provides additional evidence for our results because disease-associated AS events should be eliminated during evolution.Interestingly,these differences still existed even after comparison Of MES and SES events with similarlength skipped regions.These results demonstrate that MES events mav be associated with tumors and suggest that MES isoforms might be useful in cancer diagnosis.

  11. Becker muscular dystrophy patients with deletions around exon 51; a promising outlook for exon skipping therapy in Duchenne patients.

    NARCIS (Netherlands)

    Helderman-van den Enden, A.T.; Straathof, C.S.; Aartsma-Rus, A.; Dunnen, J.T. den; Verbist, B.M.; Bakker, E.; Verschuuren, J.J.; Ginjaar, H.B.

    2010-01-01

    Theoretically, 13% of patients with Duchenne muscular dystrophy may benefit from antisense-mediated skipping of exon 51 to restore the reading frame, which results in the production of a shortened dystrophin protein. We give a detailed description with longitudinal follow up of three patients with B

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

    Science.gov (United States)

    2016-10-01

    RyR antags for RNASeQ (18 months; 70% complete) We are in the process of prioritizing based on initial findings. As of now CDMD1003 exon 45...sequence analysis Subtask 1 - Optimize alternate splicing assay using exon capture and RNASeq (12 months, 80% complete). Additionally, we have...begun optimizing the exon capture and performed preliminary RNASeq experiments as described using exon capture. Subtask 2 - High depth RNASeQ on

  13. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept.

    Science.gov (United States)

    Rutten, Julie W; Dauwerse, Hans G; Peters, Dorien J M; Goldfarb, Andrew; Venselaar, Hanka; Haffner, Christof; van Ommen, Gert-Jan B; Aartsma-Rus, Annemieke M; Lesnik Oberstein, Saskia A J

    2016-04-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in the NOTCH3 gene. NOTCH3 mutations in CADASIL result in an uneven number of cysteine residues in one of the 34 epidermal growth factor like-repeat (EGFr) domains of the NOTCH3 protein. The consequence of an unpaired cysteine residue in an EGFr domain is an increased multimerization tendency of mutant NOTCH3, leading to toxic accumulation of the protein in the (cerebro)vasculature, and ultimately reduced cerebral blood flow, recurrent stroke and vascular dementia. There is no therapy to delay or alleviate symptoms in CADASIL. We hypothesized that exclusion of the mutant EGFr domain from NOTCH3 would abolish the detrimental effect of the unpaired cysteine and thus prevent toxic NOTCH3 accumulation and the negative cascade of events leading to CADASIL. To accomplish this NOTCH3 cysteine correction by EGFr domain exclusion, we used pre-mRNA antisense-mediated skipping of specific NOTCH3 exons. Selection of these exons was achieved using in silico studies and based on the criterion that skipping of a particular exon or exon pair would modulate the protein in such a way that the mutant EGFr domain is eliminated, without otherwise corrupting NOTCH3 structure and function. Remarkably, we found that this strategy closely mimics evolutionary events, where the elimination and fusion of NOTCH EGFr domains led to the generation of four functional NOTCH homologues. We modelled a selection of exon skip strategies using cDNA constructs and show that the skip proteins retain normal protein processing, can bind ligand and be activated by ligand. We then determined the technical feasibility of targeted NOTCH3 exon skipping, by designing antisense oligonucleotides targeting exons 2-3, 4-5 and 6, which together harbour the majority of distinct CADASIL-causing mutations

  14. 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.

  15. Selection preserves Ubiquitin Specific Protease 4 alternative exon skipping in therian mammals.

    Science.gov (United States)

    Vlasschaert, Caitlyn; Xia, Xuhua; Gray, Douglas A

    2016-02-02

    Ubiquitin specific protease 4 (USP4) is a highly networked deubiquitinating enzyme with reported roles in cancer, innate immunity and RNA splicing. In mammals it has two dominant isoforms arising from inclusion or skipping of exon 7 (E7). We evaluated two plausible mechanisms for the generation of these isoforms: (A) E7 skipping due to a long upstream intron and (B) E7 skipping due to inefficient 5' splice sites (5'SS) and/or branchpoint sites (BPS). We then assessed whether E7 alternative splicing is maintained by selective pressure or arose from genetic drift. Both transcript variants were generated from a USP4-E7 minigene construct with short flanking introns, an observation consistent with the second mechanism whereby differential splice signal strengths are the basis of E7 skipping. Optimization of the downstream 5'SS eliminated E7 skipping. Experimental validation of the correlation between 5'SS identity and exon skipping in vertebrates pinpointed the +6 site as the key splicing determinant. Therian mammals invariably display a 5'SS configuration favouring alternative splicing and the resulting isoforms have distinct subcellular localizations. We conclude that alternative splicing of mammalian USP4 is under selective maintenance and that long and short USP4 isoforms may target substrates in various cellular compartments.

  16. The silent mutation nucleotide 744 G --> A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Steffensen, Ane Y; Jønson, Lars

    2009-01-01

    Germ-line mutations in BRCA2 predispose to breast and ovarian cancer. Mutations are widespread throughout the gene and include disease-causing mutations as frameshift, nonsense, splicing mutations and large genomic rearrangements. However a large number of mutations, including missense, silent...... and intron variants are of unknown significance. Here, we describe the functional characterization of a silent mutation (nucleotide 744 G --> A/c.516 G --> A, Lys172Lys) in exon 6 of BRCA2 in a Danish family with breast and ovarian cancer. Exon trapping analysis showed that the mutation results in skipping...... of exon 6 and/or both exon 5 and 6, which was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. We therefore conclude that the BRCA2 silent mutation Lys172Lys is a disease-causing mutation....

  17. Refinement of antisense oligonucleotide mediated exon skipping as therapy for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Heemskerk, Johannes Antonius

    2011-01-01

    In recent years, modulation of mRNA has emerged as a promising therapeutic tool. For instance, in the field of neuromuscular disorders therapeutic strategies are being developed for several diseases, including antisense oligonucleotide (AON) mediated exon skipping for Duchenne Muscular Dystrophy (DM

  18. Refinement of antisense oligonucleotide mediated exon skipping as therapy for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Heemskerk, Johannes Antonius

    2011-01-01

    In recent years, modulation of mRNA has emerged as a promising therapeutic tool. For instance, in the field of neuromuscular disorders therapeutic strategies are being developed for several diseases, including antisense oligonucleotide (AON) mediated exon skipping for Duchenne Muscular Dystrophy (DM

  19. 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.

  20. Effective exon skipping and dystrophin restoration by 2'-o-methoxyethyl antisense oligonucleotide in dystrophin-deficient mice.

    Directory of Open Access Journals (Sweden)

    Lu Yang

    Full Text Available Antisense oligonucleotide (AO-mediated exon-skipping therapy is one of the most promising therapeutic strategies for Duchenne Muscular Dystrophy (DMD and several AO chemistries have been rigorously investigated. In this report, we focused on the effect of 2'-O-methoxyethyl oligonucleotides (MOE on exon skipping in cultured mdx myoblasts and mice. Efficient dose-dependent skipping of targeted exon 23 was achieved in myoblasts with MOE AOs of different lengths and backbone chemistries. Furthermore, we established that 25-mer MOE phosphorothioate (PS AOs provided the greatest exon-skipping efficacy. When compared with 2'O methyl phosphorothioate (2'OmePS AOs, 25-mer MOE (PS AOs also showed higher exon-skipping activity in vitro and in mdx mice after intramuscular injections. Characterization of uptake in vitro corroborated with exon-skipping results, suggesting that increased uptake of 25-mer MOE PS AOs might partly contribute to the difference in exon-skipping activity observed in vitro and in mdx mice. Our findings demonstrate the substantial potential for MOE PS AOs as an alternative option for the treatment of DMD.

  1. Antisense oligonucleotide-mediated exon skipping as a strategy to reduce proteolytic cleavage of ataxin-3.

    Science.gov (United States)

    Toonen, Lodewijk J A; Schmidt, Iris; Luijsterburg, Martijn S; van Attikum, Haico; van Roon-Mom, Willeke M C

    2016-10-12

    Spinocerebellar ataxia type-3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in the ataxin-3 protein. Cleavage of mutant ataxin-3 by proteolytic enzymes yields ataxin-3 fragments containing the polyglutamine stretch. These shorter ataxin-3 fragments are thought to be involved in SCA3 pathogenesis due to their increased cellular toxicity and their involvement in formation of the characteristic neuronal aggregates. As a strategy to prevent formation of toxic cleavage fragments, we investigated an antisense oligonucleotide-mediated modification of the ataxin-3 pre-mRNA through exon skipping of exon 8 and 9, resulting in the removal of a central 88 amino acid region of the ataxin-3 protein. This removed protein region contains several predicted cleavage sites and two ubiquitin-interacting motifs. In contrast to unmodified mutant ataxin-3, the internally truncated ataxin-3 protein did not give rise to potentially toxic cleavage fragments when incubated with caspases. In vitro experiments did not show cellular toxicity of the modified ataxin-3 protein. However, the modified protein was incapable of binding poly-ubiquitin chains, which may interfere with its normal deubiquitinating function. Low exon skipping efficiencies combined with reduction in important ataxin-3 protein functions suggest that skipping of exon 8 and 9 is not a viable therapeutic option for SCA3.

  2. Endogenous Multiple Exon Skipping and Back-Splicing at the DMD Mutation Hotspot

    Science.gov (United States)

    Suzuki, Hitoshi; Aoki, Yoshitsugu; Kameyama, Toshiki; Saito, Takashi; Masuda, Satoru; Tanihata, Jun; Nagata, Tetsuya; Mayeda, Akila; Takeda, Shin’ichi; Tsukahara, Toshifumi

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45–55 of the DMD gene, might improve patients’ symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. Thus, exon 45–55 skipping treatments for DMD have been proposed as a potential clinical cure. Herein, we detected the expression of endogenous exons 44–56 connected mRNA transcript of the DMD using total RNAs derived from human normal skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), and identified a total of eight types of MES products around the hotspot. Surprisingly, the 5′ splice sites of recently reported post-transcriptional introns (remaining introns after co-transcriptional splicing) act as splicing donor sites for MESs. We also tested exon combinations to generate DMD circular RNAs (circRNAs) and determined the preferential splice sites of back-splicing, which are involved not only in circRNA generation, but also in MESs. Our results fit the current circRNA-generation model, suggesting that upstream post-transcriptional introns trigger MES and generate circRNA because its existence is critical for the intra-intronic interaction or for extremely distal splicing. PMID:27754374

  3. 2′-O-Methyl RNA/Ethylene-Bridged Nucleic Acid Chimera Antisense Oligonucleotides to Induce Dystrophin Exon 45 Skipping

    Directory of Open Access Journals (Sweden)

    Tomoko Lee

    2017-02-01

    Full Text Available Duchenne muscular dystrophy (DMD is a fatal muscle-wasting disease characterized by dystrophin deficiency from mutations in the dystrophin gene. Antisense oligonucleotide (AO-mediated exon skipping targets restoration of the dystrophin reading frame to allow production of an internally deleted dystrophin protein with functional benefit for DMD patients who have out-of-frame deletions. After accelerated US approval of eteplirsen (Exondys 51, which targets dystrophin exon 51 for skipping, efforts are now focused on targeting other exons. For improved clinical benefits, this strategy requires more studies of the delivery method and modification of nucleic acids. We studied a nucleotide with a 2′-O,4′-C-ethylene-bridged nucleic acid (ENA, which shows high nuclease resistance and high affinity for complementary RNA strands. Here, we describe the process of developing a 2′-O-methyl RNA(2′-OMeRNA/ENA chimera AO to induce dystrophin exon 45 skipping. One 18-mer 2′-OMeRNA/ENA chimera (AO85 had the most potent activity for inducing exon 45 skipping in cultured myotubes. AO85 was administered to mdx mice without significant side effects. AO85 transfection into cultured myotubes from 13 DMD patients induced exon 45 skipping in all samples at different levels and dystrophin expression in 11 patients. These results suggest the possible efficacy of AO-mediated exon skipping changes in individual patients and highlight the 2′-OMeRNA/ENA chimera AO as a potential fundamental treatment for DMD.

  4. Wild-type mouse models to screen antisense oligonucleotides for exon-skipping efficacy in Duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Limin Cao

    Full Text Available A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD, a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs.

  5. Chemical and mechanistic toxicology evaluation of exon skipping phosphorodiamidate morpholino oligomers in mdx mice.

    Science.gov (United States)

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane; Nelson, Keith; Shrewsbury, And Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) designed to induce skipping of dystrophin exon 51 and restore its expression in patients with Duchenne muscular dystrophy (DMD). Preclinically, restoration of dystrophin in the dystrophic mdx mouse model requires skipping of exon 23, achieved with the mouse-specific PMO, AVI-4225. Herein, we report the potential toxicological consequences of exon skipping and dystrophin restoration in mdx mice using AVI-4225. We also evaluated the toxicological effects of AVI-4658 in both mdx and wild-type mice. In both studies, animals were dosed once weekly for 12 weeks up to the maximum feasible dose of 960 mg/kg per injection. Both AVI-4658 and AVI-4225 were well-tolerated at all doses. Findings in AVI-4225-treated animals were generally limited to mild renal tubular basophilia/vacuolation, without any significant changes in renal function and with evidence of reversing. No toxicity associated with the mechanism of action of AVI-4225 in a dystrophic animal was observed.

  6. 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.

  7. 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.

  8. 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

  9. TET2 exon 2 skipping is an independent favorable prognostic factor for cytogenetically normal acute myelogenous leukemia (AML): TET2 exon 2 skipping in AML.

    Science.gov (United States)

    Mohamed, Aminetou Mint; Balsat, Marie; Koering, Catherine; Maucort-Boulch, Delphine; Boissel, Nicolas; Payen-Gay, Lea; Cheok, Meyling; Mortada, Hussein; Auboeuf, Didier; Pinatel, Christiane; El-Hamri, Mohamed; Tigaud, Isabelle; Hayette, Sandrine; Dumontet, Charles; Cros, Emeline; Flandrin-Gresta, Pascale; Nibourel, Olivier; Preudhomme, Claude; Thomas, Xavier; Nicolini, Franck-Emmanuel; Solly, Françoise; Guyotat, Denis; Campos, Lydia; Michallet, Mauricette; Ceraulo, Antony; Mortreux, Franck; Wattel, Eric

    2017-01-16

    In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2S(high) patients were found to be younger than TET2(low) patients without a difference in the rate of complete remission. However, TET2E2S(high) patients exhibited a significantly lower CIR (p<10(-4)). TET2E2S and FLT3-ITD, but not age or NPM1 mutation status were independent prognostic factors for DFS and event-free survival (EFS), while TET2E2S was the sole prognostic factor that we identified for overall survival (OS). In both the intermediate-1 and favorable ELN genetic categories, TET2E2S remained significantly associated with prolonged survival. There was no correlation between TET2E2S status and outcomes in 34 additional AML patients who were unfit for IC. Therefore our results suggest that assessments of TET2 exon 2 splicing status might improve risk stratification in CN-AML patients treated with IC.

  10. Novel Cationic Carotenoid Lipids as Delivery Vectors of Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Vassilia Partali

    2012-01-01

    Full Text Available Duchenne Muscular Dystrophy (DMD is a common, inherited, incurable, fatal muscle wasting disease caused by deletions that disrupt the reading frame of the DMD gene such that no functional dystrophin protein is produced. Antisense oligonucleotide (AO-directed exon skipping restores the reading frame of the DMD gene, and truncated, yet functional dystrophin protein is expressed. The aim of this study was to assess the efficiency of two novel rigid, cationic carotenoid lipids, C30-20 and C20-20, in the delivery of a phosphorodiamidate morpholino (PMO AO, specifically designed for the targeted skipping of exon 45 of DMD mRNA in normal human skeletal muscle primary cells (hSkMCs. The cationic carotenoid lipid/PMO-AO lipoplexes yielded significant exon 45 skipping relative to a known commercial lipid, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC.

  11. Identification of a novel mutation in hereditary vitamin D resistant rickets causing exon skipping.

    Science.gov (United States)

    Hawa, N S; Cockerill, F J; Vadher, S; Hewison, M; Rut, A R; Pike, J W; O'Riordan, J L; Farrow, S M

    1996-07-01

    Hereditary vitamin D resistant rickets (HVDRR) is an autosomal recessive disorder resulting in target organ resistance to the actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). In many cases, this disorder has been shown to be due to mutations in the gene encoding vitamin D receptors (VDR). In a patient with characteristic features of this disorder, we investigated the functional defect and sequenced the coding region of the gene for mutations. Skin fibroblasts from patient and control were used to measure binding of 1,25(OH)2D3 and functional responses to the hormone. These cells were also used to prepare RNA from which cDNA was prepared and sequenced. Furthermore, genomic DNA was prepared from the fibroblasts and the intron/exon boundaries sequenced. A child with classic features of HVDRR with alopecia diagnosed as having rickets due to resistance to 1,25(OH)2D3. Nuclear association of 1,25(OH)2D3 was determined in patient and control cells and the functional response to 1,25(OH)2D3 was assessed by measurement of 25-hydroxyvitamin D-24-hydroxylase(24-hydroxylase) activity. VDR cDNA and genomic DNA prepared from patient and control cells were sequenced. Cells from the patient with HVDRR had undetectable amounts of VDR compared to control cells and did not show induction of 24-hydroxylase activity following treatment with 1,25(OH)2D3. Sequencing of the VDR coding region after RT-PCR of RNA revealed an absence of exon 4 in patient RNA which was not due to a deletion in genomic DNA but was caused by exon skipping during RNA processing. In addition, the deletion of exon 4 sequences from RNA leads to a frameshift in translation resulting in a premature stop codon. Amplification of genomic DNA around the intron/exon boundary of exon 4 revealed a point mutation in the 5' donor splice site of intron 4. In this study, we have identified a novel mutation in the gene for vitamin D receptors in a patient with the characteristic phenotype of hereditary vitamin D resistant

  12. 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.

  13. Digital Droplet PCR for the Absolute Quantification of Exon Skipping Induced by Antisense Oligonucleotides in (Pre-)Clinical Development for Duchenne Muscular Dystrophy

    Science.gov (United States)

    Verheul, Ruurd C.; van Deutekom, Judith C. T.; Datson, Nicole A.

    2016-01-01

    Antisense oligonucleotides (AONs) in clinical development for Duchenne muscular dystrophy (DMD) aim to induce skipping of a specific exon of the dystrophin transcript during pre-mRNA splicing. This results in restoration of the open reading frame and consequently synthesis of a dystrophin protein with a shorter yet functional central rod domain. To monitor the molecular therapeutic effect of exon skip-inducing AONs in clinical studies, accurate quantification of pre- and post-treatment exon skip levels is required. With the recent introduction of 3rd generation digital droplet PCR (ddPCR), a state-of-the-art technology became available which allows absolute quantification of transcript copy numbers with and without specific exon skip with high precision, sensitivity and reproducibility. Using Taqman assays with probes targeting specific exon-exon junctions, we here demonstrate that ddPCR reproducibly quantified cDNA fragments with and without exon 51 of the DMD gene over a 4-log dynamic range. In a comparison of conventional nested PCR, qPCR and ddPCR using cDNA constructs with and without exon 51 mixed in different molar ratios using, ddPCR quantification came closest to the expected outcome over the full range of ratios (0–100%), while qPCR and in particular nested PCR overestimated the relative percentage of the construct lacking exon 51. Highest accuracy was similarly obtained with ddPCR in DMD patient-derived muscle cells treated with an AON inducing exon 51 skipping. We therefore recommend implementation of ddPCR for quantification of exon skip efficiencies of AONs in (pre)clinical development for DMD. PMID:27612288

  14. 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.

  15. Cellular trafficking determines the exon skipping activity of Pip6a-PMO in mdx skeletal and cardiac muscle cells.

    Science.gov (United States)

    Lehto, Taavi; Castillo Alvarez, Alejandra; Gauck, Sarah; Gait, Michael J; Coursindel, Thibault; Wood, Matthew J A; Lebleu, Bernard; Boisguerin, Prisca

    2014-03-01

    Cell-penetrating peptide-mediated delivery of phosphorodiamidate morpholino oligomers (PMOs) has shown great promise for exon-skipping therapy of Duchenne Muscular Dystrophy (DMD). Pip6a-PMO, a recently developed conjugate, is particularly efficient in a murine DMD model, although mechanisms responsible for its increased biological activity have not been studied. Here, we evaluate the cellular trafficking and the biological activity of Pip6a-PMO in skeletal muscle cells and primary cardiomyocytes. Our results indicate that Pip6a-PMO is taken up in the skeletal muscle cells by an energy- and caveolae-mediated endocytosis. Interestingly, its cellular distribution is different in undifferentiated and differentiated skeletal muscle cells (vesicular versus nuclear). Likewise, Pip6a-PMO mainly accumulates in cytoplasmic vesicles in primary cardiomyocytes, in which clathrin-mediated endocytosis seems to be the pre-dominant uptake pathway. These differences in cellular trafficking correspond well with the exon-skipping data, with higher activity in myotubes than in myoblasts or cardiomyocytes. These differences in cellular trafficking thus provide a possible mechanistic explanation for the variations in exon-skipping activity and restoration of dystrophin protein in heart muscle compared with skeletal muscle tissues in DMD models. Overall, Pip6a-PMO appears as the most efficient conjugate to date (low nanomolar EC50), even if limitations remain from endosomal escape.

  16. Polyquaternium-mediated delivery of morpholino oligonucleotides for exon-skipping in vitro and in mdx mice.

    Science.gov (United States)

    Wang, Mingxing; Wu, Bo; Shah, Sapana N; Lu, Peijuan; Lu, Qilong

    2017-11-01

    Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that Luviquat(TM) series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro. Significant enhancement in skipping dystrophin exon 23 has also been achieved with PQ-3 up to seven-fold when compared to PMO alone in mdx mice. Cytotoxicity of the PQs was lower than Endoporter and PEI 25 K in vitro and muscle damage not clearly detected in vivo under the tested concentrations. These results together demonstrate that the optimization of PQ in molecular size, composition and distribution of positive charges is the key factor to achieve enhanced PMO exon-skipping efficiency. The higher efficiency and lower toxicity endow polyquaternium series as AO delivery enhancing agents for treating muscular dystrophy and other diseases.

  17. Peptide conjugation of 2'-O-methyl phosphorothioate antisense oligonucleotides enhances cardiac uptake and exon skipping in mdx mice.

    Science.gov (United States)

    Jirka, Silvana M G; Heemskerk, Hans; Tanganyika-de Winter, Christa L; Muilwijk, Daan; Pang, Kar Him; de Visser, Peter C; Janson, Anneke; Karnaoukh, Tatyana G; Vermue, Rick; 't Hoen, Peter A C; van Deutekom, Judith C T; Aguilera, Begoña; Aartsma-Rus, Annemieke

    2014-02-01

    Antisense oligonucleotide (AON)-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy that is currently being tested in various clinical trials. This approach is based on restoring the open reading frame of dystrophin transcripts resulting in shorter but partially functional dystrophin proteins as found in patients with Becker muscular dystrophy. After systemic administration, a large proportion of AONs ends up in the liver and kidneys. Therefore, enhancing AON uptake by skeletal and cardiac muscle would improve the AONs' therapeutic effect. For phosphorodiamidate morpholino oligomer, AONs use nonspecific positively charged cell penetrating peptides to enhance efficacy. However, this is challenging for negatively charged 2'-O-methyl phosphorothioate oligomer. Therefore, we screened a 7-mer phage display peptide library to identify muscle and heart homing peptides in vivo in the mdx mouse model and found a promising candidate peptide capable of binding muscle cells in vitro and in vivo. Upon systemic administration in dystrophic mdx mice, conjugation of a 2'-O-methyl phosphorothioate AON to this peptide indeed improved uptake in skeletal and cardiac muscle, and resulted in higher exon skipping levels with a significant difference in heart and diaphragm. Based on these results, peptide conjugation represents an interesting strategy to enhance the therapeutic effect of exon skipping with 2'-O-methyl phosphorothioate AONs for Duchenne muscular dystrophy.

  18. Aminoacylase I deficiency due to ACY1 mRNA exon skipping.

    Science.gov (United States)

    Ferri, L; Funghini, S; Fioravanti, A; Biondi, E G; la Marca, G; Guerrini, R; Donati, M A; Morrone, A

    2014-10-01

    Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism of which less than 20 observations have been described. Patients exhibit urinary excretion of specific N-acetyl amino acids and manifest a heterogeneous clinical spectrum including intellectual disability, motor delay, seizures, moderate to severe mental retardation, absent speech, growth delay, muscular hypotonia and autistic features. Here, we report the case of ACY1 enzyme deficiency in a 6-year-old girl presenting severe intellectual disability, motor retardation, absence of spontaneous locomotor activity and severe speech delay. Urinary excretion of N-acetylated amino acids was present. Mutational analysis of ACY1 gene identified the new homozygous c.1001_1001+5del6 mutation, which alters the mRNA transcription leading to exon 13 skipping and inclusion of a premature stop codon (p.Lys308Glufs*7). A quantitative fluorescent multiplex-polymerase chain reaction (QFM-PCR) assay has been set up and confirmed homozygosity of the mutation in the patient's DNA. Biochemical analysis showed absence of ACY1 enzyme activity in the patient's fibroblasts. The structure of the mutated protein has been defined by homology modeling (HM). Our data endorse the hypothesis of a link between this inborn error of metabolism and the neurological manifestations observed in patients with ACY1 deficiency. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion.

    Science.gov (United States)

    Pajusalu, Sander; Talvik, Inga; Noormets, Klari; Talvik, Tiina; Põder, Haide; Joost, Kairit; Puusepp, Sanna; Piirsoo, Andres; Stenzel, Werner; Goebel, Hans H; Nikopensius, Tiit; Annilo, Tarmo; Nõukas, Margit; Metspalu, Andres; Õunap, Katrin; Reimand, Tiia

    2016-03-01

    Here we report on a case of MYH7-related myopathy in a boy with early onset of muscular weakness and delayed motor development in infancy. His most affected muscles were neck extensors showing a dropped head sign, proximal muscles of lower limbs with positive Gower's sign, and trunk muscles. Brain and spinal cord MRI scans, echocardiography, and laboratory analyses including creatine kinase and lactate did not reveal any abnormalities. Muscle histopathology showed fiber-type disproportion. Whole exome sequencing of the parents-offspring trio revealed a novel de novo c.5655G>A p.(Ala1885=) synonymous substitution of the last nucleotide in exon 38 of the MYH7 gene. Further RNA investigations proved the skipping of exon 38 (p.1854_1885del). This is a first report of an exon-skipping mutation in the MYH7 gene causing myopathy. This report broadens both the phenotypic and genotypic spectra of MYH7-related myopathies. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Synthesis of a Morpholino Nucleic Acid (MNA-Uridine Phosphoramidite, and Exon Skipping Using MNA/2′-O-Methyl Mixmer Antisense Oligonucleotide

    Directory of Open Access Journals (Sweden)

    Suxiang Chen

    2016-11-01

    Full Text Available In this study, we synthesised a morpholino nucleoside-uridine (MNA-U phosphoramidite and evaluated the potential of a MNA-modified antisense oligonucleotide (AO sequences to induce exon 23 skipping in mdx mouse myotubes in vitro towards extending the applicability of morpholino chemistry with other nucleotide monomers. We designed, synthesised, and compared exon skipping efficiencies of 20 mer MNA-modified 2′-O-methyl RNA mixmer AO on a phosphorothioate backbone (MNA/2′-OMePS to the corresponding fully modified 2′-O-methyl RNA AO (2′-OMePS as a control. Our results showed that the MNA/2′-OMePS efficiently induced exon 23 skipping. As expected, the 2′-OMePS AO control yielded efficient exon 23 skipping. Under the applied conditions, both the AOs showed minor products corresponding to exon 22/23 dual exon skipping in low yield. As these are very preliminary data, more detailed studies are necessary; however, based on the preliminary results, MNA nucleotides might be useful in constructing antisense oligonucleotides.

  1. A TALEN-Exon Skipping Design for a Bethlem Myopathy Model in Zebrafish.

    Directory of Open Access Journals (Sweden)

    Zlatko Radev

    Full Text Available Presently, human collagen VI-related diseases such as Ullrich congenital muscular dystrophy (UCMD and Bethlem myopathy (BM remain incurable, emphasizing the need to unravel their etiology and improve their treatments. In UCMD, symptom onset occurs early, and both diseases aggravate with ageing. In zebrafish fry, morpholinos reproduced early UCMD and BM symptoms but did not allow to study the late phenotype. Here, we produced the first zebrafish line with the human mutation frequently found in collagen VI-related disorders such as UCMD and BM. We used a transcription activator-like effector nuclease (TALEN to design the col6a1ama605003-line with a mutation within an essential splice donor site, in intron 14 of the col6a1 gene, which provoke an in-frame skipping of exon 14 in the processed mRNA. This mutation at a splice donor site is the first example of a template-independent modification of splicing induced in zebrafish using a targetable nuclease. This technique is readily expandable to other organisms and can be instrumental in other disease studies. Histological and ultrastructural analyzes of homozygous and heterozygous mutant fry and 3 months post-fertilization (mpf fish revealed co-dominantly inherited abnormal myofibers with disorganized myofibrils, enlarged sarcoplasmic reticulum, altered mitochondria and misaligned sarcomeres. Locomotion analyzes showed hypoxia-response behavior in 9 mpf col6a1 mutant unseen in 3 mpf fish. These symptoms worsened with ageing as described in patients with collagen VI deficiency. Thus, the col6a1ama605003-line is the first adult zebrafish model of collagen VI-related diseases; it will be instrumental both for basic research and drug discovery assays focusing on this type of disorders.

  2. A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxygenase gene (Hpd) causes skipping of the constitutive exon and hypertyrosinemia in mouse strain III

    Energy Technology Data Exchange (ETDEWEB)

    Endo, Fumio; Awata, Hisataka; Matsuda, Ichiro [Kumamoto Univ. (Japan)

    1995-01-01

    4-Hydroxyphenylpyruvic acid dioxygenase (HPD; EC 1.13.11.27) is an important enzyme in tyrosine catabolism in most organisms. Decreased activity of 4-hydroxyphenylpyruvic acid dioxygenase in the liver of mouse strain III is associated with tyrosinemia. We report a nucleotide substitution that generates a termination codon in exon 7 of the 4-hydroxyphenylpyruvic acid dioxygenase gene in III mice. This mutation is associated with partial exon skipping, and most of the mRNA lacks sequences corresponding to exon 7. The partial exon skipping apparently is the result of a nonsense mutation in the exon. Mouse strain III is a model for human tyrosinemia type 3 (McKusick 276710), and this train together with recently established models for tyrosinemia type 1 will facilitate studies of hereditary tyrosinemias.

  3. A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxygenase gene (Hpd) causes skipping of the constitutive exon and hypertyrosinemia in mouse strain III.

    Science.gov (United States)

    Endo, F; Awata, H; Katoh, H; Matsuda, I

    1995-01-01

    4-Hydroxyphenylpyruvic acid dioxygenase (HPD; EC 1.13.11.27) is an important enzyme in tyrosine catabolism in most organisms. Decreased activity of 4-hydroxyphenylpyruvic acid dioxygenase in the liver of mouse strain III is associated with tyrosinemia. We report a nucleotide substitution that generates a termination codon in exon 7 of the 4-hydroxyphenylpyruvic acid dioxygenase gene in III mice. This mutation is associated with partial exon skipping, and most of the mRNA lacks sequences corresponding to exon 7. The partial exon skipping apparently is the result of a nonsense mutation in the exon. Mouse strain III is a model for human tyrosinemia type 3 (McKusick 276710), and this strain together with recently established models for tyrosinemia type 1 will facilitate studies of hereditary tyrosinemias.

  4. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice.

    Science.gov (United States)

    Gedicke-Hornung, Christina; Behrens-Gawlik, Verena; Reischmann, Silke; Geertz, Birgit; Stimpel, Doreen; Weinberger, Florian; Schlossarek, Saskia; Précigout, Guillaume; Braren, Ingke; Eschenhagen, Thomas; Mearini, Giulia; Lorain, Stéphanie; Voit, Thomas; Dreyfus, Patrick A; Garcia, Luis; Carrier, Lucie

    2013-07-01

    Exon skipping mediated by antisense oligoribonucleotides (AON) is a promising therapeutic approach for genetic disorders, but has not yet been evaluated for cardiac diseases. We investigated the feasibility and efficacy of viral-mediated AON transfer in a Mybpc3-targeted knock-in (KI) mouse model of hypertrophic cardiomyopathy (HCM). KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs. We identified an alternative variant (Var-4) deleted of exons 5-6 in wild-type and KI mice. To enhance its expression and suppress aberrant mRNAs we designed AON-5 and AON-6 that mask splicing enhancer motifs in exons 5 and 6. AONs were inserted into modified U7 small nuclear RNA and packaged in adeno-associated virus (AAV-U7-AON-5+6). Transduction of cardiac myocytes or systemic administration of AAV-U7-AON-5+6 increased Var-4 mRNA/protein levels and reduced aberrant mRNAs. Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy. Although the therapeutic effect was transient and therefore requires optimization to be maintained over an extended period, this proof-of-concept study paves the way towards a causal therapy of HCM.

  5. 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.

  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

    Full Text Available BACKGROUND: 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". METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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. Exon skipping and Duchenne muscular dystrophy: Hope, hype and how feasible?

    Directory of Open Access Journals (Sweden)

    Wilton Steve

    2008-01-01

    Full Text Available Duchenne muscular dystrophy (DMD, the most common and serious form of childhood muscle wasting is generally caused by protein-truncating mutations in the large DMD gene. Specific removal of an exon from a defective DMD gene transcript has the potential to allow synthesis of a semi-functional dystrophin, thereby reducing the severity and presumably progression of muscle wasting. The efficacy of this treatment will vary greatly between the different mutations that preclude the synthesis of a functional dystrophin. Restoration of the reading frame from a large multi-exon genomic deletion, typically greater than 36 exons, may lead to synthesis of a protein with only partial function and limited clinical benefit, whereas excising a nonsense mutation in a redundant exon should generate a near normal dystrophin. A clinical trial has recently confirmed proof-of-principle that exclusion of Exon 51 from human dystrophin mRNAs, carrying frame-shifting deletions adjacent to this exon, results in dystrophin expression. No major side-effects after local administration of the antisense oligomer were reported. Additional trials are underway, targeting the same exon but using an oligomer of different backbone chemistry. If functional dystrophin synthesis is demonstrated, and safety issues are addressed, subsequent trials will involve systemic delivery. Great challenges are ahead, some technical; establishing an effective delivery regimen, some ethical; choosing subsequent targets for therapy, and others of an administrative and regulatory nature.

  8. Cationic polyelectrolyte-mediated delivery of antisense morpholino oligonucleotides for exon-skipping in vitro and in mdx mice.

    Science.gov (United States)

    Wang, Mingxing; Wu, Bo; Tucker, Jason D; Lu, Peijuan; Lu, Qilong

    2015-01-01

    In this study, we investigated a series of cationic polyelectrolytes (PEs) with different size and composition for their potential to improve delivery of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that the poly(diallyldimethylammonium chloride) (PDDAC) polymer series, especially PE-3 and PE-4, improves the delivery efficiency of PMO, comparable with Endoporter-mediated PMO delivery in vitro. The enhanced PMO delivery and targeting to dystrophin exon 23 was further observed in mdx mice, up to fourfold with the PE-4, compared with PMO alone. The cytotoxicity of the PEs was lower than that of Endoporter and polyethylenimine 25,000 Da in vitro, and was not clearly detected in muscle in vivo under the tested concentrations. Together, these results demonstrate that optimization of PE molecular size, composition, and distribution of cationic charge are key factors to achieve enhanced PMO exon-skipping efficiency. The increased efficiency and lower toxicity show this PDDAC series to be capable gene/antisense oligonucleotide delivery-enhancing agents for treating muscular dystrophy and other diseases.

  9. A case of Becker muscular dystrophy resulting from the skipping of four contiguous exons (71-74) of the dystrophin gene during mRNA maturation.

    Science.gov (United States)

    Patria, S Y; Alimsardjono, H; Nishio, H; Takeshima, Y; Nakamura, H; Matsuo, M

    1996-07-01

    The mutations in one-third of both Duchenne and Becker muscular dystrophy patients remain unknown because they do not involve gross rearrangements of the dystrophin gene. Here we report the first example of multiple exon skipping during the splicing of dystrophin mRNA precursor encoded by an apparently normal dystrophin gene. A 9-year-old Japanese boy exhibiting excessive fatigue and high serum creatine kinase activity was examined for dystrophinopathy. An immunohistochemical study of muscle tissue biopsy disclosed faint and discontinuous staining of the N-terminal and rod domains of dystrophin but no staining at all of the C-terminal domain of dystrophin. The dystrophin transcript from muscle tissue was analyzed by the reverse transcriptase polymerase chain reaction. An amplified product encompassing exons 67-79 of dystrophin cDNA was found to be smaller than that of the wild-type product. Sequence analysis of this fragment showed that the 3' end of exon 70 was directly connected to the 5' end of exon 75 and, thus, that exons 71-74 were completely absent. As a result, a truncated dystrophin protein lacking 110 amino acids from the C-terminal domain should result from translation of this truncated mRNA, and the patient was diagnosed as having Becker muscular dystrophy at the molecular level. Genomic DNA was analyzed to identify the cause of the disappearance of these exons. Every exon-encompassing region could be amplified from genomic DNA, indicating that the dystrophin gene is intact. Furthermore, sequencing of these amplified products did not disclose any particular nucleotide change that could be responsible for the multiple exon skipping observed. Considering that exons 71-74 are spliced out alternatively in some tissue-specific isoforms, to suppose that the alternative splicing machinery is present in the muscle tissue of the index case and that it is activated by an undetermined mechanism is reasonable. These results illustrate a novel genetic anomaly that

  10. Parallel synthesis of cell-penetrating peptide conjugates of PMO toward exon skipping enhancement in Duchenne muscular dystrophy.

    Science.gov (United States)

    O'Donovan, Liz; Okamoto, Itaru; Arzumanov, Andrey A; Williams, Donna L; Deuss, Peter; Gait, Michael J

    2015-02-01

    We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the SELection of PEPtide CONjugates (SELPEPCON) approach previously developed for parallel peptide-peptide nucleic acid (PNA) synthesis. However, these new methods allow for the utilization of commercial PMO as cargo with both C- and N-termini unfunctionalized. The synthetic methods involve conjugation in solution phase, followed by rapid purification via biotin-streptavidin immobilization and subsequent reductive release into solution, avoiding the need for painstaking high-performance liquid chromatography purifications. The synthesis methods were applied for screening of PMO conjugates of a 16-member library of variants of a 10-residue ApoE peptide, which was suggested for blood-brain barrier crossing. In this work the conjugate library was tested in an exon skipping assay using skeletal mouse mdx cells, a model of Duchene's muscular dystrophy where higher activity peptide-PMO conjugates were identified compared with the starting peptide-PMO. The results demonstrate the power of the parallel synthesis methods for increasing the speed of optimization of peptide sequences in conjugates of PMO for therapeutic screening.

  11. Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Δ48-50 DMD cells

    Science.gov (United States)

    De Angelis, Fernanda Gabriella; Sthandier, Olga; Berarducci, Barbara; Toso, Silvia; Galluzzi, Giuliana; Ricci, Enzo; Cossu, Giulio; Bozzoni, Irene

    2002-01-01

    Deletions and point mutations in the dystrophin gene cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. Because internal in-frame deletions in the protein produce only mild myopathic symptoms, it should be possible, by preventing the inclusion of specific mutated exon(s) in the mature dystrophin mRNA, to restore a partially corrected phenotype. Such control has been previously accomplished by the use of synthetic oligonucleotides; nevertheless, a significant drawback to this approach is caused by the fact that oligonucleotides would require periodic administrations. To circumvent this problem, we have produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. In this paper we show that antisense molecules against exon 51 splice junctions are able to direct skipping of this exon in the human DMD deletion 48–50 and to rescue dystrophin synthesis. We also show that the highest skipping activity was found when antisense constructs against the 5′ and 3′ splice sites are coexpressed in the same cell. PMID:12077324

  12. Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

    Directory of Open Access Journals (Sweden)

    Sirsi Shashank R

    2008-04-01

    Full Text Available Abstract Background Exon skipping oligonucleotides (ESOs of 2'O-Methyl (2'OMe and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD. However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine (PEI and poly(ethylene glycol (PEG are regarded as effective agents for enhanced delivery of nucleic acids in various applications. Results We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 μg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG or adsorbtion of colloidal gold (CG, respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3–60 μg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal

  13. Thousands of exon skipping events differentiate among splicing patterns in sixteen human tissues [v2; ref status: indexed, http://f1000r.es/2dl

    Directory of Open Access Journals (Sweden)

    Liliana Florea

    2013-11-01

    Full Text Available Alternative splicing is widely recognized for its roles in regulating genes and creating gene diversity. However, despite many efforts, the repertoire of gene splicing variation is still incompletely characterized, even in humans. Here we describe a new computational system, ASprofile, and its application to RNA-seq data from Illumina’s Human Body Map project (>2.5 billion reads.  Using the system, we identified putative alternative splicing events in 16 different human tissues, which provide a dynamic picture of splicing variation across the tissues. We detected 26,989 potential exon skipping events representing differences in splicing patterns among the tissues. A large proportion of the events (>60% were novel, involving new exons (~3000, new introns (~16000, or both. When tracing these events across the sixteen tissues, only a small number (4-7% appeared to be differentially expressed (‘switched’ between two tissues, while 30-45% showed little variation, and the remaining 50-65% were not present in one or both tissues compared.  Novel exon skipping events appeared to be slightly less variable than known events, but were more tissue-specific. Our study represents the first effort to build a comprehensive catalog of alternative splicing in normal human tissues from RNA-seq data, while providing insights into the role of alternative splicing in shaping tissue transcriptome differences. The catalog of events and the ASprofile software are freely available from the Zenodo repository (http://zenodo.org/record/7068; doi:10.5281/zenodo.7068 and from our web site http://ccb.jhu.edu/software/ASprofile.

  14. PNA-mediated modulation and redirection of Her-2 pre-mRNA splicing: specific skipping of erbB-2 exon 19 coding for the ATP catalytic domain

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Nielsen, Birgit N; Shiraishi, Takehiko;

    2010-01-01

    The Her-2 receptor coded for by the proto-oncogenic erbB-2 gene is a clinically validated target for treatment of a significant genetic subclass of breast cancers, and Her-2 is also overexpressed or mutated in a range of other cancers. In an approach to exploit antisense mediated splicing...... oligomers that specifically induce skipping of exon 19 as this exon is coding for the ATP catalytic domain of Her-2, and if expressed such truncated version of the Her-2 protein should be functionally inactive in a dominant negative fashion. Therefore, antisense compounds having efficient erbB-2 exon 19...

  15. Skipping of exons by premature termination of transcription and alternative splicing within intron-5 of the sheep SCF gene: a novel splice variant.

    Directory of Open Access Journals (Sweden)

    Siva Arumugam Saravanaperumal

    Full Text Available Stem cell factor (SCF is a growth factor, essential for haemopoiesis, mast cell development and melanogenesis. In the hematopoietic microenvironment (HM, SCF is produced either as a membrane-bound (- or soluble (+ forms. Skin expression of SCF stimulates melanocyte migration, proliferation, differentiation, and survival. We report for the first time, a novel mRNA splice variant of SCF from the skin of white merino sheep via cloning and sequencing. Reverse transcriptase (RT-PCR and molecular prediction revealed two different cDNA products of SCF. Full-length cDNA libraries were enriched by the method of rapid amplification of cDNA ends (RACE-PCR. Nucleotide sequencing and molecular prediction revealed that the primary 1519 base pair (bp cDNA encodes a precursor protein of 274 amino acids (aa, commonly known as 'soluble' isoform. In contrast, the shorter (835 and/or 725 bp cDNA was found to be a 'novel' mRNA splice variant. It contains an open reading frame (ORF corresponding to a truncated protein of 181 aa (vs 245 aa with an unique C-terminus lacking the primary proteolytic segment (28 aa right after the D(175G site which is necessary to produce 'soluble' form of SCF. This alternative splice (AS variant was explained by the complete nucleotide sequencing of splice junction covering exon 5-intron (5-exon 6 (948 bp with a premature termination codon (PTC whereby exons 6 to 9/10 are skipped (Cassette Exon, CE 6-9/10. We also demonstrated that the Northern blot analysis at transcript level is mediated via an intron-5 splicing event. Our data refine the structure of SCF gene; clarify the presence (+ and/or absence (- of primary proteolytic-cleavage site specific SCF splice variants. This work provides a basis for understanding the functional role and regulation of SCF in hair follicle melanogenesis in sheep beyond what was known in mice, humans and other mammals.

  16. A one base pair deletion in the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrier.

    Directory of Open Access Journals (Sweden)

    Anne Wöhlke

    2011-10-01

    Full Text Available Neuronal ceroid lipofuscinosis (NCL is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5-7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA 2 at 83.71-84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9. Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies.

  17. Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype

    Science.gov (United States)

    Pierson, Christopher R.; Dulin-Smith, Ashley N.; Durban, Ashley N.; Marshall, Morgan L.; Marshall, Jordan T.; Snyder, Andrew D.; Naiyer, Nada; Gladman, Jordan T.; Chandler, Dawn S.; Lawlor, Michael W.; Buj-Bello, Anna; Dowling, James J.; Beggs, Alan H.

    2012-01-01

    X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of certain preclinical therapeutics. Many MTM patients succumb early in life, but some have a more favorable prognosis. We used human genotype–phenotype correlation data to develop a myotubularin-deficient mouse model with a less severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early muscle atrophy prior to the onset of weakness at 2 months. The median survival period is 66 weeks. Histopathology shows small myofibers with centrally placed nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T base change induced exon 4 skipping in most mRNAs, leading to premature termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the mutation is present, which provides enough myotubularin activity to account for the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for phenotypic variability among human patients with MTM1 p.R69C mutations and establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less severe phenotype will expand the scope of testable preclinical therapies. PMID:22068590

  18. An Intronic SINE insertion in FAM161A that causes exon-skipping is associated with progressive retinal atrophy in Tibetan Spaniels and Tibetan Terriers.

    Directory of Open Access Journals (Sweden)

    Louise M Downs

    Full Text Available Progressive retinal atrophy (PRA in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 19 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s responsible have yet to be identified. Using genome-wide association with 22 Tibetan Spaniel PRA cases and 10 controls, we identified a novel PRA locus, PRA3, on CFA10 (p(raw = 2.01 × 10(-5, p(genome = 0.014, where a 3.8 Mb region was homozygous within 12 cases. Using targeted next generation sequencing, a short interspersed nuclear element insertion was identified near a splice acceptor site in an intron of a provocative gene, FAM161A. Analysis of mRNA from an affected dog revealed that the SINE causes exon skipping, resulting in a frame shift, leading to a downstream premature termination codon and possibly a truncated protein product. This mutation segregates with the disease in 22 out of 35 cases tested (63%. Of the PRA controls, none are homozygous for the mutation, 15% carry the mutation and 85% are homozygous wildtype. This mutation was also identified in Tibetan Terriers, although our results indicate that PRA is genetically heterogeneous in both Tibetan Spaniels and Tibetan Terriers.

  19. Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

    DEFF Research Database (Denmark)

    Madsen, Pia Pinholt; Kibaek, Maria; Roca, Xavier

    2006-01-01

    -causing in both families. Using a minigene approach, we show that the IVS3+3A>G mutation causes exon 3 skipping, despite the fact that it does not appear to disrupt the consensus sequence of the 5' splice site. Based on these results and numerous literature examples, we suggest that this type of mutation (IVS+3A...... of C5-carnitine in blood may indicate SBCADD, the disorder may be detected by MS/MS-based routine newborn screening. It is, therefore, important to gain more knowledge about the clinical presentation and the mutational spectrum of SBCADD. In the present study, we have studied two unrelated families....../MS currently lacks sensitivity in detecting SBCADD. Until now, seven mutations in the SBCAD gene have been reported, but only three have been tested experimentally. Here, we identify and characterize an IVS3+3A>G mutation (c.303+3A>G) in the SBCAD gene, and provide evidence that this mutation is disease...

  20. Exon-skipping strategy by ratio modulation between cytoprotective versus pro-apoptotic clusterin forms increased sensitivity of LNCaP to cell death.

    Directory of Open Access Journals (Sweden)

    Abdellatif Essabbani

    Full Text Available BACKGROUND: In prostate cancer the secreted form of clusterin (sCLU has been described as an anti-apoptotic protein whose expression is increased after therapeutic intervention, whereas, the nuclear protein form nCLU was reported to have pro-apoptotic properties. METHODOLOGY: In order to provide new therapeutic approaches targeting CLU, we developed a strategy based on exon skipping by using a lentiviral construct to preferentially induce the nuclear spliced form of the protein. The molecular construct was transduced in LNCaP cells for testing the modulation of sensitivity of the transduced cells to pro-apoptotic stress. RESULTS AND CONCLUSIONS: We showed an increase of nCLU/sCLU expression ratio in the prostate cancer cell line "LNCaP" after lentiviral vector-U7 nCLU transduction. Moreover, we showed a significant inhibition of cell proliferation in nCLU-U7 LNCaP cells after treatment with cisplatin and after exposure to ionizing radiation compared to control cells. Finally, we showed that nCLU-U7 LNCaP cells exposure to UV-C significantly reduced an increase of cell death compared to control. Finally, we showed that modulating nCLU expression had profound impact on Ku70/Bax interaction as well as Rad17 expression which could be a key mechanism in sensitizing cells to cell death. In conclusion, this is the first report showing that increasing of nCLU/sCLU expression ratio by using an "on demand alternative splicing" strategy successfully increased sensitivity to radiotherapy and chemotherapy of prostate cancer cells.

  1. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Alberto Malerba

    2012-01-01

    Full Text Available The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD. In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO. Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.

  2. A novel point mutation (G[sup [minus]1] to T) in a 5[prime] splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker Muscular Dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Hagiwara, Yoko; Nishio, Hisahide; Kitoh, Yoshihiko; Takeshima, Yasuhiro; Narita, Naoko; Wada, Hiroko; Yokoyama, Mitsuhiro; Nakamura, Hajime; Matsuo, Masafumi (Kobe Univ. School of Medicine (Japan))

    1994-01-01

    The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. The authors now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5[prime] splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5[prime] splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G[sup [minus]1]-to-T mutation at the 5[prime] splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection. 48 refs., 5 figs.

  3. Gaucher disease: A G[sup +1][yields]A[sup +1] IVS2 splice donor site mutation causing exon 2 skipping in the acid [beta]-glucosidase mRNA

    Energy Technology Data Exchange (ETDEWEB)

    He, Guo-Shun (Mount Siani School of Medicine, New York, NY (United States)); Grabowski, G.A. (Children' s Hospital Medical Center, Cincinnati, OH (United States))

    1992-10-01

    Gaucher disease is the most frequent lysosomal storage disease and the most prevalent Jewish genetic disease. About 30 identified missense mutations are causal to the defective activity of acid [beta]-glucosidase in this disease. cDNAs were characterized from a moderately affected 9-year-old Ashkenazi Jewish Gaucher disease type 1 patient whose 80-years-old, enzyme-deficient, 1226G (Asn[sup 370][yields]Ser [N370S]) homozygous grandfather was nearly asymptomatic. Sequence analyses revealed four populations of cDNAs with either the 1226G mutation, an exact exon 2 ([Delta] EX2) deletion, a deletion of exon 2 and the first 115 bp of exon 3 ([Delta] EX2-3), or a completely normal sequence. About 50% of the cDNAs were the [Delta] EX2, the [Delta] EX2-3, and the normal cDNAs, in a ratio of 6:3:1. Specific amplification and characterization of exon 2 and 5[prime] and 3[prime] intronic flanking sequences from the structural gene demonstrated clones with either the normal sequence or with a G[sup +1][yields]A[sup +1] transition at the exon 2/intron 2 boundary. This mutation destroyed the splice donor consensus site (U1 binding site) for mRNA processing. This transition also was present at the corresponding exon/intron boundary of the highly homologous pseudogene. This new mutation, termed [open quotes]IVS2 G[sup +1],[close quotes] is the first in the Ashkenazi Jewish population. The occurrence of this [open quotes]pseudogene[close quotes]-type mutation in the structural gene indicates the role of acid [beta]-glucosidase pseudogene and structural gene rearrangements in the pathogenesis of this disease. 33 refs., 8 figs., 1 tab.

  4. Stability in skipping gaits

    Science.gov (United States)

    Andrada, Emanuel; Müller, Roy; Blickhan, Reinhard

    2016-11-01

    As an alternative to walking and running, humans are able to skip. However, adult humans avoid it. This fact seems to be related to the higher energetic costs associated with skipping. Still, children, some birds, lemurs and lizards use skipping gaits during daily locomotion. We combined experimental data on humans with numerical simulations to test whether stability and robustness motivate this choice. Parameters for modelling were obtained from 10 male subjects. They locomoted using unilateral skipping along a 12 m runway. We used a bipedal spring loaded inverted pendulum to model and to describe the dynamics of skipping. The subjects displayed higher peak ground reaction forces and leg stiffness in the first landing leg (trailing leg) compared to the second landing leg (leading leg). In numerical simulations, we found that skipping is stable across an amazing speed range from skipping on the spot to fast running speeds. Higher leg stiffness in the trailing leg permits longer strides at same system energy. However, this strategy is at the same time less robust to sudden drop perturbations than skipping with a stiffer leading leg. A slightly higher stiffness in the leading leg is most robust, but might be costlier.

  5. Predicting mutually exclusive spliced exons based on exon length, splice site and reading frame conservation, and exon sequence homology

    Directory of Open Access Journals (Sweden)

    Hammesfahr Björn

    2011-06-01

    Full Text Available Abstract Background Alternative splicing of pre-mature RNA is an important process eukaryotes utilize to increase their repertoire of different protein products. Several types of different alternative splice forms exist including exon skipping, differential splicing of exons at their 3'- or 5'-end, intron retention, and mutually exclusive splicing. The latter term is used for clusters of internal exons that are spliced in a mutually exclusive manner. Results We have implemented an extension to the WebScipio software to search for mutually exclusive exons. Here, the search is based on the precondition that mutually exclusive exons encode regions of the same structural part of the protein product. This precondition provides restrictions to the search for candidate exons concerning their length, splice site conservation and reading frame preservation, and overall homology. Mutually exclusive exons that are not homologous and not of about the same length will not be found. Using the new algorithm, mutually exclusive exons in several example genes, a dynein heavy chain, a muscle myosin heavy chain, and Dscam were correctly identified. In addition, the algorithm was applied to the whole Drosophila melanogaster X chromosome and the results were compared to the Flybase annotation and an ab initio prediction. Clusters of mutually exclusive exons might be subsequent to each other and might encode dozens of exons. Conclusions This is the first implementation of an automatic search for mutually exclusive exons in eukaryotes. Exons are predicted and reconstructed in the same run providing the complete gene structure for the protein query of interest. WebScipio offers high quality gene structure figures with the clusters of mutually exclusive exons colour-coded, and several analysis tools for further manual inspection. The genome scale analysis of all genes of the Drosophila melanogaster X chromosome showed that WebScipio is able to find all but two of the 28

  6. NextSearch: A Search Engine for Mass Spectrometry Data against a Compact Nucleotide Exon Graph.

    Science.gov (United States)

    Kim, Hyunwoo; Park, Heejin; Paek, Eunok

    2015-07-02

    Proteogenomics research has been using six-frame translation of the whole genome or amino acid exon graphs to overcome the limitations of reference protein sequence database; however, six-frame translation is not suitable for annotating genes that span over multiple exons, and amino acid exon graphs are not convenient to represent novel splice variants and exon skipping events between exons of incompatible reading frames. We propose a proteogenomic pipeline NextSearch (Nucleotide EXon-graph Transcriptome Search) that is based on a nucleotide exon graph. This pipeline consists of constructing a compact nucleotide exon graph that systematically incorporates novel splice variations and a search tool that identifies peptides by directly searching the nucleotide exon graph against tandem mass spectra. Because our exon graph stores nucleotide sequences, it can easily represent novel splice variations and exon skipping events between incompatible reading frame exons. Searching for peptide identification is performed against this nucleotide exon graph, without converting it into a protein sequence in FASTA format, achieving an order of magnitude reduction in the size of the sequence database storage. NextSearch outputs the proteome-genome/transcriptome mapping results in a general feature format (GFF) file, which can be visualized by public tools such as the UCSC Genome Browser.

  7. Grade Skipping in Gifted Education

    Institute of Scientific and Technical Information of China (English)

    徐云婕

    2016-01-01

    Grade skipping has been heatedly discussed with the development of gifted education. Experts and scholars are trying to do ifnd out the better way to cultivate those gifted children, to develop their potential, and make full use of their talent. Although grade skipping has long history, there is no certain comment about whether it is beneiftial to the gifted children.

  8. 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.

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

    Science.gov (United States)

    Saito, Takashi; Nakamura, Akinori; Aoki, Yoshitsugu; Yokota, Toshifumi; Okada, Takashi; Osawa, Makiko; Takeda, Shin'ichi

    2010-08-18

    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. 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. 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.

  10. An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.

    Science.gov (United States)

    Collins, Katherine M; Kainov, Yaroslav A; Christodolou, Evangelos; Ray, Debashish; Morris, Quaid; Hughes, Timothy; Taylor, Ian A; Makeyev, Eugene V; Ramos, Andres

    2017-04-04

    RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1-ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interaction with the intronic 3΄ site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping.

  11. Stemcell Information: SKIP000253 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000253 ... Diseased GM23760 GM23760 ... 統合失調症 F20 Schizophrenia 181500 ... ...(SCZD) .episodes of agitatation, delusions of persecutation, fear of assassination, father also affected. 統合

  12. Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements.

    Science.gov (United States)

    Di Giacomo, Daniela; Gaildrat, Pascaline; Abuli, Anna; Abdat, Julie; Frébourg, Thierry; Tosi, Mario; Martins, Alexandra

    2013-11-01

    Exonic variants can alter pre-mRNA splicing either by changing splice sites or by modifying splicing regulatory elements. Often these effects are difficult to predict and are only detected by performing RNA analyses. Here, we analyzed, in a minigene assay, 26 variants identified in the exon 7 of BRCA2, a cancer predisposition gene. Our results revealed eight new exon skipping mutations in this exon: one directly altering the 5' splice site and seven affecting potential regulatory elements. This brings the number of splicing regulatory mutations detected in BRCA2 exon 7 to a total of 11, a remarkably high number considering the total number of variants reported in this exon (n = 36), all tested in our minigene assay. We then exploited this large set of splicing data to test the predictive value of splicing regulator hexamers' scores recently established by Ke et al. (). Comparisons of hexamer-based predictions with our experimental data revealed high sensitivity in detecting variants that increased exon skipping, an important feature for prescreening variants before RNA analysis. In conclusion, hexamer scores represent a promising tool for predicting the biological consequences of exonic variants and may have important applications for the interpretation of variants detected by high-throughput sequencing.

  13. 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.

  14. 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......-phenotype correlations. Therefore, recognizing such mutations enhances our ability to predict the BH(4)-response. Copyright © 2012 Elsevier Inc. All rights reserved. PMID:22698810[PubMed - in process]...

  15. Exon exchange approach to repair Duchenne dystrophin transcripts.

    Directory of Open Access Journals (Sweden)

    Stéphanie Lorain

    Full Text Available BACKGROUND: Trans-splicing strategies for mRNA repair involve engineered transcripts designed to anneal target mRNAs in order to interfere with their natural splicing, giving rise to mRNA chimeras where endogenous mutated exons have been replaced by exogenous replacement sequences. A number of trans-splicing molecules have already been proposed for replacing either the 5' or the 3' part of transcripts to be repaired. Here, we show the feasibility of RNA surgery by using a double trans-splicing approach allowing the specific substitution of a given mutated exon. METHODOLOGY/PRINCIPAL FINDINGS: As a target we used a minigene encoding a fragment of the mdx dystrophin gene enclosing the mutated exon (exon 23. This minigene was cotransfected with a variety of exon exchange constructions, differing in their annealing domains. We obtained accurate and efficient replacement of exon 23 in the mRNA target. Adding up a downstream intronic splice enhancer DISE in the exon exchange molecule enhanced drastically its efficiency up to 25-45% of repair depending on the construction in use. CONCLUSIONS/SIGNIFICANCE: These results demonstrate the possibility to fix up mutated exons, refurbish deleted exons and introduce protein motifs, while keeping natural untranslated sequences, which are essential for mRNA stability and translation regulation. Conversely to the well-known exon skipping, exon exchange has the advantage to be compatible with almost any type of mutations and more generally to a wide range of genetic conditions. In particular, it allows addressing disorders caused by dominant mutations.

  16. TALE-directed local modulation of H3K9 methylation shapes exon recognition.

    Science.gov (United States)

    Bieberstein, Nicole I; Kozáková, Eva; Huranová, Martina; Thakur, Prasoon K; Krchňáková, Zuzana; Krausová, Michaela; Carrillo Oesterreich, Fernando; Staněk, David

    2016-07-21

    In search for the function of local chromatin environment on pre-mRNA processing we established a new tool, which allows for the modification of chromatin using a targeted approach. Using Transcription Activator-Like Effector domains fused to histone modifying enzymes (TALE-HME), we show locally restricted alteration of histone methylation modulates the splicing of target exons. We provide evidence that a local increase in H3K9 di- and trimethylation promotes inclusion of the target alternative exon, while demethylation by JMJD2D leads to exon skipping. We further demonstrate that H3K9me3 is localized on internal exons genome-wide suggesting a general role in splicing. Consistently, targeting of the H3K9 demethylase to a weak constitutive exon reduced co-transcriptional splicing. Together our data show H3K9 methylation within the gene body is a factor influencing recognition of both constitutive and alternative exons.

  17. Stemcell Information: SKIP000261 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000261 ... Diseased GM23762 GM23762 ... 統合失調症 F20 Schizophrenia 181500 ... ...cally affected with Shizophrenia(SCZD) . 統合失調症患者線維芽細胞(GM02497)由来iPS細胞株。 | human ES-like -- Retrovirus Oct4,

  18. Stemcell Information: SKIP001116 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001116 ... Diseased D2-2 D2-2 ... 統合失調症 F209 schizophrenia ... 605210 ... 39 ...upted in schizophrenia 1 ( DISC1 ) 統合失調症患者由来iPS細胞 human ES-like Research Grade Plasmid OCT4,SOX2,KLF4,c-MYC,

  19. Stemcell Information: SKIP001115 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001115 ... Diseased D2-1 D2-1 ... 統合失調症 F209 schizophrenia ... 605210 ... 39 ...upted in schizophrenia 1 ( DISC1 ) 統合失調症患者由来iPS細胞 human ES-like Research Grade Plasmid OCT4,SOX2,KLF4,c-MYC,

  20. Stemcell Information: SKIP000260 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000260 ... Diseased GM23761 GM23761 ... 統合失調症 F20 Schizophrenia 181500 ... ...h Shizophrenia(SCZD) . | 統合失調症患者線維芽細胞(GM01835)由来iPS細胞株| human ES-like -- Lentivirus Oct4, Sox2, Klf4, c-Myc,

  1. Stemcell Information: SKIP000858 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000858 ... αβT αβT Normal 585A1 585A1 ... 30 30-39 Male Japanese Japanese -- No hiPSC Generat...ion from Peripheral Blood.Medium contained IL-2 and antibodies against CD3 and CD28

  2. Stemcell Information: SKIP000859 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000859 ... αβT αβT Normal 585B1 585B1 ... 30 30-39 Male Japanese Japanese -- No hiPSC Generat...ion from Peripheral Blood.Medium contained IL-2 and antibodies against CD3 and CD28

  3. Stemcell Information: SKIP000845 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000845 ... unknown 不明 Diseased Sporadic PD-1 Sporadic PD-1 10005.117.01 10005.117.01 パーキンソン...oradic Parkinson Disease patient.Using CytoTune iPS Sendai reprogramming protocol (Life Technologies). 孤発性パーキンソン

  4. Stemcell Information: SKIP000265 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000265 ... Diseased HPS0264 HPS0264 ... パーキンソン病 G20 Parkinson disease ... ... ... 40-49 Male ... Yes No iPS cell line derived from Parkinson disease patient. パーキンソン病患者由来| human ES-like -- Re

  5. Stemcell Information: SKIP000279 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000279 ... Diseased HPS0192 HPS0192 ... 杉花粉症 J301 Allergic rhinitis (Pollen allergy) 607154 食物...アレルギー(カニ) T781 food allergy (crab) ... -- -- Japanese Japanese No No Disease specific iPS

  6. Stemcell Information: SKIP000189 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000189 ... Diseased GM23404 GM23404 ... フリードライヒ運動失調症 G111 Friedreich ataxia (a...sitory http://ccr.coriell.org/Sections/Collections/NIGMS/ipsc_list.aspx?PgId=696 ... 21040903 10.1016/j.stem.2010.09.014 Friedrei

  7. Stemcell Information: SKIP000245 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000245 ... Diseased HPS0164 HPS0164 ... デュシェンヌ型筋ジストロフィー G710 Duchenne Muscular... Dystrophy 310200 ... -- -- ... Yes No intractable disease-specific iPSC derived from Duchenne Muscular Dystrophy. デュシェンヌ

  8. Stemcell Information: SKIP000916 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000916 ... fibroblast 線維芽細胞 Normal WT#5J WT#5J ... -- -- ... -- No iPS cell line iPS cell...essful disease-specific induced pluripotent stem cell generation from patients with kidney transplantation.

  9. Stemcell Information: SKIP001066 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001066 ... Diseased LQT3 LQT3 ... QT延長症候群 I45.81 Long QT Syndrome 192500 ... ... ... -- Unknown ... Yes No Specific disease iPS cell line from patient with Long QT Syndrom QT延長症候群患者由来iPS細胞 hu

  10. Stemcell Information: SKIP001117 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001117 ... Diseased D3-1 D3-1 ... 大うつ病 F33.3 major depression 605210 ... ...-- Male ... Yes No iPS cells derived from fibroblasts of a patient in which a frameshift mutation of disrupted in major depression

  11. Stemcell Information: SKIP001118 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001118 ... Diseased D3-2 D3-2 ... 大うつ病 F33.3 major depression 605210 ... ...-- Male ... Yes No iPS cells derived from fibroblasts of a patient in which a frameshift mutation of disrupted in major depression

  12. Stemcell Information: SKIP000269 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ease specific iPS cell line derived from a patient: Mitochondrial myopathy, Encephalopathy, Lactic acidosis,...Encephalopathy, Lactic acidosis, and Stroke-like episodes 540000 ... -- -- Japanese Japanese Yes No Dis... SKIP000269 ... Diseased HPS0070 HPS0070 ... ミトコンドリア病 E888 Mitochondrial myopathy,

  13. Stemcell Information: SKIP000095 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000095 ... Diseased A000052#3 A000052#3 ... 高乳酸血症 R798 hyperlactacidemia ... ... ... -- -- ... Yes No intractable disease-specific iPSC, congenital hyperlactacidemia, suspicous 難病性疾患克服事業iPS細胞バンク 先天性高乳酸血症

  14. Stemcell Information: SKIP000733 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000733 ... Diseased GM24666 GM24666 sAD2 sAD2 アルツハイマー病 G309 ALZHEIMER DISEAS...E 104300 ... 83 80-89 Male ... Yes Yes ALZHEIMER DISEASE(Sporadic AD) hiPSC derived from fibroblast アルツハイマー

  15. Stemcell Information: SKIP000856 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000856 ... Diseased HPS0256 HPS0256 ... アルツハイマー病 G309 Alzheimer disease 104300... ... -- -- ... No No Disease specific iPS cell line derived from a patient with Alzheimer disease アルツハイマー

  16. Stemcell Information: SKIP000855 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000855 ... Diseased HPS0255 HPS0255 ... アルツハイマー病 G309 Alzheimer disease 104300... ... -- -- Japanese Japanese No No Disease specific iPS cell line derived from a patient with Alzheimer disease アルツハイマー

  17. Stemcell Information: SKIP000854 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000854 ... Diseased HPS0254 HPS0254 ... アルツハイマー病 G309 Alzheimer disease 104300... ... -- -- Japanese Japanese No No Disease specific iPS cell line derived from a patient with Alzheimer disease アルツハイマー

  18. Stemcell Information: SKIP000239 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000239 ... Diseased HPS0214 HPS0214 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC derived from Ehlers-Danlos syndrome, ne

  19. Stemcell Information: SKIP000555 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000555 ... Diseased HPS0191 HPS0191 ... ベルナール・スーリエ症候群 D69.1 Bernard-Soulier syndrome... 231200 ... -- -- ... No No Disease specific iPS cell line derived from Bernard-Soulier syndrome patient ベルナール·スーリエ症候群

  20. A founder synonymous COL7A1 mutation in three Danish families with dominant dystrophic epidermolysis bullosa pruriginosa identifies exonic regulatory sequences required for exon 87 splicing

    DEFF Research Database (Denmark)

    Covaciu, C; Grosso, F; Pisaneschi, E

    2011-01-01

    a previously unrecognized translationally silent exonic COL7A1 mutation that results in skipping of exon 87 and is associated with DDEB-Pr phenotypes in several members of three apparently unrelated Danish families. A haplotype segregation study suggested a common ancestor in these kindred. Functional splicing...... shoulders. DEB-Pr is caused by either dominant (DDEB-Pr) or recessive mutations in the COL7A1 gene encoding type VII collagen (COLVII). The full spectrum of COL7A1 mutations in DEB-Pr remains elusive and the genotype-phenotype correlation is largely incomplete. Here, we report and functionally characterize...... analysis of the mutant exon by a COL7A1 minigene construct and computational prediction for splicing regulatory cis-sequences prove that the mutation alters the activity of an exonic splicing enhancer (ESE) critical for exon inclusion. These findings substantiate for the first time the involvement...

  1. Rodent-specific alternative exons are more frequent in rapidly evolving genes and in paralogs

    Directory of Open Access Journals (Sweden)

    Mironov Andrey A

    2009-06-01

    Full Text Available Abstract Background Alternative splicing is an important mechanism for generating functional and evolutionary diversity of proteins in eukaryotes. Here, we studied the frequency and functionality of recently gained, rodent-specific alternative exons. Results We projected the data about alternative splicing of mouse genes to the rat, human, and dog genomes, and identified exons conserved in the rat genome, but missing in more distant genomes. We estimated the frequency of rodent-specific exons while controlling for possible residual conservation of spurious exons. The frequency of rodent-specific exons is higher among predominantly skipped exons and exons disrupting the reading frame. Separation of all genes by the rate of sequence evolution and by gene families has demonstrated that rodent-specific cassette exons are more frequent in rapidly evolving genes and in rodent-specific paralogs. Conclusion Thus we demonstrated that recently gained exons tend to occur in fast-evolving genes, and their inclusion rate tends to be lower than that of older exons. This agrees with the theory that gain of alternative exons is one of the major mechanisms of gene evolution.

  2. Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons.

    Science.gov (United States)

    Zhang, Xiang H-F; Chasin, Lawrence A

    2006-09-05

    Orthologous gene structures in eight vertebrate species were compared on a genomic scale to detect the birth and maturation of new internal exons during the course of evolution. We found that 40% of new human exons are alternatively spliced, and most of these are cassette exons (exons that are either included or skipped in their entirety) with low inclusion rates. This proportion decreases steadily as older and older exons are examined, even as splicing efficiency increases. Remarkably, the great majority of new cassette exons are composed of highly repeated sequences, especially Alu. Many new cassette exons are 5' untranslated exons; the proportion that code for protein increases steadily with age. New protein-coding exons evolve at a high rate, as evidenced by the initially high substitution rates (K(s) and K(a)), as well as the SNP density compared with older exons. This dynamic picture suggests that de novo recruitment rather than shuffling is the major route by which exons are added to genes, and that species-specific repeats could play a significant role in recent evolution.

  3. Stemcell Information: SKIP000182 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000182 ... Diseased GM23226 GM23226 ... 1型糖尿病 E10 diabetes (mellitus), juvenil...roblast. Multifactorial Defect 遺伝性若年発症I型糖尿病患者線維芽細胞(GM02416)由来iPS細胞 多因子の異常 human ES-like -- Retrovirus Oct4,

  4. Stemcell Information: SKIP000861 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000861 ... αβT αβT Normal 648B1 648B1 ... 30 30-39 Male Japanese Japanese -- No hiPSC Generat...ion from Peripheral Blood by using non-T medium. 末梢血由来iPS細胞。|T細胞の増殖には関与しない培地で作製。 hu

  5. Stemcell Information: SKIP000283 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000283 ... Diseased HPS0082 HPS0082 iPWS5 iPWS5 プラダー・ウィリー症候群 Q871 Prader Wil...patient of Prader Willi syndrome(RCB1560 PWS-Yamaguchi). del(15) was found in lymphocytes of the patient. 疾患特異的iPS細胞株。プラダー

  6. Stemcell Information: SKIP000262 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000262 ... Diseased GM23913 GM23913 ... フリードライヒ運動失調症 G111 Friedreich ataxia 22...9300 ... 30 30-39 Male ... Yes No iPS cell line derived from GM04078 fibroblast. Clinically affected with Friedrei...3 10.1016/j.stem.2010.09.014 Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA-

  7. Stemcell Information: SKIP000625 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000625 ... Diseased HPS0171 HPS0171 ... デュシェンヌ型筋ジストロフィー G710 Duchenne Muscular...ent : Muscular dystrophy, Duchenne type. HPS0169 is derived from the same patient. ... デュシェンヌ型筋ジストロフィー患者由来iPS細胞

  8. Stemcell Information: SKIP000827 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000827 ... Diseased HPS0312 HPS0312 ... デュシェンヌ型筋ジストロフィー G710 ... Muscular dystrop...d from a muscular dystrophy, Duchenne type patient デュシェンヌ型筋ジストロフィー症患者由来iPS細胞株 human ES-like Research Grade R

  9. Stemcell Information: SKIP000618 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available o Disease specific iPS cell line derived from a muscular dystrophy, Duchenne type (manifestig carrier) patient デュシェンヌ... SKIP000618 ... Fibroblast derived from the skeletal muscle 骨格筋組織中の線維芽細胞 Gene carrier HPS0317 HPS0317 ... デュシェ...ンヌ型筋ジストロフィー G710 MUSCULAR DYSTROPHY, DUCHENNE TYPE 310200 ... -- Female ... No N

  10. Stemcell Information: SKIP000619 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available o Disease specific iPS cell line derived from a muscular dystrophy, Duchenne type (manifestig carrier) patient デュシェンヌ... SKIP000619 ... Fibroblast derived from the skeletal muscle 骨格筋組織中の線維芽細胞 Gene carrier HPS0322 HPS0322 ... デュシェ...ンヌ型筋ジストロフィー G710 Muscular dystrophy, Duchenne type 310200 ... -- Female ... No N

  11. Stemcell Information: SKIP000244 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000244 ... Diseased HPS0169 HPS0169 ... デュシェンヌ型筋ジストロフィー G710 Duchenne Muscular...ent : Muscular dystrophy, Duchenne type. HPS0171 is derived from the same patient. ... デュシェンヌ型筋ジストロフィー患者由来iPS細胞

  12. Stemcell Information: SKIP000330 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000330 ... mesenchymal stem cell 間葉系幹細胞 polydactylous human fingers 指 Normal Yub...ovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cellbank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3377 ... ...621BMC Yub621BMC JCRB1113 JCRB1113 ... -- -- ... -- No JCRB1113 ... bone marrow-derived mesenchymal stem cell

  13. Stemcell Information: SKIP000792 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available tient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome QT 延長症候群 1 型患者由来iPS細胞 human ES-like... SKIP000792 ... Diseased LQT1 PII-2a LQT1 PⅡ-2a ... 遺伝性QT延長症候群1型 I45.81 long-QT syn

  14. Stemcell Information: SKIP000614 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000614 ... Diseased HPS0142 HPS0142 ... 家族性筋萎縮性側索硬化症 G122 Amyotrophic lateral sclerosis, Familia... a patient.Amyotrophic lateral sclerosis, Familial type. ... 疾患特異的iPS細胞株。家族性筋萎縮性側索硬化症患者由来。 human ES-like Resear

  15. Stemcell Information: SKIP000613 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000613 ... Diseased HPS0140 HPS0140 ... 家族性筋萎縮性側索硬化症 G122 Amyotrophic lateral sclerosis, Familia... a patient.Amyotrophic lateral sclerosis, Familial type. ... 疾患特異的iPS細胞株。家族性筋萎縮性側索硬化症患者由来。 human ES-like Resear

  16. Stemcell Information: SKIP001105 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001105 ... Diseased APP1E111 APP1E111 ... 家族性アルツハイマー病 G309 Alzheimer's disease... F693 ... -- -- ... Yes No Disease specific iPS cells from a patient of Alzheimer's disease. 疾患特異的iPS細胞株。APP-E693Δ変異家族性アルツハイマー

  17. Stemcell Information: SKIP000807 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000807 ... Diseased HPS0060 HPS0060 ... アルツハイマー型認知症 G30.9+ Dementia of Alzheim...tia of Alzheimers type. Order Form to RIKEN BRC (C-0042, C-0057, C-0007). 疾患特異的iPS細胞株。アルツハイマー型認知症患者由来。ガラス化法(

  18. Stemcell Information: SKIP000734 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000734 ... Diseased GM24675 GM24675 APPDp2 APPDp2 アルツハイマー病 G309 ALZHEIMER DI... hiPSC derived from fibroblast 家族性アルツハイマー病患者(APP遺伝子重複)維芽細胞由来iPS細胞 human ES-like Research Grade Retrovirus OC

  19. Stemcell Information: SKIP000791 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000791 ... Diseased 7643-32 7643-32 ... ティモシー症候群 I45.8 Timothy syndrome 601005... ... -- -- ... Yes No Human iPSCs.The Timothy syndrome iPSCs preserved the Timothy syndrome mutation. 疾患特異的iPS細胞。ティモシー症候群... investigate cardiac phenotypes in Timothy syndrome. Yazawa M, Hsueh B, Jia X, Pa

  20. Stemcell Information: SKIP000390 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000390 ... Diseased GM23764 GM23764 ... 統合失調症 F209 Schizophrenia 181500 ... ...より人工多能性幹細胞 (iPSC) を樹立。23回継代の凍結サンプル。同一人由来のリンパ球GM01490も参照。青年期から神経性無食欲症を発症。鬱<統合失調症。

  1. Stemcell Information: SKIP000272 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000272 ... Diseased HPS0129 HPS0129 ... 孤発性筋萎縮性側索硬化症 ... (classical, with UMN) G1...22 Amyotrophic lateral sclerosis, Sporadic type ... (classical, with UMN). ... -- -- Japanese Japanese N...o No Disease specific iPS cell line derived from a patient: Amyotrophic lateral sclerosis, Sporadic type (classical..., with UMN). ... 疾患特異的iPS細胞株。孤発性筋萎縮性側索硬化症 (classical, with UMN)患者由来。センダイウイルスベ

  2. Stemcell Information: SKIP000581 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000581 ... Diseased HCM 090909 HCM 090909 HCM 1 HCM 1 肥大型心筋症 I422 Hypertrophic cardiomyopathy...TPM1-Arg91Cys mutation that might be causal mutation of hypertrophic cardiomyopathy, by using four classic r... Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy...ding (mouse) reprogramming factors constructed by the laboratory of Dr Yamanaka were obtained from Addgene. TPM1-Arg91Cys変異(肥大型心筋症

  3. Stemcell Information: SKIP000992 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000992 ... Diseased PARK8-LA11 PARK8-LA11 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON D...n's disease patient ... 遺伝性パーキンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Ye...ISEASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 66 60-69 Female ... Yes No iPS cells from familial Parkinso

  4. Stemcell Information: SKIP000993 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000993 ... Diseased PARK8-LB16 PARK8-LB16 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON D...n's disease patient ... 遺伝性パーキンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Ye...ISEASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 78 70-79 Female ... Yes No iPS cells from familial Parkinso

  5. Stemcell Information: SKIP000994 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000994 ... Diseased PARK8-LB21 PARK8-LB21 ... 遺伝性パーキンソン病:PARK8 G20 PARKINSON D...n's disease patient ... 遺伝性パーキンソン病患者由来iPS細胞 human ES-like Research Grade Lentivirus Klf4, Sox2, Oct4, c-Myc ... Ye...ISEASE 8, AUTOSOMAL DOMINANT; PARK8 607060 ... 78 70-79 Female ... Yes No iPS cells from familial Parkinso

  6. Stemcell Information: SKIP001095 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(1439 KURABO)| 新生児皮膚繊維芽細胞(1439 KURABO)由来iPS細胞 human ES-like Research ...on, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001095 ... Normal WT-1-#1 WT-1-#1 ... 0-9 Male ... -- No Nomal human iPS cell...ling type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cell

  7. Stemcell Information: SKIP000644 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000644 ... umbilical cord 臍帯(線維芽細胞) Normal HiPS-RIKEN-2D HiPS-RIKEN-2D ... ...bilical cord fibroblast, male) 臍帯由来線維芽細胞(RCB0197 HUC-Fm)iPS細胞. human ES-like Research Grade Retrovirus ... Oct3... ... Fetus Male Japanese Japanese -- No Human iPS cell line. Parent cell line of RCB0197 HUC-Fm(Normal um...010.00091.x Establishment of induced pluripotent stem cells from human neonatal tissues. Fujioka T, Shimizu

  8. Stemcell Information: SKIP001121 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available lines(C3) using transcription activator-like effector nuclease (TALEN; Fig. 3a ). TALENを用いてゲノム編集したiPS細胞... SKIP001121 ... Normal C-3-1-3M C-3-1-3M ... -- Female ... -- No Isogenic iPS cell...(C3) human ES-like Research Grade Plasmid ... -- ... Yes Differentiation of iPS cells into foreb...0.1038/nature13716 Synaptic dysregulation in a human iPS cell model of mental disorders. Wen Z, Nguyen HN, G

  9. Stemcell Information: SKIP000639 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000639 ... umbilical cord 臍帯(線維芽細胞) Normal HiPS-RIKEN-1D HiPS-RIKEN-1D ... ... umbilical cord fibroblast,Female) 臍帯由来線維芽細胞(RCB0436 HUC-F2)iPS細胞. human ES-like Research Grade Retrovirus O... ... Fetus Female Japanese Japanese -- No Human iPS cell line. Parent cell line of ... RCB0436 HUC-F2(Normal...774.2010.00091.x Establishment of induced pluripotent stem cells from human neonatal tissues. Fujioka T, Shi

  10. Stemcell Information: SKIP000949 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available inson disease 168006 ... 51 50-59 Female ... No No iPS cell line iPS細胞 human ES-like Research Grade Retrov... SKIP000949 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP16.2 SP16.2 ... パーキンソン病 G20 Park...irus SOX2, KLF4 and OCT3/4 Yes Yes MEFs Lines of patient-specific iPS cells were maintained by mechanical di...ssociation of colonies and splitting 1:3 onto feeder cells in hESC medium or by l

  11. Stemcell Information: SKIP000953 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available inson disease 168006 ... 44 40-49 Male ... Yes No iPS cell line iPS細胞 human ES-like Research Grade Retrovi... SKIP000953 ... dermal fibroblast 表皮繊維芽細胞 Diseased SP06.1 SP06.1 ... パーキンソン病 G20 Park...rus SOX2, KLF4 and OCT3/4 Yes Yes MEFs Lines of patient-specific iPS cells were maintained by mechanical dis...sociation of colonies and splitting 1:3 onto feeder cells in hESC medium or by li

  12. Stemcell Information: SKIP000793 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ndrome type 1 192500 ... 42 40-49 Male ... Yes No Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome... SKIP000793 ... Diseased LQT1 PIII-2a LQT1 PⅢ-2a ... 遺伝性QT延長症候群1型 I45.81 long-QT sy... type1 QT 延長症候群 1 型患者由来iPS細胞 human ES-like Research Grade Retrovirus OCT3/4 SOX2 KLF4 c-MY

  13. Stemcell Information: SKIP000380 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ce-Moon(-Bardet)-Biedl Syndrome 209900 ... -- -- Japanese 日本人 No No Disease specific iPS cell line derived from Bardet-Biedl Syn...drome patient. HPS0156 is derived from the same patient. Bardet-Biedls症候群患者由来iPS細胞。疾患特異的iPS細胞株。バルデー·ビードル症候群... SKIP000380 ... Diseased HPS0157 HPS0157 ... ローレンス・ムーン症候群(バルデー・ビードル症候群) Q878 Lauren

  14. Stemcell Information: SKIP000794 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available drome type 2 613688 ... 28 20-29 Female ... Yes No Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome... SKIP000794 ... Diseased LQTS-hiPSCs LQTS-hiPSCs ... 遺伝性QT延長症候群2型 I45.8 long-QT syn... type2 QT 延長症候群 2 型患者由来iPS細胞 -- -- Retrovirus SOX-2, KLF-4, OCT-4 ... Yes MEF ES medium and

  15. Stemcell Information: SKIP000264 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ce-Moon(-Bardet)-Biedl Syndrome 209900 ... -- -- ... No No iPS cell line derived from Bardet-Biedl Syndrome... SKIP000264 ... Diseased HPS0156 HPS0156 ... ローレンス・ムーン症候群(バルデー・ビードル症候群) Q878 Lauren... patient. Bardet-Biedls症候群患者由来iPS細胞。| human ES-like -- Sendai virus SeV18+HS-OCT3/4/TSdeltaF, SeV18+HS-SOX

  16. Stemcell Information: SKIP000172 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000172 ... Diseased HPS0118 HPS0118 ... CINCA症候群 ... CINCA syndrome 607115 ... ... ... -- Male ... Yes No iPSC from CINCA syndrome patient with mutaion 1709A>G (Y570C) in NLRP3 as somatic mosaicism iPSC from CINCA syndr...12-03-417881 Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic m...ome(CINCA症候群) patient with mutaion 1709A>G (Y570C) in NLRP3 as somatic mosaicism hu

  17. Stemcell Information: SKIP000787 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000787 ... Diseased 7643-5 7643-5 ... ティモシー症候群 I45.8 Timothy syndrome 601005 ... ... ... -- -- ... Yes No Human iPSCs.The Timothy syndrome iPSCs preserved the Timothy syndrome mutation. 疾患特異的iPS細胞。ティモシー症候群...duced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome....--Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Yazawa M, Hs

  18. Stemcell Information: SKIP000105 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000105 ... Diseased A000180#2 A000180#2 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC, Ehlers-Danlos syndrome, new varien...t 難病性疾患克服事業iPS細胞バンク 新型エーラース・ダンロス症候群 human ES-like -- Sendai virus Sendai Virus (DNAVEC: CytoTuneTM-iPS Cat.

  19. Stemcell Information: SKIP000790 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000790 ... Diseased 9862-61 9862-61 ... ティモシー症候群 I45.8 Timothy syndrome 601005... ... -- -- ... Yes No Human iPSCs.The Timothy syndrome iPSCs preserved the Timothy syndrome mutation. 疾患特異的iPS細胞。ティモシー症候群...induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome....--Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Yazawa M,

  20. Stemcell Information: SKIP000267 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000267 ... Diseased HPS0083 HPS0083 iCK2 iCK2 コケイン症候群 Q871 Cockayne's syndrome... 216400 ... -- Female japanese japanese No No Disease specific iPS cell line derived from a patient of Cockayne's syndrome.... コケイン症候群患者由来細胞(RCB0397 NCU-F10)に4因子(Oct3/4, Sox2, Klf4, c-Myc)を導入。|| human ES-like --

  1. Stemcell Information: SKIP000106 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000106 ... Diseased A000180#5 A000180#5 ... エーラース・ダンロス症候群 Q796 Ehlers-Danlos syndrome... 130000 ... -- -- ... Yes No intractable disease-specific iPSC, Ehlers-Danlos syndrome, new varien...t 難病性疾患克服事業iPS細胞バンク 新型エーラース・ダンロス症候群 human ES-like -- Sendai virus Sendai Virus (DNAVEC: CytoTuneTM-iPS Cat.

  2. Adolescent Breakfast Skipping: An Australian Study.

    Science.gov (United States)

    Shaw, Mary E.

    1998-01-01

    Reports on the findings of an Australian survey of adolescents concerning the extent of skipping breakfast. Finds that skippers are more likely to be dissatisfied with their body shape and to be on a diet to lose weight. Findings suggest that skipping breakfast is a matter of individual choice rather than a result of poverty. (Author/GCP)

  3. Stemcell Information: SKIP000186 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available s derived from GM03814(GMO3813'S mother) Fibroblast. SMN1 exons 7-8 deleted. Unaffected Coriell ID: GM23241 ... SMA1患者(GOM03813)母親線維芽細胞...038/nature07677 Stem Cell Model of Spinal Muscular Atrophy--Induced pluripotent stem cell

  4. Stemcell Information: SKIP001005 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001005 ... Normal ChiPSC18 ChiPSC18 Y00305 Y00305 ... 32 30-39 Male European.../North African European/North African -- No Cellartis human iPS cell line 18 (ChiPSC18)|Research Gra... ... Yes ... Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパ...AB Takara Bio Europe AB. タカラバイオヨーロッパAB Available Takara Bio Europe AB. タカラバイオヨーロッパAB http://www.clonte

  5. Stemcell Information: SKIP001001 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001001 ... Normal P11032 P11032 Y00225 Y00225 ... 38 30-39 Female European/North African Euro...F4,c-Myc ... -- ... Negative ... Yes ... Yes ... Yes G-banding Yes ... Yes ... Takara Bio Europe AB. タカラバイオヨーロッパ...AB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパ...AB Not Available Takara Bio Europe AB. タカラバイオヨーロッパAB http://www.clontech.com/JP/Support/Contact_Technical_Support?sitex=10025:22372:US ... takarabio ...pean/North African -- No Cellartis human iPS cell line P11032|Research Grade(commer

  6. Stemcell Information: SKIP001006 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001006 ... Normal ChiPSC21 ChiPSC21 Y00315 Y00315 ... 26 20-29 Male European.../North African European/North African -- No Cellartis human iPS cell line 21 (ChiPSC21)|Research Gra... ... Yes ... Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパ...AB Takara Bio Europe AB. タカラバイオヨーロッパAB Available Takara Bio Europe AB. タカラバイオヨーロッパAB http://www.clonte

  7. Stemcell Information: SKIP001003 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001003 ... Normal ChiPSC7 ChiPSC7 Y00275 Y00275 ... 20 20-29 Female European.../North African European/North African -- No Cellartis human iPS cell line 7 (ChiPSC7)|Research Grade...es ... Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパ...AB Takara Bio Europe AB. タカラバイオヨーロッパAB Available Takara Bio Europe AB. タカラバイオヨーロッパAB http://www.clontech.c

  8. Stemcell Information: SKIP001004 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001004 ... Normal ChiPSC12 ChiPSC12 Y00285 Y00285 ... 24 20-29 Male European.../North African European/North African -- No Cellartis human iPS cell line 12 (ChiPSC12)|Research Gra... ... Yes ... Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパ...AB Takara Bio Europe AB. タカラバイオヨーロッパAB Available Takara Bio Europe AB. タカラバイオヨーロッパAB http://www.clonte

  9. Stemcell Information: SKIP001007 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001007 ... Normal ChiPSC22 ChiPSC22 Y00325 Y00325 ... 32 30-39 Male European.../North African European/North African -- No Cellartis human iPS cell line 22 (ChiPSC22)|Research Gra... ... Yes ... Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパAB Takara Bio Europe AB. タカラバイオヨーロッパ...AB Takara Bio Europe AB. タカラバイオヨーロッパAB Available Takara Bio Europe AB. タカラバイオヨーロッパAB http://www.clonte

  10. Stemcell Information: SKIP000583 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000583 ... Diseased HCM HJ HCM HJ HCM3 HCM3 肥大型心筋症 I422 Hypertrophic cardiomyopathy...ly999-Gln1004del mutation that is commonly causal mutation of hypertrophic cardiomyopathy, by using four sen...ndothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopath...MYBPC3-Gly999-Gln1004del変異(肥大型心筋症の原因遺伝子の可能性をもつ)を持つ血液からiPS細胞を樹立した。4つのセンダイウイルスベクター(

  11. Stemcell Information: SKIP000543 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available l vectors pMXs-Oct4, pMXs-Sox2, pMXs-Klf4, and pMXs-c-Myc encoding (mouse) reprogramming factors. 健常人の皮膚細胞から...4つのレトロウイルスベクター(pMXs-Oct4, pMXs-Sox2, pMXs-Klf4, and pMXs-c-Mycを用いてiPS細胞を樹立した。 hum... SKIP000543 ... Normal iPS 090707 iPS 090707 ... -- -- ... -- No iPS cell...broblast (MEF) the standard hES cell medium (80% DMEM/F12, 20% KO Serum Replacement (Invitrogen) with 4 ng/m...y and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived ca

  12. Stemcell Information: SKIP000504 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ate chip Chocolate chip ... Fetus Unknown ... -- No MRC-iPS-92|MRC5-derived iPS cells| MRC5由来iPS細胞| h... SKIP000504 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-92 MRC-iPS-92 Chocol...365-2443.2010.01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cell...s.--DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazak....nlm.nih.gov/pubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  13. Stemcell Information: SKIP000445 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available a Alameda ... Fetus Unknown ... -- No MRC-iPS-33|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like R... SKIP000445 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-33 MRC-iPS-33 Alamed...01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.-...-DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Ita...ubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  14. Stemcell Information: SKIP001190 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001190 ... blood mononuclear cell 血中単核細胞 Diseased HPS0414 HPS0414 ... 原発性側索硬化症 G...m a patient :Primary lateral sclerosis (PLS). ... 原発性側索硬化症由来iPS細胞株。 human ES-like Research Grade Other Oct3/4, ...122 Primary Lateral Sclerosis ... -- -- Japanese 日本人 Yes No Disease specific iPS cell line derived fro...EN BioResource Center 理化学研究所 バイオリソースセンター ... Available RIKEN BioResource Center 理化学研究所 バイオリソースセンター ... http://www2.brc.riken.jp/lab/cell/detail.cgi?cell_no=HPS0414&type=1 ...

  15. Stemcell Information: SKIP001099 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available line derived from a neonate.(789013 KURABO)| 新生児皮膚繊維芽細胞(789013 KURABO)由来iPS細胞 human ES-like Res...ication, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Research and Application,Kyoto University 京都大学iPS細胞... SKIP001099 ... Normal WT-2-#32 WT-2-#32 ... 0-9 Male ... -- No Nomal human iPS cell... Modeling type II collagenopathy skeletal dysplasia by directed conversion and in...duced pluripotent stem cells. Okada M, Ikegawa S, Morioka M, Yamashita A, Saito A, Sawai H, Murotsuki J, Oha

  16. Stemcell Information: SKIP000442 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available es Speckles ... Fetus Unknown ... -- No MRC-iPS-30|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like... SKIP000442 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-30 MRC-iPS-30 Speckl...0.01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells....--DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, I.../pubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  17. Stemcell Information: SKIP000465 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Smoky ... Fetus Unknown ... -- No MRC-iPS-53|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like Resea... SKIP000465 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-53 MRC-iPS-53 Smoky ...9.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.--DNA... methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Itakura...d/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  18. Stemcell Information: SKIP000507 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ach Rorschach ... Fetus Unknown ... -- No MRC-iPS-96|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-li... SKIP000507 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-96 MRC-iPS-96 Rorsch...010.01459.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cell...s.--DNA methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M,...ov/pubmed/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  19. Stemcell Information: SKIP000469 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available Rufus ... Fetus Unknown ... -- No MRC-iPS-57|MRC5-derived iPS cells| MRC5由来iPS細胞| human ES-like Resea... SKIP000469 ... fetal lung fibroblast 胎児肺線維芽細胞 Unknown MRC-iPS-57 MRC-iPS-57 Rufus ...9.x--10.1371/journal.pgen.1002085 Lectin microarray analysis of pluripotent and multipotent stem cells.--DNA... methylation dynamics in human induced pluripotent stem cells over time. Toyoda M, Yamazaki-Inoue M, Itakura...d/21155951--http://www.ncbi.nlm.nih.gov/pubmed/21637780 -- Some of clones of the same original cells have been used in the papers.

  20. Stemcell Information: SKIP000287 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP000287 ... mesenchymal stem cell 間葉系幹細胞 Umbilical cord blood 臍帯血 Normal UCB408E7...ot Available National Institute of Biomedical Innovation. 独立行政法人医薬基盤研究所JCRB細胞バンク http://cellbank.nibio.go.jp/~cell...s with transgenic HPV E7. finite proliferation 臍帯血由来間葉系幹細胞 (有限増殖) fibroblast-like -- Retr...-32 UCB408E7-32 JCRB1109 JCRB1109 ... -- -- ... -- No JCRB1109 ... Human umbilical cord blood-derived mesenchymal stem cell...bank/cgi-bin/search_res_det.cgi?DB_NUM=1&ID=3373 ... 15647378 ... Immortalization of human fetal cell

  1. Stemcell Information: SKIP000382 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available alpha-Thalassemia, Mental Retardation Syndrome (ATR-X syndrome) 301040 ... -- -- ... No No Disease speci...fic iPS cell line derived from a patient : X-Linked alpha-Thalassemia, Mental Retardation Syndrome (ATR-X sy... SKIP000382 ... Diseased HPS0244 HPS0244 ... X連鎖αサラセミア·精神遅滞(ATR-X)症候群 D560 X-Linked...ndrome) 疾患特異的iPS細胞株。X連鎖alphaサラセミア·精神遅滞(ATR-X)症候群患者由来。 human ES-like Research Grad

  2. Stemcell Information: SKIP000388 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available l line derived from a patient :Alpha-Thalassemia/Mental Retardation Syndrome, X-Linked; ATRX. ... 疾患特異的iPS細胞株。X...alassemia/Mental Retardation Syndrome, X-Linked; ATRX 301040 ... -- -- ... No No Disease specific iPS cel... SKIP000388 ... Diseased HPS0207 HPS0207 ... X連鎖アルファ-サラセミア・精神遅滞(ATR-X)症候群 ... Alpha-Th...連鎖アルファ-サラセミア·精神遅滞(ATR-X)症候群患者由来。 human ES-like Research Grade Sendai virus SeV18+

  3. Stemcell Information: SKIP000876 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ient with F52L mutation in DCTN1. DCTN1にF52L遺伝子変異をもつPerry症候群患者1名から作製したiPS細胞 human E... SKIP000876 ... Diseased Perry syndrome patient iPSCs Perry syndrome patient iPSC...016.06.007 Cytoplasmic aggregates of dynactin in iPSC-derived tyrosine hydroxylase-positive neurons from a patient...s ... ペリー症候群 G20 Perry syndrome 168605 ... 61 60-69 Male ... Yes No ... Induced pluripotent stem cells (iPSCs) from a Perry syndrome pat

  4. Stemcell Information: SKIP000838 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ich deleated exon 6 and 7 in parkin gene.DNAVEC: SeV vectors, which were produced by DNAVEC Corp.(Cytotune). パーキンソン病患者T細胞より樹立したiPS細胞... ... 50-59 Male ... Yes No TPB27(DNAVEC) is iPSC line reprogrammed from a Parkinson disease patient's T-cells, wh

  5. Unusual intron conservation near tissue-regulated exons found by splicing microarrays.

    Directory of Open Access Journals (Sweden)

    Charles W Sugnet

    2006-01-01

    Full Text Available Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.

  6. Antisense Oligonucleotide-mediated Exon Skipping as a Systemic Therapeutic Approach for Recessive Dystrophic Epidermolysis Bullosa : Exon Skipping as Systemic Therapy for RDEB

    NARCIS (Netherlands)

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

    2016-01-01

    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 patie

  7. Stemcell Information: SKIP000680 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ions in the ratio 3:1:1:1:1. 胎児肺線維芽細胞由来iPS細胞。|低酸素下でKlf4, c-Myc, Oct4, Sox2とLIN28を...3:1:1:1:1の割合でコードした合成RNAを、線維芽細胞株に20日間毎日添加し、遺伝子を細胞へ導入した。 human ES-like Research Grade Other OCT4 , SOX2 , KLF4... SKIP000680 ... Lung Lung Normal MRC5-RiPS-1.11 MRC5-RiPS-1.11 ... Fetus Male ... -- No hiPS-cell...s derived from human fetal lung fibroblast cells (MRC-5 Line).They were derived using...on ... 20888316 10.1016/j.stem.2010.08.012 Highly efficient reprogramming to pluripotency and directed differentiation of human cell

  8. Stemcell Information: SKIP001102 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available SKIP001102 ... induced chondrogenic (iChon) cells ダイレクトリプログラミングで作製した軟骨細胞 ... Normal WT...n Dermal Fibroblasts(789013 KURABO). 新生児皮膚繊維芽細胞(789013 KURABO)をダイレクトリプログラミングにより軟骨細胞へと誘導(iChon細胞) Other Resea...n, Kyoto University 京都大学iPS細胞研究所 ... Information Only Center for iPS Cell Researc...h and Application,Kyoto University 京都大学iPS細胞研究所 CiRA https://www.cira.kyoto-u.ac.jp/e/index.html ... 2518757...-2-iChon WT-2-iChon ... 0-9 Male ... -- No Direct iInduction of Chondrogenic(iChon) cells from Huma

  9. Stemcell Information: SKIP000221 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available N-2A HPS0009 HPS0009 ... -- Male ... -- No Human iPS cell line. ヒトiPS細胞。臍帯由来線維芽細胞(RCB0197 HUC-Fm)由来。 ... SKIP000221 ... Umbilical cord(Fibroblast) 臍帯(線維芽細胞) Normal HiPS-RIKEN-2A HiPS-RIKE...human ES-like -- Retrovirus Retroviral vector pMXs, Oct3/4, Sox2, Klf4, c-Myc ... Yes MEF (X-rays:5000R or MMC) 1-1.5x10^(6) cell.../www2.brc.riken.jp/lab/cell/detail.cgi?cell_no=HPS0009&type=1 ... ...学研究所バイオリソースセンター RIKEN BRC 理化学研究所バイオリソースセンター Yukio Nakamura 中村幸夫 Available RIKEN BRC 理化学研究所バイオリソースセンター http:/

  10. Stemcell Information: SKIP000677 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ns in the ratio 3:1:1:1:1. 胎児肺線維芽細胞由来iPS細胞。|低酸素下でKlf4, c-Myc, Oct4, Sox2とLIN28を3:...1:1:1:1の割合でコードした合成RNAを、線維芽細胞株に20日間毎日添加し、遺伝子を細胞へ導入した。 human ES-like Research Grade Other OCT4 , SOX2 , KLF4 ,... SKIP000677 ... Lung Lung Normal MRC5-RiPS-1.2 MRC5-RiPS-1.2 ... Fetus Male ... -- No hiPS-cell...s derived from human fetal lung fibroblast cells (MRC-5 Line).They were derived using m...8.012 Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthe

  11. Stemcell Information: SKIP000679 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ns in the ratio 3:1:1:1:1. 胎児肺線維芽細胞由来iPS細胞。|低酸素下でKlf4, c-Myc, Oct4, Sox2とLIN28を3:...1:1:1:1の割合でコードした合成RNAを、線維芽細胞株に20日間毎日添加し、遺伝子を細胞へ導入した。 human ES-like Research Grade Other OCT4 , SOX2 , KLF4 ,... SKIP000679 ... Lung Lung Normal MRC5-RiPS-1.9 MRC5-RiPS-1.9 ... Fetus Male ... -- No hiPS-cell...s derived from human fetal lung fibroblast cells (MRC-5 Line).They were derived using m....1016/j.stem.2010.08.012 Highly efficient reprogramming to pluripotency and directed differentiation of human cell

  12. Reading Skill and Word Skipping: Implications for Visual and Linguistic Accounts of Word Skipping

    Science.gov (United States)

    Eskenazi, Michael A.; Folk, Jocelyn R.

    2015-01-01

    We investigated whether high-skill readers skip more words than low-skill readers as a result of parafoveal processing differences based on reading skill. We manipulated foveal load and word length, two variables that strongly influence word skipping, and measured reading skill using the Nelson-Denny Reading Test. We found that reading skill did…

  13. Reading Skill and Word Skipping: Implications for Visual and Linguistic Accounts of Word Skipping

    Science.gov (United States)

    Eskenazi, Michael A.; Folk, Jocelyn R.

    2015-01-01

    We investigated whether high-skill readers skip more words than low-skill readers as a result of parafoveal processing differences based on reading skill. We manipulated foveal load and word length, two variables that strongly influence word skipping, and measured reading skill using the Nelson-Denny Reading Test. We found that reading skill did…

  14. The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development.

    Science.gov (United States)

    Vulin, Adeline; Wein, Nicolas; Simmons, Tabatha R; Rutherford, Andrea M; Findlay, Andrew R; Yurkoski, Jacqueline A; Kaminoh, Yuuki; Flanigan, Kevin M

    2015-11-01

    Exon duplication mutations account for up to 11% of all cases of Duchenne muscular dystrophy (DMD), and a duplication of exon 2 is the most common duplication in patients. For use as a platform for testing of duplication-specific therapies, we developed a mouse model that carries a Dmd exon 2 duplication. By using homologous recombination we duplicated exon 2 within intron 2 at a location consistent with a human duplication hotspot. mRNA analysis confirms the inclusion of a duplicated exon 2 in mouse muscle. Dystrophin expression is essentially absent by immunofluorescent and immunoblot analysis, although some muscle specimens show very low-level trace dystrophin expression. Phenotypically, the mouse shows similarities to mdx, the standard laboratory model of DMD. In skeletal muscle, areas of necrosis and phagocytosis are seen at 3 weeks, with central nucleation prominent by four weeks, recapitulating the "crisis" period in mdx. Marked diaphragm fibrosis is noted by 6 months, and remains unchanged at 12 months. Our results show that the Dup2 mouse is both pathologically (in degree and distribution) and physiologically similar to mdx. As it recapitulates the most common single exon duplication found in DMD patients, this new model will be a useful tool to assess the potential of duplicated exon skipping.

  15. Skip segment Hirschsprung's disease: a systematic review.

    LENUS (Irish Health Repository)

    O'Donnell, Anne-Marie

    2012-02-01

    PURPOSE: Hirschsprung\\'s disease is characterised by the congenital absence of ganglion cells beginning in the distal rectum and extending proximally for varying distances. \\'Zonal aganglionosis\\' is a phenomenon involving a zone of aganglionosis occurring within normally innervated intestine. \\'Skip segment\\' Hirschsprung\\'s disease (SSHD) involves a \\'skip area\\' of normally ganglionated intestine, surrounded proximally and distally by aganglionosis. While Hirschsprung\\'s disease is believed to be the result of incomplete craniocaudal migration of neural crest-derived cells, the occurrence of SSHD has no clear embryological explanation. The aim of this study was to perform a systematic review of SSHD, reported in the literature between 1954 and 2009, in order to determine the clinical characteristics of this rare entity and its significance. METHODS: The first reported case of SSHD was published in 1954. A systematic review of SSHD cases in the literature, from 1954 to 2009, was carried out using the electronic database \\'Pubmed\\'. Detailed information was recorded regarding the age, gender, presenting symptoms and location of the skip segment in each patient. RESULTS: 24 cases of SSHD have been reported in the literature to date. 18\\/24 (75%) of these cases were males and 6\\/24 (25%) were females. Of these, 22\\/24 (92%) were cases of total colonic aganglionosis (TCA), and 2\\/24 (8%) were rectosigmoid Hirschsprung\\'s disease. Of the 22 TCA cases, 9 (41%) had a skip segment in the transverse colon, 6 (27%) in the ascending colon, 2 (9%) in the caecum and 5 (23%) had multiple skip segments. In both rectosigmoid Hirschsprung\\'s disease cases, the skip segment was in the sigmoid colon. Overall, the length of the skip segment was variable, with the entire transverse colon ganglionated in some cases. CONCLUSION: SSHD occurs predominantly in patients with TCA. The existence of a skip area of normally innervated colon in TCA may influence surgical

  16. Evolutionary history of exon shuffling.

    Science.gov (United States)

    França, Gustavo S; Cancherini, Douglas V; de Souza, Sandro J

    2012-06-01

    Exon shuffling has been characterized as one of the major evolutionary forces shaping both the genome and the proteome of eukaryotes. This mechanism was particularly important in the creation of multidomain proteins during animal evolution, bringing a number of functional genetic novelties. Here, genome information from a variety of eukaryotic species was used to address several issues related to the evolutionary history of exon shuffling. By comparing all protein sequences within each species, we were able to characterize exon shuffling signatures throughout metazoans. Intron phase (the position of the intron regarding the codon) and exon symmetry (the pattern of flanking introns for a given exon or block of adjacent exons) were features used to evaluate exon shuffling. We confirmed previous observations that exon shuffling mediated by phase 1 introns (1-1 exon shuffling) is the predominant kind in multicellular animals. Evidence is provided that such pattern was achieved since the early steps of animal evolution, supported by a detectable presence of 1-1 shuffling units in Trichoplax adhaerens and a considerable prevalence of them in Nematostella vectensis. In contrast, Monosiga brevicollis, one of the closest relatives of metazoans, and Arabidopsis thaliana, showed no evidence of 1-1 exon or domain shuffling above what it would be expected by chance. Instead, exon shuffling events are less abundant and predominantly mediated by phase 0 introns (0-0 exon shuffling) in those non-metazoan species. Moreover, an intermediate pattern of 1-1 and 0-0 exon shuffling was observed for the placozoan T. adhaerens, a primitive animal. Finally, characterization of flanking intron phases around domain borders allowed us to identify a common set of symmetric 1-1 domains that have been shuffled throughout the metazoan lineage.

  17. Power inverter implementing phase skipping control

    Science.gov (United States)

    Somani, Utsav; Amirahmadi, Ahmadreza; Jourdan, Charles; Batarseh, Issa

    2016-10-18

    A power inverter includes a DC/AC inverter having first, second and third phase circuitry coupled to receive power from a power source. A controller is coupled to a driver for each of the first, second and third phase circuitry (control input drivers). The controller includes an associated memory storing a phase skipping control algorithm, wherein the controller is coupled to receive updating information including a power level generated by the power source. The drivers are coupled to control inputs of the first, second and third phase circuitry, where the drivers are configured for receiving phase skipping control signals from the controller and outputting mode selection signals configured to dynamically select an operating mode for the DC/AC inverter from a Normal Control operation and a Phase Skipping Control operation which have different power injection patterns through the first, second and third phase circuitry depending upon the power level.

  18. The Relation between Breakfast Skipping and School Performance in Adolescents

    Science.gov (United States)

    Boschloo, Annemarie; Ouwehand, Carolijn; Dekker, Sanne; Lee, Nikki; de Groot, Renate; Krabbendam, Lydia; Jolles, Jelle

    2012-01-01

    Breakfast skipping is common in adolescents, but research on the effects of breakfast skipping on school performance is scarce. This current cross-sectional survey study of 605 adolescents aged 11-18 years investigated whether adolescents who habitually skip breakfast have lower end-of-term grades than adolescents who eat breakfast daily.…

  19. Stemcell Information: SKIP000206 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available kin遺伝子のexon毎に設計したprimerを用いてgenomic PCR解析を行った。|      その結果、患者由来線維芽細胞およびPA1.9.22iPSにおいてExon2,3,4のhomozygous del... : ICC法| Tra-1-81 : ICC法||染色体解析 : 実施 CGH array解析済み。PARK2遺伝子の欠損以外、変異は見当たらなかった。|胚葉体...形成実験 : 実施 胚葉体形成確認|テラトーマ形成実験 : 実施 テラトーマ形成確認|in vitro分化能解析 : 実施 神経への分化確認|マイコプラズマ汚染検査 : 実施 陰性|細胞同定検査(STR多型解析) : 未実施|クローニング : ||その他の特性情報 : 樹立に用いた外来遺伝子の発現抑制を確認した。

  20. Stemcell Information: SKIP000207 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available arkin遺伝子のexon毎に設計したprimerを用いてgenomic PCR解析を行った。|      その結果、患者由来線維芽細胞およびPA1.9.22iPSにおいてExon2,3,4のhomozygous d...60 : ICC法| Tra-1-81 : ICC法||染色体解析 : 実施 CGH array解析済み。PARK2遺伝子の欠損以外、変異は見当たらなかった。|胚...葉体形成実験 : 実施 胚葉体形成確認|テラトーマ形成実験 : 実施 テラトーマ形成確認|in vitro分化能解析 : 実施 神経への分化確認|マイコプラズマ汚染検査 : 実施 陰性|細胞同定検査(STR多型解析) : 未実施|クローニング : ||その他の特性情報 : 樹立に用いた外来遺伝子の発現抑制を確認した。

  1. Stemcell Information: SKIP000521 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available kin遺伝子のexon毎に設計したprimerを用いてgenomic PCR解析を行った。|      その結果、患者由来線維芽細胞およびPA1.9.22iPSにおいてExon2,3,4のhomozygous del... : ICC法| Tra-1-81 : ICC法||染色体解析 : 実施 CGH array解析済み。PARK2遺伝子の欠損以外、変異は見当たらなかった。|胚葉体...形成実験 : 実施 胚葉体形成確認|テラトーマ形成実験 : 実施 テラトーマ形成確認|in vitro分化能解析 : 実施 神経への分化確認|マイコプラズマ汚染検査 : 実施 陰性|細胞同定検査(STR多型解析) : 未実施|クローニング : ||その他の特性情報 : 樹立に用いた外来遺伝子の発現抑制を確認した。

  2. EasyExonPrimer: automated primer design for exon sequences.

    Science.gov (United States)

    Wu, Xiaolin; Munroe, David J

    2006-01-01

    EasyExonPrimer is a web-based software that automates the design of PCR primers to amplify exon sequences from genomic DNA. EasyExonPrimer is written in Perl and uses Primer3 to design PCR primers based on the genome builds and annotation databases available at the University of California, Santa Cruz (UCSC) Genome Browser database (http://genome.ucsc.edu/). It masks repeats and known single nucleotide polymorphism (SNP) sites in the genome and designs standardised primers using optimised conditions. Users can input genes by RefSeq mRNA ID, gene name or keyword. The primer design is optimised for large-scale resequencing of exons. For exons larger than 1 kb, the user has the option of breaking the exon sequence down into overlapping smaller fragments. All primer pairs are then verified using the In-Silico PCR software to test for uniqueness in the genome. We have designed >1000 pairs of primers for 90 genes; 95% of the primer pairs successfully amplified exon sequences under standard PCR conditions without requiring further optimisation. EasyExonPrimer is available from http://129.43.22.27/~primer/. The source code is also available upon request. Xiaolin Wu (forestwu@mail.nih.gov).

  3. DESIGN OF OPTIMAL CARRY SKIP ADDER AND CARRY SKIP BCD ADDER USING REVERSIBLE LOGIC GATES

    OpenAIRE

    Praveena Murugesan; Thanushkodi Keppanagounder

    2014-01-01

    Reversible logic circuits have the ability to produce zero power dissipation which has found its importance in quantum computing, optical computing and low power digital circuits. The study presents improved and efficient reversible logic circuits for carry skip adder and carry skip BCD adder. The performance of the proposed architecture is better than the existing works in terms of gate count, garbage outputs and constant inputs. This design forms the basis for different quantum ALU and embe...

  4. Correlates of meal skipping in young adults: a systematic review.

    Science.gov (United States)

    Pendergast, Felicity J; Livingstone, Katherine M; Worsley, Anthony; McNaughton, Sarah A

    2016-12-01

    Meal skipping rates may be highest during young adulthood, a period of transition and development. Although these dietary behaviours may increase future risk of chronic disease, limited research has investigated correlates of meal skipping in young adults. A systematic literature search was conducted to identify studies that investigated correlates of meal skipping behaviours in young adults (aged 18-30 years). EBSCO host, MEDLINE Complete, Global Health, Scopus, EMBASE, Web of Science and Informit platforms were searched for eligible articles. Correlates were defined as any factor that was either associated with meal skipping or was self-reported by the participant to have an influence on meal skipping. Randomised controlled trials, prospective cohort studies, case-control studies, nested case-control studies, cross-sectional studies, and longitudinal studies were eligible for inclusion. Three-hundred and thirty-one articles were identified, 141 full-text articles assessed for eligibility, resulting in 35 included studies. Multiple methodological and reporting weaknesses were apparent in the reviewed studies with 28 of the 35 studies scoring a negative rating in the risk of bias assessment. Meal skipping (any meal), defined as the skipping of any meal throughout the day, was reported in 12 studies with prevalence ranging between 5 and 83%. The remaining 25 studies identified specific meals and their skipping rates, with breakfast the most frequently skipped meal 14-88% compared to lunch 8-57% and dinner 4-57%. Lack of time was consistently reported as an important correlate of meal skipping, compared with correlates such as cost and weight control, while sex was the most commonly reported associated correlate. Breakfast skipping was more common among men while lunch or dinner skipping being more common among women. This review is the first to examine potential correlates of meal skipping in young adults. Future research would benefit from stronger design and

  5. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

    Science.gov (United States)

    Pilotto, Sara; Gkountakos, Anastasios; Carbognin, Luisa; Scarpa, Aldo; Tortora, Giampaolo

    2017-01-01

    The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients’ subgroup, are explored. PMID:28164087

  6. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy.

    Science.gov (United States)

    Pilotto, Sara; Gkountakos, Anastasios; Carbognin, Luisa; Scarpa, Aldo; Tortora, Giampaolo; Bria, Emilio

    2017-01-01

    The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

  7. Alternative Splicing of a Novel Inducible Exon Diversifies the CASK Guanylate Kinase Domain

    Directory of Open Access Journals (Sweden)

    Jill A. Dembowski

    2012-01-01

    Full Text Available Alternative pre-mRNA splicing has a major impact on cellular functions and development with the potential to fine-tune cellular localization, posttranslational modification, interaction properties, and expression levels of cognate proteins. The plasticity of regulation sets the stage for cells to adjust the relative levels of spliced mRNA isoforms in response to stress or stimulation. As part of an exon profiling analysis of mouse cortical neurons stimulated with high KCl to induce membrane depolarization, we detected a previously unrecognized exon (E24a of the CASK gene, which encodes for a conserved peptide insertion in the guanylate kinase interaction domain. Comparative sequence analysis shows that E24a appeared selectively in mammalian CASK genes as part of a >3,000 base pair intron insertion. We demonstrate that a combination of a naturally defective 5 splice site and negative regulation by several splicing factors, including SC35 (SRSF2 and ASF/SF2 (SRSF1, drives E24a skipping in most cell types. However, this negative regulation is countered with an observed increase in E24a inclusion after neuronal stimulation and NMDA receptor signaling. Taken together, E24a is typically a skipped exon, which awakens during neuronal stimulation with the potential to diversify the protein interaction properties of the CASK polypeptide.

  8. Maternal and best friends' influences on meal-skipping behaviours.

    Science.gov (United States)

    Pearson, Natalie; Williams, Lauren; Crawford, David; Ball, Kylie

    2012-09-01

    Skipping meals is particularly common during adolescence and can have a detrimental effect on multiple aspects of adolescent health. Understanding the correlates of meal-skipping behaviours is important for the design of nutrition interventions. The present study examined maternal and best friends' influences on adolescent meal-skipping behaviours. Frequency of skipping breakfast, lunch and dinner was assessed using a Web-based survey completed by 3001 adolescent boys and girls from years 7 and 9 of secondary schools in Victoria, Australia. Perceived best friend and maternal meal skipping, modelling of healthy eating (eating healthy food, limiting junk food, eating fruit and vegetables) and weight watching were assessed. Best friend and maternal factors were differentially associated with meal-skipping behaviours. For example, boys and girls who perceived that their best friend often skipped meals were more likely to skip lunch (OR = 2·01, 95 % CI 1·33, 3·04 and OR = 1·93, 95 % CI 1·41, 2·65; P adolescents on how to assess and interpret unhealthy eating behaviours that they observe from significant others may be one nutrition promotion strategy to reduce meal-skipping behaviour. The involvement of mothers may be particularly important in such efforts. Encouraging a peer subculture that promotes regular consumption of meals and educates adolescents on the detrimental impact of meal-skipping behaviour on health may also offer a promising nutrition promotion strategy.

  9. IVs to Skip for Immunizing WEP against FMS Attack

    Science.gov (United States)

    Kobara, Kazukuni; Imai, Hideki

    The WEP (Wired Equivalent Privacy) is a part of IEEE 802.11 standard designed for protecting over-the-air communication. While almost all of the WLAN (Wireless LAN) cards and the APs (Access Points) support WEP, a serious key recovery attack (aka FMS attack) was identified by Fluhrer et al. The FMS attack can basically be prevented by skipping IVs (Initial Values) used in the attack, but naive skip methods reveal information on the WEP key since most of them depend on the WEP key and the patterns of the skipped IV reveal it. In order to skip IVs safely, the skip patterns must be chosen carefully. In this paper, we review the attack conditions (6) and (7), whose success probability is the highest, 0.05, amongst all known conditions to guess one key-byte from one packet. Then we identify their safe skip patterns.

  10. Proteins, exons and molecular evolution.

    Science.gov (United States)

    Holland, S K; Blake, C C

    1987-01-01

    The discovery of the eukaryotic gene structure has prompted research into the potential relationship between protein structure and function and the corresponding exon/intron patterns. The exon shuffling hypothesis put forward by Gilbert and Blake suggests the encodement of structural and functional protein elements by exons which can recombine to create novel proteins. This provides an explanation for the relatively rapid evolution of proteins from a few primordial molecules. As the number of gene and protein structures increases, evidence of exon shuffling is becoming more apparent and examples are presented both from modern multi-domain proteins and ancient proteins. Recent work into the chemical properties and catalytic functions of RNA have led to hypotheses based upon the early existence of RNA. These theories suggest that the split gene structure originated in the primordial soup as a result of random RNA synthesis. Stable regions of RNA, or exons, were utilised as primitive enzymes. In response to selective pressures for information storage, the activity was directly transferred from the RNA enzymes or ribozymes, to proteins. These short polypeptides fused together to create larger proteins with a wide range of functions. Recent research into RNA processing and exon size, discussed in this review, provides a clearer insight into the evolutionary development of the gene and protein structure.

  11. SkipCor: skip-mention coreference resolution using linear-chain conditional random fields.

    Directory of Open Access Journals (Sweden)

    Slavko Žitnik

    Full Text Available Coreference resolution tries to identify all expressions (called mentions in observed text that refer to the same entity. Beside entity extraction and relation extraction, it represents one of the three complementary tasks in Information Extraction. In this paper we describe a novel coreference resolution system SkipCor that reformulates the problem as a sequence labeling task. None of the existing supervised, unsupervised, pairwise or sequence-based models are similar to our approach, which only uses linear-chain conditional random fields and supports high scalability with fast model training and inference, and a straightforward parallelization. We evaluate the proposed system against the ACE 2004, CoNLL 2012 and SemEval 2010 benchmark datasets. SkipCor clearly outperforms two baseline systems that detect coreferentiality using the same features as SkipCor. The obtained results are at least comparable to the current state-of-the-art in coreference resolution.

  12. Optimization Research of Mine Skip Quantitative Loading System

    Science.gov (United States)

    Wang, Shuang; Hu, Kun; Cheng, Gang; Li, De-yong

    2016-06-01

    The size and change of the impact load of coal material applied to the skip are studied aiming at the quantitative loading system of the skip. Based on the impulse theorem and with reasonable assumption, the calculation formula for impact force of the coal material is deducted and the impact characteristic of the impact force to the quantitative loading system of the skip is analyzed. The process of the coal material falling from quantitative conveyor to skip is analyzed with the discrete element simulation so that the distributed load of the impact force of the coal material at the skip bottom is obtained. The results show that the coal material produces large impact force (687 N) to the skip bottom the moment the coal material falls into the skip, and then the force decreases rapidly to about 245 N and increases gradually during the fluctuation; the impact force applied to the skip bottom increases with the increase of the coal transportation speed and the size of discharging port of the chute, but it is not in direct proportional relationship. The simulation results are basically the same as the experimental results. Finally the optimization parameters of the speed of quantitative conveyor and the size of the discharging port of the chute are searched for so as to improve the capacity of the conveyor and impact load assumed by the skip bottom.

  13. Skipped spawning in fishes: More common than you might think

    DEFF Research Database (Denmark)

    Rideout, Rick M.; Tomkiewicz, Jonna

    2011-01-01

    on elemental and isotope signatures. Skipped spawning is most commonly attributed to deficient diet and poor nutritional condition. Advances made in this field of study in recent years include descriptions of hormonal changes that precede and perhaps initiate skipped spawning, the development of life history...... research on skipped spawning, covering a broad range of fishes with diverse life history strategies. Evidence for skipped spawning has been collected by use of traditional histological techniques as well as modern technological advances, such as satellite tags and the ability to track fish movements based...

  14. 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

    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...... 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...... either of the two mutated receptors lacked basal or stimulated IR beta-subunit autophosphorylation. A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype....

  15. Decoding of exon splicing patterns in the human RUNX1-RUNX1T1 fusion gene.

    Science.gov (United States)

    Grinev, Vasily V; Migas, Alexandr A; Kirsanava, Aksana D; Mishkova, Olga A; Siomava, Natalia; Ramanouskaya, Tatiana V; Vaitsiankova, Alina V; Ilyushonak, Ilia M; Nazarov, Petr V; Vallar, Laurent; Aleinikova, Olga V

    2015-11-01

    The t(8;21) translocation is the most widespread genetic defect found in human acute myeloid leukemia. This translocation results in the RUNX1-RUNX1T1 fusion gene that produces a wide variety of alternative transcripts and influences the course of the disease. The rules of combinatorics and splicing of exons in the RUNX1-RUNX1T1 transcripts are not known. To address this issue, we developed an exon graph model of the fusion gene organization and evaluated its local exon combinatorics by the exon combinatorial index (ECI). Here we show that the local exon combinatorics of the RUNX1-RUNX1T1 gene follows a power-law behavior and (i) the vast majority of exons has a low ECI, (ii) only a small part is represented by "exons-hubs" of splicing with very high ECI values, and (iii) it is scale-free and very sensitive to targeted skipping of "exons-hubs". Stochasticity of the splicing machinery and preferred usage of exons in alternative splicing can explain such behavior of the system. Stochasticity may explain up to 12% of the ECI variance and results in a number of non-coding and unproductive transcripts that can be considered as a noise. Half-life of these transcripts is increased due to the deregulation of some key genes of the nonsense-mediated decay system in leukemia cells. On the other hand, preferred usage of exons may explain up to 75% of the ECI variability. Our analysis revealed a set of splicing-related cis-regulatory motifs that can explain "attractiveness" of exons in alternative splicing but only when they are considered together. Cis-regulatory motifs are guides for splicing trans-factors and we observed a leukemia-specific profile of expression of the splicing genes in t(8;21)-positive blasts. Altogether, our results show that alternative splicing of the RUNX1-RUNX1T1 transcripts follows strict rules and that the power-law component of the fusion gene organization confers a high flexibility to this process.

  16. Comparative Training Responses to Rope Skipping and Jogging.

    Science.gov (United States)

    Buyze, Michael T.; And Others

    1986-01-01

    This study compared physiological adaptations of 26 sedentary volunteers to six-week programs of jogging and rope skipping in order to test whether 10 minutes of rope skipping is equal to 30 minutes of jogging for improved cardiovascular efficiency. Results are discussed. (Author/MT)

  17. Efficient carry skip Adder design using full adder and carry skip block based on reversible Logic

    Directory of Open Access Journals (Sweden)

    Varun Pratap Singh

    2015-12-01

    Full Text Available In recent years, Reversible Logic is becoming more and more prominent technology having its applications in Quantum Computing, Nanotechnology, and Optical Computing. Reversibility plays an important role when energy efficient computations are considered. In this paper, binary full Adder with Design I and Design II are proposed. The performance analysis is verified using number of reversible gates, Garbage input/outputs, delay, number of logical calculations and Quantum Cost. According to the suitability of full adder design I and design II carry skip adder block is also constructed with some improvement in terms of delay in block carry generation. It is observed that Reversible carry skip Binary Adder with Design II is efficient compared to Design I

  18. Update History of This Database - SKIP Stemcell Database | LSDB Archive [Life Science Database Archive metadata

    Lifescience Database Archive (English)

    Full Text Available List Contact us SKIP Stemcell Database Update History of This Database Date Update contents 2017/03/13 SKIP Stemcell Database... English archive site is opened. 2013/03/29 SKIP Stemcell Database ( https://www.skip.med.k...eio.ac.jp/SKIPSearch/top?lang=en ) is opened. About This Database Database Description Download License Upda...te History of This Database Site Policy | Contact Us Update History of This Database - SKIP Stemcell Database | LSDB Archive ...

  19. Kinematic characteristics of motor patterns in rope skipping

    OpenAIRE

    Luiz Henrique da Silva; Ana Maria Pellegrini

    2009-01-01

    Rope skipping seems to be an easy task to be performed. However, careful analysis of this motor skill shows how complex the execution of this task is. The objective of this study was to examine kinematic variables of jump patterns as a function of skipping frequency. Eight male university students performed a sequence of 30 rope jumps using two jump patterns (alternating support of the feet and simultaneous support of the feet) at three skipping frequencies (1.5, 1.7,1.9 Hz). Frequencies were...

  20. Modeling and Analysis of Pulse Skip Modulation

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    The state space average model and the large signal models of Pulse Skip Modulation (PSM) mode are given in this paper. Farther more, based on these models and simulations of PSM converter circuits, the analysis of the characteristics of PSM converter is described in this paper, of which include efficiency, frequency spectrum analysis, output voltage ripple, response speed and interference rejection capability. Compared with PWM control mode, PSM converter has high efficiency, especially with light loads, quick response, good interference rejection and good EMC characteristic. Improved PSM slightly, it could be a kind of good independent regulating mode during the whole operating process for a DC-DC converter. Finally, some experimental results are also presented in this paper.

  1. GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells

    Directory of Open Access Journals (Sweden)

    Erik van der Wal

    2017-06-01

    Full Text Available Pompe disease is a metabolic myopathy caused by deficiency of the acid α-glucosidase (GAA enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1 GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells. To test this, we expanded induced pluripotent stem cell (iPSC-derived myogenic progenitors and differentiated these to multinucleated myotubes. AONs restored splicing in myotubes to a similar extent as in fibroblasts, suggesting that they act by modulating the action of shared splicing regulators. AONs targeted the putative polypyrimidine tract of a cryptic splice acceptor site that was part of a pseudo exon in GAA intron 1. Blocking of the cryptic splice donor of the pseudo exon with AONs likewise promoted GAA exon 2 inclusion. The simultaneous blocking of the cryptic acceptor and cryptic donor sites restored the majority of canonical splicing and alleviated GAA enzyme deficiency. These results highlight the relevance of cryptic splicing in human disease and its potential as therapeutic target for splicing modulation using AONs.

  2. Skip the Antibiotics for Mild Eczema in Kids

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_164083.html Skip the Antibiotics for Mild Eczema in Kids Skin condition cleared ... March 14, 2017 (HealthDay News) -- Despite widespread use, antibiotics are not an effective treatment for milder cases ...

  3. Snacking behaviours of adolescents and their association with skipping meals

    OpenAIRE

    Worsley Anthony; Ball Kylie; MacFarlane Abbie; Savige Gayle; Crawford David

    2007-01-01

    Abstract Background Snacking is likely to play an important role in the development of overweight and obesity, yet little is known about the contexts of snacking in adolescents or how snacking may influence other dietary habits, like meal skipping. This study examines the contexts in which adolescents snack and whether these contexts are associated with demographic characteristics of adolescents and with meal skipping. Methods A cross-sectional, self-reported online food habits survey was adm...

  4. Optimal design method for fast carry-skip adders

    Science.gov (United States)

    Lee, Songjun; Swartzlander, Earl E., Jr.

    2001-11-01

    A carry-skip adder is faster than a ripple carry adder and it has a simple structure. To maximize the speed it is necessary to optimize the width of the blocks that comprise the carry skip adder. This paper presents a simple algorithm to select the size of each block. Assuming that each logic gate has a unit delay, the algorithm achieves slightly faster designs for 64 and 128 bit adders than previous methods developed by Guyot, et al. and Kantabutra.

  5. Quantization Skipping Method for H.264/AVC Video Coding

    Institute of Scientific and Technical Information of China (English)

    Won-seon SONG; Min-cheol HONG

    2010-01-01

    This paper presents a quantization skipping method for H.264/AVC video coding standard. In order to reduce the computational-cost of quantization process coming from integer discrete cosine transform of H.264/AVC, a quantization skipping condition is derived by the analysis of integer transform and quantization procedures. The experimental results show that the proposed algorithm has the capability to reduce the computational cost about 10%~25%.

  6. Gene correction of a duchenne muscular dystrophy mutation by meganuclease-enhanced exon knock-in.

    Science.gov (United States)

    Popplewell, Linda; Koo, Taeyoung; Leclerc, Xavier; Duclert, Aymeric; Mamchaoui, Kamel; Gouble, Agnés; Mouly, Vincent; Voit, Thomas; Pâques, Frédéric; Cédrone, Frédéric; Isman, Olga; Yáñez-Muñoz, Rafael J; Dickson, George

    2013-07-01

    Duchenne muscular dystrophy (DMD) is a severe inherited, muscle-wasting disorder caused by mutations in the DMD gene. Gene therapy development for DMD has concentrated on vector-based DMD minigene transfer, cell-based gene therapy using genetically modified adult muscle stem cells or healthy wild-type donor cells, and antisense oligonucleotide-induced exon-skipping therapy to restore the reading frame of the mutated DMD gene. This study is an investigation into DMD gene targeting-mediated correction of deletions in human patient myoblasts using a target-specific meganuclease (MN) and a homologous recombination repair matrix. The MN was designed to cleave within DMD intron 44, upstream of a deletion hotspot, and integration-competent lentiviral vectors expressing the nuclease (LVcMN) were generated. MN western blotting and deep gene sequencing for LVcMN-induced non-homologous end-joining InDels (microdeletions or microinsertions) confirmed efficient MN expression and activity in transduced DMD myoblasts. A homologous repair matrix carrying exons 45-52 (RM45-52) was designed and packaged into integration-deficient lentiviral vectors (IDLVs; LVdRM45-52). After cotransduction of DMD myoblasts harboring a deletion of exons 45 to 52 with LVcMN and LVdRM45-52 vectors, targeted knock-in of the RM45-52 region in the correct location in DMD intron 44, and expression of full-length, correctly spliced wild-type dystrophin mRNA containing exons 45-52 were observed. This work demonstrates that genome surgery on human DMD gene mutations can be achieved by MN-induced locus-specific genome cleavage and homologous recombination knock-in of deleted exons. The feasibility of human DMD gene repair in patient myoblasts has exciting therapeutic potential.

  7. The emergence of alternative 3' and 5' splice site exons from constitutive exons.

    Directory of Open Access Journals (Sweden)

    Eli Koren

    2007-05-01

    Full Text Available Alternative 3' and 5' splice site (ss events constitute a significant part of all alternative splicing events. These events were also found to be related to several aberrant splicing diseases. However, only few of the characteristics that distinguish these events from alternative cassette exons are known currently. In this study, we compared the characteristics of constitutive exons, alternative cassette exons, and alternative 3'ss and 5'ss exons. The results revealed that alternative 3'ss and 5'ss exons are an intermediate state between constitutive and alternative cassette exons, where the constitutive side resembles constitutive exons, and the alternative side resembles alternative cassette exons. The results also show that alternative 3'ss and 5'ss exons exhibit low levels of symmetry (frame-preserving, similar to constitutive exons, whereas the sequence between the two alternative splice sites shows high symmetry levels, similar to alternative cassette exons. In addition, flanking intronic conservation analysis revealed that exons whose alternative splice sites are at least nine nucleotides apart show a high conservation level, indicating intronic participation in the regulation of their splicing, whereas exons whose alternative splice sites are fewer than nine nucleotides apart show a low conservation level. Further examination of these exons, spanning seven vertebrate species, suggests an evolutionary model in which the alternative state is a derivative of an ancestral constitutive exon, where a mutation inside the exon or along the flanking intron resulted in the creation of a new splice site that competes with the original one, leading to alternative splice site selection. This model was validated experimentally on four exons, showing that they indeed originated from constitutive exons that acquired a new competing splice site during evolution.

  8. 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.

  9. Exon circularization in mammalian nuclear extracts.

    Science.gov (United States)

    Pasman, Z; Been, M D; Garcia-Blanco, M A

    1996-06-01

    Correct ligation of exons in pre-mRNA splicing requires splice site juxtaposition (splice site pairing), usually involving a 5' splice site and a downstream 3' splice site. Splicing of a 5' splice site to an upstream 3' splice site, however, is predicted to result in a circular RNA. This mode of splice site pairing across the axon has been hypothesized to account for rare RNAs containing scrambled exons (Nigro JM et al., 1991, Celt 64:607-613; Cocquerelle C et al., 1992, EMBO J 11:1 095-1098). Additionally, this mode of splice site pairing has been postulated to explain the formation of SRY circular transcripts in mouse testis (Capel B et al., 1993, Celt 73:1019- 1030). Here we show that splice site pairing across the exon can result in exon circularization in vitro. These results indicate that spliceosome-mediated axon circularization indeed can account for the formation of scrambled exons and circular RNAs. Exon circularization efficiency decreased dramatically as the length of the exon was increased from 95 nt to 274 nt. Circularization of this longer exon was restored, however, when intronic complementary sequences were included in the RNA substrate. These complementary sequences could form a stem that served to bring the splice sites into proximity and thereby promote splice site pairing. Therefore, the splicing of this structured RNA recapitulated SRY-like exon circularization in vitro.

  10. Mechanistic Evaluation for Mixed-field Agglutination in the K562 Cell Study Model with Exon 3 Deletion of A1 Gene.

    Science.gov (United States)

    Chen, Ding-Ping; Tseng, Ching-Ping; Lin, Chi-Jui; Wang, Wei-Ting; Sun, Chien-Feng

    2015-01-01

    In the case of blood type B3 with typical mixed-field agglutination of RBCs in the presence of anti-B or anti-AB antibody, a number of genetic alternations have been reported. It is well known that the IVS3+5G→A mutation in the B gene destroys the consensus of the splice donor site leading to exon 3 skipping during mRNA splicing. The lack of exon 3 likely causes a short stem region, producing an unstable B3 protein, and is concomitant with a decrease in B3 protein expression. Whether the phenomenon also appears in the type A blood group is of question. In this study, we evaluate whether exon 3 deletion in the blood type A gene also results in mixed-field phenotype. Site-directed mutagenesis was used to generate cDNA encoding A1 gene with exon 3 deletion. The cDNA was stably expressed in K562 cells. The expression of A antigen was compared with expression in parental K562 cells that did not express A antigen and in the stable K562 cell line expressing A(1) cDNA by flow cytometry analyses. The expression of A antigen in A1 stable cells and parental K562 cells was set as 100% and 0%, respectively. The mean relative percentage of A antigen expression for the cells of A1 with exon 3 deletion was 59.9% of A1 stable cells. Consistent with the observations of B3, which is B gene with exon 3 deletion, mixed field agglutination was observed for the cells expressing A1 with exon 3 deletion. Exon 3 deletion results in mixed field phenotype in both type A and B RBCs. However, the degree of antigen expression change for exon 3 deletion in A gene was less severe when compared with the deletion occurred in B gene.

  11. One Way to Design a Valence-Skip Compound

    Science.gov (United States)

    Hase, I.; Yanagisawa, T.; Kawashima, K.

    2017-02-01

    Valence-skip compound is a good candidate with high T c and low anisotropy because it has a large attractive interaction at the site of valence-skip atom. However, it is not easy to synthesize such compound because of (i) the instability of the skipping valence state, (ii) the competing charge order, and (iii) that formal valence may not be true in some compounds. In the present study, we show several examples of the valence-skip compounds and discuss how we can design them by first principles calculations. Furthermore, we calculated the electronic structure of a promising candidate of valence skipping compound RbTlCl3 from first principles. We confirmed that the charge-density wave (CDW) is formed in this compound, and the Tl atoms in two crystallographic different sites take the valence Tl1+ and Tl3+. Structure optimization study reveals that this CDW is stable at the ambient pressure, while this CDW gap can be collapsed when we apply pressure with several gigapascals. In this metallic phase, we can expect a large charge fluctuation and a large electron-phonon interaction.

  12. Skipped words and fixated words are processed differently during reading.

    Science.gov (United States)

    Eskenazi, Michael A; Folk, Jocelyn R

    2015-04-01

    The purpose of this study was to investigate whether words are processed differently when they are fixated during silent reading than when they are skipped. According to a serial processing model of eye movement control (e.g., EZ Reader) skipped words are fully processed (Reichle, Rayner, Pollatsek, Behavioral and Brain Sciences, 26(04):445-476, 2003), whereas in a parallel processing model (e.g., SWIFT) skipped words do not need to be fully processed (Engbert, Nuthmann, Richter, Kliegl, Psychological Review, 112(4):777-813, 2005). Participants read 34 sentences with target words embedded in them while their eye movements were recorded. All target words were three-letter, low-frequency, and unpredictable nouns. After the reading session, participants completed a repetition priming lexical decision task with the target words from the reading session included as the repetition prime targets, with presentation of those same words during the reading task acting as the prime. When participants skipped a word during the reading session, their reaction times on the lexical decision task were significantly longer (M = 656.42 ms) than when they fixated the word (M = 614.43 ms). This result provides evidence that skipped words are sometimes not processed to the same degree as fixated words during reading.

  13. Breakfast Skipping, Extreme Commutes, and the Sex Composition at Birth.

    Science.gov (United States)

    Mazumder, Bhashkar; Seeskin, Zachary

    2015-01-01

    A growing body of literature has shown that environmental exposures in the period around conception can affect the sex ratio at birth through selective attrition that favors the survival of female conceptuses. Glucose availability is considered a key indicator of the fetal environment, and its absence as a result of meal skipping may inhibit male survival. We hypothesize that breakfast skipping during pregnancy may lead to a reduction in the fraction of male births. Using time use data from the United States we show that women with commute times of 90 minutes or longer are 20 percentage points more likely to skip breakfast. Using U.S. census data we show that women with commute times of 90 minutes or longer are 1.2 percentage points less likely to have a male child under the age of 2. Under some assumptions, this implies that routinely skipping breakfast around the time of conception leads to a 6 percentage point reduction in the probability of a male child. Skipping breakfast during pregnancy may therefore constitute a poor environment for fetal health more generally.

  14. 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.

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

    Science.gov (United States)

    Numata, Kazuyuki; Yoshida, Ryo; Nagasaki, Masao; Saito, Ayumu; Imoto, Seiya; Miyano, Satoru

    2008-01-01

    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 . 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. PMID:19036125

  16. Delay Efficient 32-Bit Carry-Skip Adder

    Directory of Open Access Journals (Sweden)

    Yu Shen Lin

    2008-01-01

    Full Text Available The design of a 32-bit carry-skip adder to achieve minimum delay is presented in this paper. A fast carry look-ahead logic using group generate and group propagate functions is used to speed up the performance of multiple stages of ripple carry adders. The group generate and group propagate functions are generated in parallel with the carry generation for each block. The optimum block sizes are decided by considering the critical path into account. The new architecture delivers the sum and carry outputs in lesser unit delays than existing carry-skip adders. The adder is implemented in 0.25 m CMOS technology at 3.3 V. The critical delay for the proposed adder is 3.4 nanoseconds. The simulation results show that the proposed adder is 18% faster than the current fastest carry-skip adder.

  17. Metabolic and Cardiorespiratory Responses of Young Women to Skipping and Jogging.

    Science.gov (United States)

    Allen, T. Earl; And Others

    1987-01-01

    Nine 18- to 29-year-old females were studied while jogging and skipping at treadmill speeds of 4.0, 4.8, and 5.4 miles per hour. Comparison of metabolic demand, musculoskeletal stress, and perceived exertion indicated skipping imposed significantly greater metabolic demands and caused higher heart rates than jogging. Skipping was also rated more…

  18. Social inequalities in young children's meal skipping behaviors: The Generation R Study

    NARCIS (Netherlands)

    A.I. Wijtzes (Anne); W. Jansen (Wilma); V.W.V. Jaddoe (Vincent W. V.); O.H. Franco (Oscar); A. Hofman (Albert); F.J. van Lenthe (Frank); H. Raat (Hein)

    2015-01-01

    textabstractBackground: Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young

  19. Social inequalities in young children's meal skipping behaviors: The Generation R Study

    NARCIS (Netherlands)

    A.I. Wijtzes (Anne); W. Jansen (Wilma); V.W.V. Jaddoe (Vincent W. V.); O.H. Franco (Oscar); A. Hofman (Albert); F.J. van Lenthe (Frank); H. Raat (Hein)

    2015-01-01

    textabstractBackground: Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young school

  20. Children's Perceptions of Parental Attitude Affecting Breakfast Skipping in Primary Sixth-Grade Students

    Science.gov (United States)

    Cheng, Tereza Sy; Tse, Lap Ah; Yu, Ignatius Tak-Sun; Griffiths, Sian

    2008-01-01

    Background: Breakfast skipping is an international public health concern. This study investigated the prevalence of breakfast skipping among primary sixth-grade students in Hong Kong and the impact of students' perceptions of parental attitudes on breakfast skipping. Methods: A total of 426 students aged 10-14 years in 4 local schools participated…

  1. Snacking behaviours of adolescents and their association with skipping meals

    Directory of Open Access Journals (Sweden)

    Worsley Anthony

    2007-09-01

    Full Text Available Abstract Background Snacking is likely to play an important role in the development of overweight and obesity, yet little is known about the contexts of snacking in adolescents or how snacking may influence other dietary habits, like meal skipping. This study examines the contexts in which adolescents snack and whether these contexts are associated with demographic characteristics of adolescents and with meal skipping. Methods A cross-sectional, self-reported online food habits survey was administered to 3,250 secondary students in years seven and nine. The students were drawn from 37 secondary schools in Victoria, Australia during 2004–2005. Frequencies of meal skipping, and snacking in eight contexts, were compared across gender, year level and region of residence. Logistic regressions were performed to examine associations between snacking contexts and meal skipping adjusting for gender and region. Results The most common contexts for snacking among adolescents were after school (4.6 times per week, while watching TV (3.5 times per week and while hanging out with friends (2.4 times per week. Adolescents were least likely to snack all day long (0.8 times per week or in the middle of the night (0.4 times per week. Snacking contexts were variously associated with gender, year level and region. In contrast, meal skipping was associated with gender and region of residence but not year level. Adolescents who reported more frequent snacking on the run, on the way to or from school, all day long, or in the middle of the night were more likely to skip meals. Conclusion These data suggest adolescents snack frequently, especially in their leisure time. In addition, adolescents who snack on the run, on the way to or from school, all day long or in the middle of the night are more likely to skip meals than are adolescents who don't snack at these times. Understanding the contexts in which adolescents snack, and their associations with skipping meals

  2. Remarkable selective constraints on exonic dinucleotide repeats.

    Science.gov (United States)

    Haasl, Ryan J; Payseur, Bret A

    2014-09-01

    Long dinucleotide repeats found in exons present a substantial mutational hazard: mutations at these loci occur often and generate frameshifts. Here, we provide clear and compelling evidence that exonic dinucleotides experience strong selective constraint. In humans, only 18 exonic dinucleotides have repeat lengths greater than six, which contrasts sharply with the genome-wide distribution of dinucleotides. We genotyped each of these dinucleotides in 200 humans from eight 1000 Genomes Project populations and found a near-absence of polymorphism. More remarkably, divergence data demonstrate that repeat lengths have been conserved across the primate phylogeny in spite of what is likely considerable mutational pressure. Coalescent simulations show that even a very low mutation rate at these loci fails to explain the anomalous patterns of polymorphism and divergence. Our data support two related selective constraints on the evolution of exonic dinucleotides: a short-term intolerance for any change to repeat length and a long-term prevention of increases to repeat length. In general, our results implicate purifying selection as the force that eliminates new, deleterious mutants at exonic dinucleotides. We briefly discuss the evolution of the longest exonic dinucleotide in the human genome--a 10 x CA repeat in fibroblast growth factor receptor-like 1 (FGFRL1)--that should possess a considerably greater mutation rate than any other exonic dinucleotide and therefore generate a large number of deleterious variants. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  3. How are exons encoding transmembrane sequences distributed in the exon-intron structure of genes?

    Science.gov (United States)

    Sawada, Ryusuke; Mitaku, Shigeki

    2011-01-01

    The exon-intron structure of eukaryotic genes raises a question about the distribution of transmembrane regions in membrane proteins. Were exons that encode transmembrane regions formed simply by inserting introns into preexisting genes or by some kind of exon shuffling? To answer this question, the exon-per-gene distribution was analyzed for all genes in 40 eukaryotic genomes with a particular focus on exons encoding transmembrane segments. In 21 higher multicellular eukaryotes, the percentage of multi-exon genes (those containing at least one intron) within all genes in a genome was high (>70%) and with a mean of 87%. When genes were grouped by the number of exons per gene in higher eukaryotes, good exponential distributions were obtained not only for all genes but also for the exons encoding transmembrane segments, leading to a constant ratio of membrane proteins independent of the exon-per-gene number. The positional distribution of transmembrane regions in single-pass membrane proteins showed that they are generally located in the amino or carboxyl terminal regions. This nonrandom distribution of transmembrane regions explains the constant ratio of membrane proteins to the exon-per-gene numbers because there are always two terminal (i.e., the amino and carboxyl) regions - independent of the length of sequences.

  4. Skipping Syntactically Illegal "the" Previews: The Role of Predictability

    Science.gov (United States)

    Abbott, Matthew J.; Angele, Bernhard; Ahn, Y. Danbi; Rayner, Keith

    2015-01-01

    Readers tend to skip words, particularly when they are short, frequent, or predictable. Angele and Rayner (2013) recently reported that readers are often unable to detect syntactic anomalies in parafoveal vision. In the present study, we manipulated target word predictability to assess whether contextual constraint modulates…

  5. Effect of skipping breakfast on subsequent energy intake.

    Science.gov (United States)

    Levitsky, David A; Pacanowski, Carly R

    2013-07-02

    The objective was to examine the effect of consuming breakfast on subsequent energy intake. Participants who habitually ate breakfast and those who skipped breakfast were recruited for two studies. Using a randomized crossover design, the first study examined the effect of having participants consume either (a) no breakfast, (b) a high carbohydrate breakfast (335 kcals), or (c) a high fiber breakfast (360 kcals) on three occasions and measured ad libitum intake at lunch. The second study again used a randomized crossover design but with a larger, normal carbohydrate breakfast consumed ad libtum. Intake averaged 624 kcals and subsequent food intake was measured throughout the day. Participants ate only foods served from the Cornell Human Metabolic Research Unit where all foods were weighed before and after consumption. In the first study, neither eating breakfast nor the kind of breakfast consumed had an effect on the amount consumed at lunch despite a reduction in hunger ratings. In the second study, intake at lunch as well as hunger ratings were significantly increased after skipping breakfast (by 144 kcal), leaving a net caloric deficit of 408 kcal by the end of the day. These data are consistent with published literature demonstrating that skipping a meal does not result in accurate energy compensation at subsequent meals and suggests that skipping breakfast may be an effective means to reduce daily energy intake in some adults.

  6. The relation between breakfast skipping and school performance in adolescents

    NARCIS (Netherlands)

    Boschloo, Annemarie; Ouwehand, Carolijn; Dekker, Sanne; Lee, Nikki; De Groot, Renate; Krabbendam, Lydia; Jolles, Jelle

    2012-01-01

    Boschloo, A., Ouwehand, C., Dekker, S., Lee, N., De Groot, R., Krabbendam, L., & Jolles, J. (2012). The relation between breakfast skipping and school performance in adolescents. Mind, Brain, and Education, 6(2), 81-88. doi:10.1111/j.1751-228x.2012.01138.x

  7. Mutations in the unc-52 gene responsible for body wall muscle defects in adult Caenorhabditis elegans are located in alternatively spliced exons

    Energy Technology Data Exchange (ETDEWEB)

    Rogalski, T.M.; Gilchrist, E.J.; Mullen, G.P. [Univ. of British, Columbia, Vancouver (Canada)] [and others

    1995-01-01

    The unc-52 gene in Caenorhabditis elegans produces several large proteins that function in the basement membrane underlying muscle cells. Mutations in this gene result in defects in myofilament assembly and in the attachment of the myofilament lattice to the muscle cell membrane. The st549 and ut111 alleles of unc-52 produce a lethal (Pat) terminal phenotype whereas the e444, e669, e998, e1012 and e1421 mutations result in viable, paralyzed animals. We have identified the sequence alterations responsible for these mutant phenotypes. The st549 allele has a premature stop codon in exon 7 that should result in the complete elimination of unc-52 gene function, and the ut111 allele has a Tc1 transposon inserted into the second exon of the gene. The five remaining mutations are clustered in a small interval containing three adjacent, alternatively spliced exons (16, 17 and 18). These mutations affect some, but not all of the unc-52-encoded proteins. Thirteen intragenic revertants of the e669, e998, e1012 and e1421 alleles have also been sequenced. The majority of these carry the original mutation plus a G to A transition in the conserved splice acceptor site of the affected exon. This result suggests that reversion of the mutant phenotype in these strains may be the result of exon-skipping. 38 refs., 6 figs., 2 tabs.

  8. 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.

  9. Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment.

    Science.gov (United States)

    Betts, Corinne; Saleh, Amer F; Arzumanov, Andrey A; Hammond, Suzan M; Godfrey, Caroline; Coursindel, Thibault; Gait, Michael J; Wood, Matthew Ja

    2012-08-14

    Antisense oligonucleotides (AOs) are currently the most promising therapeutic intervention for Duchenne muscular dystrophy (DMD). AOs modulate dystrophin pre-mRNA splicing, thereby specifically restoring the dystrophin reading frame and generating a truncated but semifunctional dystrophin protein. Challenges in the development of this approach are the relatively poor systemic AO delivery and inefficient dystrophin correction in affected non-skeletal muscle tissues, including the heart. We have previously reported impressive heart activity including high-splicing efficiency and dystrophin restoration following a single administration of an arginine-rich cell-penetrating peptide (CPPs) conjugated to a phosphorodiamidate morpholino oligonucleotide (PMO): Pip5e-PMO. However, the mechanisms underlying this activity are poorly understood. Here, we report studies involving single dose administration (12.5 mg/kg) of derivatives of Pip5e-PMO, consecutively assigned as Pip6-PMOs. These peptide-PMOs comprise alterations to the central hydrophobic core of the Pip5e peptide and illustrate that certain changes to the peptide sequence improves its activity; however, partial deletions within the hydrophobic core abolish its efficiency. Our data indicate that the hydrophobic core of the Pip sequences is critical for PMO delivery to the heart and that specific modifications to this region can enhance activity further. The results have implications for therapeutic PMO development for DMD.

  10. Parallel Synthesis of Cell-Penetrating Peptide Conjugates of PMO Toward Exon Skipping Enhancement in Duchenne Muscular Dystrophy

    NARCIS (Netherlands)

    O'Donovan, Liz; Okamoto, Itaru; Arzumanov, Andrey A.; Williams, Donna L.; Deuss, Peter; Gait, Michael J.

    2015-01-01

    We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the

  11. Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment

    Directory of Open Access Journals (Sweden)

    Corinne Betts

    2012-01-01

    Full Text Available Antisense oligonucleotides (AOs are currently the most promising therapeutic intervention for Duchenne muscular dystrophy (DMD. AOs modulate dystrophin pre-mRNA splicing, thereby specifically restoring the dystrophin reading frame and generating a truncated but semifunctional dystrophin protein. Challenges in the development of this approach are the relatively poor systemic AO delivery and inefficient dystrophin correction in affected non-skeletal muscle tissues, including the heart. We have previously reported impressive heart activity including high-splicing efficiency and dystrophin restoration following a single administration of an arginine-rich cell-penetrating peptide (CPPs conjugated to a phosphorodiamidate morpholino oligonucleotide (PMO: Pip5e-PMO. However, the mechanisms underlying this activity are poorly understood. Here, we report studies involving single dose administration (12.5 mg/kg of derivatives of Pip5e-PMO, consecutively assigned as Pip6-PMOs. These peptide-PMOs comprise alterations to the central hydrophobic core of the Pip5e peptide and illustrate that certain changes to the peptide sequence improves its activity; however, partial deletions within the hydrophobic core abolish its efficiency. Our data indicate that the hydrophobic core of the Pip sequences is critical for PMO delivery to the heart and that specific modifications to this region can enhance activity further. The results have implications for therapeutic PMO development for DMD.

  12. A Novel Nonsense Mutation in CEP290 Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype

    NARCIS (Netherlands)

    Littink, Karin W.; Pott, Jan-Willem R.; Collin, Rob W. J.; Kroes, Hester Y.; Verheij, Joke B. G. M.; Blokland, Ellen A. W.; Miro, Marta de Castro; Hoyng, Carel B.; Klaver, Caroline C. W.; Koenekoop, Robert K.; Rohrschneider, Klaus; Cremers, Frans P. M.; van den Born, L. Ingeborgh; den Hollander, Anneke I.

    2010-01-01

    PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP)

  13. Restoring Dystrophin Expression in Duchenne Muscular Dystrophy Muscle: Progress in Exon Skipping and Stop Codon Read Through

    OpenAIRE

    Hoffman, Eric P.; Bronson, Abby; Levin, Arthur A.; Takeda, Shin'ichi; Yokota, Toshifumi; Baudy, Andreas R.; Connor, Edward M.

    2011-01-01

    The identification of the Duchenne muscular dystrophy gene and protein in the late 1980s led to high hopes of rapid translation to molecular therapeutics. These hopes were fueled by early reports of delivering new functional genes to dystrophic muscle in mouse models using gene therapy and stem cell transplantation. However, significant barriers have thwarted translation of these approaches to true therapies, including insufficient therapeutic material (eg, cells and viral vectors), challenge...

  14. Parallel Synthesis of Cell-Penetrating Peptide Conjugates of PMO Toward Exon Skipping Enhancement in Duchenne Muscular Dystrophy

    NARCIS (Netherlands)

    O'Donovan, Liz; Okamoto, Itaru; Arzumanov, Andrey A.; Williams, Donna L.; Deuss, Peter; Gait, Michael J.

    2015-01-01

    We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the SELecti

  15. Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy.

    Directory of Open Access Journals (Sweden)

    Johann Böhm

    2013-06-01

    Full Text Available Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM, a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM. However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD. Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.

  16. 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).

    Science.gov (United States)

    Vorwerk, P; Christoffersen, C T; Müller, J; Vestergaard, H; Pedersen, O; De Meyts, P

    1999-01-01

    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 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 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 either of the two mutated receptors lacked basal or stimulated IR beta-subunit autophosphorylation. A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype.

  17. 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.

  18. In vivo proof-of-concept of removal of the huntingtin caspase cleavage motif-encoding exon 12 approach in the YAC128 mouse model of Huntington's disease.

    Science.gov (United States)

    Casaca-Carreira, João; Toonen, Lodewijk J A; Evers, Melvin M; Jahanshahi, Ali; van-Roon-Mom, Willeke M C; Temel, Yasin

    2016-12-01

    Huntington's disease (HD) is a progressive autosomal dominant disease, caused by a CAG repeat expansion in the HTT gene, resulting in an expanded polyglutamine stretch at the N-terminal of the huntingtin protein. An important event in HD pathogenesis appears to be the proteolysis of the mutant protein, which forms N-terminal huntingtin fragments. These fragments form insoluble aggregates and are found in nuclei and cytoplasm of affected neurons where they interfere with normal cell functioning. Important cleavage sites are encoded by exon 12 of HTT. A novel approach is Htt protein modification through exon skipping, which has recently been proven effective both in vitro and in vivo. Here we report proof-of-concept of AON 12.1 in vivo using the YAC128 mouse model of HD. Our results support and encourage future longitudinal studies exploring the therapeutic effects of sustained infusions in the YAC128 mouse model.

  19. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

    Institute of Scientific and Technical Information of China (English)

    Zhenxun Wang; Deblina Chatterjee; Hyun Yong Jeon; Martin Akerman; Matthew G. Vander Heiden; Lewis C. Cantley; Adrian R. Krainer

    2012-01-01

    Alternative splicing of the pyruvate kinase M gene (PK-M) can generate the M2 isoform and promote aerobic glycolysis and tumor growth.However,the cancer-specific alternative splicing regulation of PK-M is not completely understood.Here,we demonstrate that PK-M is regulated by reciprocal affects on the mutually exclusive exons 9 and 10,such that exon 9 is repressed and exon 10 is activated in cancer cells.Strikingly,exonic,rather than intronic,cis-elements are key determinants ef PK-M splicing isoform ratios.Using a systematic sub-exonic duplication approach,we identify a potent exonlc splicing enhancer in exon 10,which differs from its homologous counterpart in exon 9 by only two nucleotides.We identify SRSF3 as one of the cognate factors,and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism.These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect,and also have implications for other genes with a similar pattern of alternative splicing.

  20. Variable Block Carry Skip Logic using Reversible Gates

    CERN Document Server

    Islam, Md Rafiqul; Karim, Muhammad Rezaul; Mahmud, Abdullah Al; Babu, Hafiz Md Hasan

    2010-01-01

    Reversible circuits have applications in digital signal processing, computer graphics, quantum computation and cryptography. In this paper, a generalized k*k reversible gate family is proposed and a 3*3 gate of the family is discussed. Inverter, AND, OR, NAND, NOR, and EXOR gates can be realized by this gate. Implementation of a full-adder circuit using two such 3*3 gates is given. This full-adder circuit contains only two reversible gates and produces no extra garbage outputs. The proposed full-adder circuit is efficient in terms of gate count, garbage outputs and quantum cost. A 4-bit carry skip adder is designed using this full-adder circuit and a variable block carry skip adder is discussed. Necessary equations required to evaluate these adder are presented.

  1. Skipping breakfast adversely affects menstrual disorders in young college students.

    Science.gov (United States)

    Fujiwara, Tomoko; Sato, Natsuyo; Awaji, Hiroyo; Sakamoto, Hiroko; Nakata, Rieko

    2009-01-01

    In the present study we conducted a questionnaire survey to examine the relationship between dietary habits and menstrual disorders in young women. Subjects were recruited from 315 college students and were classified as: Group I, eating breakfast; Group II, skipping breakfast; Group III, not eating fast foods; Group IV, eating fast foods; Group V, not eating processed foods; and Group VI, eating processed foods. The intensity of dysmenorrhea was scored using three grades. All participants were further divided into groups based on having regular or irregular menstruation, having premenstrual symptoms or not, and self-perception of good or poor general health. General health was poor in Groups II and VI, and dysmenorrhea scores were high in Groups II, IV and VI. The incidence of irregular menses was also high in Group II. However, there was no apparent relation between premenstrual symptoms and dietary habits. These findings suggest that skipping breakfast adversely affects menstrual disorders in young college students.

  2. Potential applications of skip SMV with thrust engine

    Science.gov (United States)

    Wang, Weilin; Savvaris, Al

    2016-11-01

    This paper investigates the potential applications of Space Maneuver Vehicles (SMV) with skip trajectory. Due to soaring space operations over the past decades, the risk of space debris has considerably increased such as collision risks with space asset, human property on ground and even aviation. Many active debris removal methods have been investigated and in this paper, a debris remediation method is first proposed based on skip SMV. The key point is to perform controlled re-entry. These vehicles are expected to achieve a trans-atmospheric maneuver with thrust engine. If debris is released at altitude below 80 km, debris could be captured by the atmosphere drag force and re-entry interface prediction accuracy is improved. Moreover if the debris is released in a cargo at a much lower altitude, this technique protects high value space asset from break up by the atmosphere and improves landing accuracy. To demonstrate the feasibility of this concept, the present paper presents the simulation results for two specific mission profiles: (1) descent to predetermined altitude; (2) descent to predetermined point (altitude, longitude and latitude). The evolutionary collocation method is adopted for skip trajectory optimization due to its global optimality and high-accuracy. This method is actually a two-step optimization approach based on the heuristic algorithm and the collocation method. The optimal-control problem is transformed into a nonlinear programming problem (NLP) which can be efficiently and accurately solved by the sequential quadratic programming (SQP) procedure. However, such a method is sensitive to initial values. To reduce the sensitivity problem, genetic algorithm (GA) is adopted to refine the grids and provide near optimum initial values. By comparing the simulation data from different scenarios, it is found that skip SMV is feasible in active debris removal and the evolutionary collocation method gives a truthful re-entry trajectory that satisfies the

  3. Delay Efficient 32-Bit Carry-Skip Adder

    OpenAIRE

    Yu Shen Lin; Damu Radhakrishnan

    2008-01-01

    The design of a 32-bit carry-skip adder to achieve minimum delay is presented in this paper. A fast carry look-ahead logic using group generate and group propagate functions is used to speed up the performance of multiple stages of ripple carry adders. The group generate and group propagate functions are generated in parallel with the carry generation for each block. The optimum block sizes are decided by considering the critical path into account. The new architecture ...

  4. An Index Based Skip Search Multiple Pattern Matching Algorithm

    OpenAIRE

    Raju Bhukya; Balram Parmer,; Anand Kulkarni

    2011-01-01

    DNA Pattern matching, the problem of finding sub sequences within a long DNA sequence has many applications in computational biology. As the sequences can be long, matching can be an expensive operation, especially as approximate matching is allowed. Searching DNA related data is a common activity for molecular biologists. In this paper we explore the applicability of a new pattern matching technique called Index based Skip Search Multiple Pattern matching algorithm (ISMPM), for DNA sequences...

  5. An Exon-Specific U1snRNA Induces a Robust Factor IX Activity in Mice Expressing Multiple Human FIX Splicing Mutants

    Directory of Open Access Journals (Sweden)

    Dario Balestra

    2016-01-01

    Full Text Available In cellular models we have demonstrated that a unique U1snRNA targeting an intronic region downstream of a defective exon (Exon-specific U1snRNA, ExSpeU1 can rescue multiple exon-skipping mutations, a relevant cause of genetic disease. Here, we explored in mice the ExSpeU1 U1fix9 toward two model Hemophilia B-causing mutations at the 5′ (c.519A > G or 3′ (c.392-8T > G splice sites of F9 exon 5. Hydrodynamic injection of wt-BALB/C mice with plasmids expressing the wt and mutant (hFIX-2G5′ss and hFIX-8G3′ss splicing-competent human factor IX (hFIX cassettes resulted in the expression of hFIX transcripts lacking exon 5 in liver, and in low plasma levels of inactive hFIX. Coinjection of U1fix9, but not of U1wt, restored exon inclusion of variants and in the intrinsically weak FIXwt context. This resulted in appreciable circulating hFIX levels (mean ± SD; hFIX-2G5′ss, 1.0 ± 0.5 µg/ml; hFIX-8G3′ss, 1.2 ± 0.3 µg/ml; and hFIXwt, 1.9 ± 0.6 µg/ml, leading to a striking shortening (from ≃100 seconds of untreated mice to ≃80 seconds of FIX-dependent coagulation times, indicating a hFIX with normal specific activity. This is the first proof-of-concept in vivo that a unique ExSpeU1 can efficiently rescue gene expression impaired by distinct exon-skipping variants, which extends the applicability of ExSpeU1s to panels of mutations and thus cohort of patients.

  6. Kinematic characteristics of motor patterns in rope skipping

    Directory of Open Access Journals (Sweden)

    Luiz Henrique da Silva

    2009-09-01

    Full Text Available Rope skipping seems to be an easy task to be performed. However, careful analysis of this motor skill shows how complex the execution of this task is. The objective of this study was to examine kinematic variables of jump patterns as a function of skipping frequency. Eight male university students performed a sequence of 30 rope jumps using two jump patterns (alternating support of the feet and simultaneous support of the feet at three skipping frequencies (1.5, 1.7,1.9 Hz. Frequencies were determined with a digital metronome and the rope was turned by the student himself. Rope jumping performance was recorded with two digital cameras for 3Danalysis. Passive markers were attached to the rope and to the ankle, knee and hip joints forcollection of the following dependent variables: continuous relative phase, time interval betweenthe loss of contact of the feet with the ground and cross of the rope under the feet of the volunteer,jump height, and rope height. ANOVA showed that for the pattern with alternating support ofthe feet the jump is executed at a lower height. In addition, analysis of the time interval revealeda delay in the withdrawal of the feet for crossing the rope in the case of the jump pattern with simultaneous support of the feet.

  7. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III)

    OpenAIRE

    Keiko Asao; Amandine Sambira Marekani; Jessica VanCleave; Amy E. Rothberg

    2016-01-01

    Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988–1994. We defined breakfast as any food...

  8. Faster exon assembly by sparse spliced alignment

    CERN Document Server

    Tiskin, Alexander

    2007-01-01

    Assembling a gene from candidate exons is an important problem in computational biology. Among the most successful approaches to this problem is \\emph{spliced alignment}, proposed by Gelfand et al., which scores different candidate exon chains within a DNA sequence of length $m$ by comparing them to a known related gene sequence of length n, $m = \\Theta(n)$. Gelfand et al.\\ gave an algorithm for spliced alignment running in time O(n^3). Kent et al.\\ considered sparse spliced alignment, where the number of candidate exons is O(n), and proposed an algorithm for this problem running in time O(n^{2.5}). We improve on this result, by proposing an algorithm for sparse spliced alignment running in time O(n^{2.25}). Our approach is based on a new framework of \\emph{quasi-local string comparison}.

  9. Social Inequalities in Young Children's Meal Skipping Behaviors: The Generation R Study.

    Directory of Open Access Journals (Sweden)

    Anne I Wijtzes

    Full Text Available Regular meal consumption is considered an important aspect of a healthy diet. While ample evidence shows social inequalities in breakfast skipping among adolescents, little is known about social inequalities in breakfast skipping and skipping of other meals among young school-aged children. Such information is crucial in targeting interventions aimed to promote a healthy diet in children.We examined data from 4704 ethnically diverse children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Information on family socioeconomic position (SEP, ethnic background, and meal skipping behaviors was assessed by parent-reported questionnaire when the child was 6 years old. Multiple logistic regression analyses were performed to assess the associations of family SEP (educational level, household income, employment status, family composition and ethnic background with meal skipping behaviors, using high SEP children and native Dutch children as reference groups.Meal skipping prevalence ranged from 3% (dinner to 11% (lunch. The prevalence of meal skipping was higher among low SEP children and ethnic minority children. Maternal educational level was independently associated with breakfast skipping ([low maternal educational level] OR: 2.21; 95% CI: 1.24,3.94. Paternal educational level was independently associated with lunch skipping ([low paternal educational level] OR: 1.53; 95% CI: 1.06,2.20 and dinner skipping ([mid-high paternal educational level] OR: 0.39; 95% CI: 0.20,0.76. Household income was independently associated with breakfast skipping ([low income] OR: 2.43, 95% CI: 1.40,4.22 and dinner skipping ([low income] OR: 2.44; 95% CI: 1.22,4.91. In general, ethnic minority children were more likely to skip breakfast, lunch, and dinner compared with native Dutch children. Adjustment for family SEP attenuated the associations of ethnic minority background with meal skipping behaviors

  10. Breakfast skipping and body mass index among adolescents in Greece: whether an association exists depends on how breakfast skipping is defined.

    Science.gov (United States)

    Dialektakou, Kiranni D; Vranas, Peter B M

    2008-09-01

    Many studies have found an association between breakfast skipping and either body mass index (BMI; calculated as kg/m(2)) or overweight/obesity among adolescents, but several studies have found no association. This cross-sectional study investigated the hypothesis that this discrepancy is partly due to three differences in methodology. First, some studies have examined BMI, but other studies have examined overweight/obesity. Second, some studies have controlled for potential confounders, but other studies have not. Third, different studies have used different definitions of breakfast skipping. This study examined both the relationship between breakfast skipping and BMI and the relationship between breakfast skipping and overweight/obesity, compared unadjusted results with results adjusted for potential confounders, and compared results for 24 definitions of breakfast skipping. The sample consisted of 811 students at high schools in Piraeus, Greece, who completed a questionnaire and had their height and weight measured. The results supported this hypothesis. First, fewer breakfast-skipping variables were associated with BMI than with overweight/obesity. Second, fewer associations were found when controlling than when not controlling for potential confounders. Third, fewer associations were found for variables corresponding to some definitions of breakfast skipping than for variables corresponding to other definitions.

  11. 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.

  12. Effect of exonic splicing regulation on synonymous codon usage in alternatively spliced exons of Dscam

    Directory of Open Access Journals (Sweden)

    Takahashi Aya

    2009-08-01

    Full Text Available Abstract Background Synonymous codon usage is typically biased towards translationally superior codons in many organisms. In Drosophila, genomic data indicates that translationally optimal codons and splice optimal codons are mostly mutually exclusive, and adaptation to translational efficiency is reduced in the intron-exon boundary regions where potential exonic splicing enhancers (ESEs reside. In contrast to genomic scale analyses on large datasets, a refined study on a well-controlled set of samples can be effective in demonstrating the effects of particular splice-related factors. Down syndrome cell adhesion molecule (Dscam has the largest number of alternatively spliced exons (ASEs known to date, and the splicing frequency of each ASE is accessible from the relative abundance of the transcript. Thus, these ASEs comprise a unique model system for studying the effect of splicing regulation on synonymous codon usage. Results Codon Bias Indices (CBI in the 3' boundary regions were reduced compared to the rest of the exonic regions among 48 and 33 ASEs of exon 6 and 9 clusters, respectively. These regional differences in CBI were affected by splicing frequency and distance from adjacent exons. Synonymous divergence levels between the 3' boundary region and the remaining exonic region of exon 6 ASEs were similar. Additionally, another sensitive comparison of paralogous exonic regions in recently retrotransposed processed genes and their parental genes revealed that, in the former, the differences in CBI between what were formerly the central regions and the boundary regions gradually became smaller over time. Conclusion Analyses of the multiple ASEs of Dscam allowed direct tests of the effect of splice-related factors on synonymous codon usage and provided clear evidence that synonymous codon usage bias is restricted by exonic splicing signals near the intron-exon boundary. A similar synonymous divergence level between the different exonic

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

    Directory of Open Access Journals (Sweden)

    Mohammad BARZEGAR

    2015-01-01

    correlations of deletions leading to Duchenne and Becker muscular dystrophies. Neurology 1989; 39(4:465-474.Koenig M1, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Müller CR, Lindlöf M, Kaariainen H, et al. The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 1989; 45(4:498-506.Helderman-van den E, Straathof CSM, Aartsma A, Dendunnen JT, Verbist BM, Bakker E, Verschuuren JJJM, Ginjaar HB. Becker muscular dystrophy patients with deletions around exon 51; a promising outlook for exon skipping therapy in Duchenne patients. Neuromuscular disorders 2010; 20:251-254.   Artsma-Rus A, Fokkema I, Verschuuren J, Ginjaar L, Deutekom GV, Ommen GJV et al. Theoretic applicability of antisense-mediated exon skipping for duchenne muscular dystrophy mutations. hummutat 2009; 30:293-9.Van Deutekom JC, Janson AA, Ginjaar LB, Frankhuizen WS, Artsma-Rus A, Bremmer-Bout Mattie et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl Med 2007; 357:2677-86.

  14. Breakfast skipping is associated with cyberbullying and school bullying victimization:a school-based cross-sectional study

    OpenAIRE

    Sampasa-Kanyinga, Hugues; Roumeliotis, Paul; Farrow, Claire V.; Shi, Yuanfeng F.

    2014-01-01

    Breakfast skipping is a health concern that has well-known negative consequences physically and psychologically. It is therefore important to understand why children skip breakfast. The purpose of this study was to establish whether the experience of bullying and cyberbullying impacts upon breakfast skipping and to further evaluate whether the inability for youths to cope with bullying victimization affects their mental health (depression), and in turn predicts breakfast skipping. Data were o...

  15. Word skipping: effects of word length, predictability, spelling and reading skill.

    Science.gov (United States)

    Slattery, Timothy J; Yates, Mark

    2017-08-31

    Readers eyes often skip over words as they read. Skipping rates are largely determined by word length; short words are skipped more than long words. However, the predictability of a word in context also impacts skipping rates. Rayner, Slattery, Drieghe and Liversedge (2011) reported an effect of predictability on word skipping for even long words (10-13 characters) that extend beyond the word identification span. Recent research suggests that better readers and spellers have an enhanced perceptual span (Veldre & Andrews, 2014). We explored whether reading and spelling skill interact with word length and predictability to impact word skipping rates in a large sample (N=92) of average and poor adult readers. Participants read the items from Rayner et al. (2011) while their eye movements were recorded. Spelling skill (zSpell) was assessed using the dictation and recognition tasks developed by Sally Andrews and colleagues. Reading skill (zRead) was assessed from reading speed (words per minute) and accuracy of three 120 word passages each with 10 comprehension questions. We fit linear mixed models to the target gaze duration data and generalized linear mixed models to the target word skipping data. Target word gaze durations were significantly predicted by zRead while, the skipping likelihoods were significantly predicted by zSpell. Additionally, for gaze durations, zRead significantly interacted with word predictability as better readers relied less on context to support word processing. These effects are discussed in relation to the lexical quality hypothesis and eye movement models of reading.

  16. Skipping breakfast is associated with reproductive dysfunction in post-adolescent female college students.

    Science.gov (United States)

    Fujiwara, Tomoko; Nakata, Rieko

    2010-12-01

    Although increasing attention has been paid to the adverse effects of skipping breakfast on quality of life, there are very few reports concerning the relationship between skipping breakfast and reproductive function. Therefore, we examined this issue by conducting a questionnaire survey of female college students aged from 18 to 20 years old. The 5 annual surveys of questionnaire demonstrated that the severity of dysmenorrhea was significantly higher in the population that skipped breakfast. The incidence of irregular menses was also higher in the population that skipped breakfast, although there was no difference in the incidence of premenstrual symptoms. The group that skipped breakfast showed a tendency to suffer from constipation. In addition, despite no difference in body mass index, there was a significantly higher incidence of a self-perception of poor general health among the group that skipped breakfast. These findings suggest that skipping breakfast is associated with menstrual disorders, and affects the physical condition of female college students who are undergoing post-adolescent maturation. Since these menstrual disorders may influence the quality of life of young women not only in the present but also in the future, skipping breakfast should be re-evaluated from the perspective of future reproductive function.

  17. Endoscopic Skipping of the Terminal Ileum in Pediatric Crohn Disease.

    Science.gov (United States)

    Mansuri, Ishrat; Fletcher, Joel G; Bruining, David H; Kolbe, Amy B; Fidler, Jeff L; Samuel, Sunil; Tung, Jeanne

    2017-06-01

    Pediatric small-bowel (SB) Crohn disease (CD) may be missed if the terminal ileum (TI) appears normal at endoscopy and SB imaging is not performed. We sought to estimate the prevalence and clinical characteristics of pediatric patients with CD and endoscopic skipping of the TI-that is, pediatric patients with active SB or upper gut inflammation and an endoscopically normal TI. This retrospective study included pediatric patients with CD who underwent both CT enterography (CTE) or MR enterography (MRE) and ileocolonoscopy within a 30-day period between July 2004 and April 2014. The physician global assessment was used as the reference standard for SB CD activity. Radiologists reviewed the CTE and MRE studies for inflammatory parameters; severity, length, and multifocality of SB inflammation; and the presence of penetrating complications. Of 170 patients who underwent ileal intubation, the TI was macroscopically normal or showed nonspecific inflammation in 73 patients (43%). Nearly half (36/73, 49%) of the patients with normal or nonspecific findings at ileocolonoscopy had radiologically active disease with a median length of SB involvement of 20 cm (range, 1 to > 100 cm). Seventeen (47%) of these patients had multifocal SB involvement and five (14%) had penetrating complications. Overall, endoscopic TI skipping was present in 43 (59%) patients with normal or nonspecific ileocolonoscopic findings: 20 with histologic inflammation (17 with positive imaging findings), 14 with inflammation at imaging only, and nine with proximal disease (upper gut, jejunum, or proximal ileum). There were no significant differences in the clinical parameters of the patients with and those without endoscopic TI skipping. Ileocolonoscopy may miss SB CD in pediatric patients that is due to isolated histologic, intramural, or proximal inflammation. Enterography is complementary to ileocolonoscopy in the evaluation of pediatric CD.

  18. 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 ...

  19. A case of an idiopathic massive osteolysis with skip lesions

    Energy Technology Data Exchange (ETDEWEB)

    Ozbayrak, Mustafa [Dept. of Radiology, Arnavutkoy State Hospital, Instanbul (Turkmenistan); Yilmaz, Mehmet Halit; Kantarci, Fatih; Ozer, Harun; Harmanci, Kemal; Babacan, Muharrem; Dervisoglu, Sergulen [Cerrahpasa Medical Faculty, Istanbul University, Istanbul (Turkmenistan)

    2013-12-15

    A patient with a 2-year history of pain in the left arm, and decreased strengths unrelieved by non-steroidal anti-inflammatory therapy, was being referred for repeating radiography. The radiologic examinations have demonstrated a unique pattern of non-contiguous osteolysis in the left elbow, proximal and distal radius, ulna, wrist, carpal bones, proximal and distal metacarpals and phalanges. Multi-site biopsies were being performed and confirmed the diagnosis of massive osteolysis. To our knowledge, this is the first case in which multifocal, non-contiguous osteolysis with skip lesions without associated nephropathy and without a hereditary pattern is being described in one extremity.

  20. Convergent and stereospecific synthesis of complex skipped polyenes and polyunsaturated fatty acids.

    Science.gov (United States)

    Macklin, Todd K; Micalizio, Glenn C

    2010-08-01

    Skipped polyenes (that is, 1,4-dienes and higher homologues) are stereodefined components of a vast array of biologically important natural products, including polyunsaturated fatty acids. Although widespread in nature, these architectures are generally considered to represent significant barriers to efficient chemical synthesis. Partial reduction of skipped poly-ynes provides a pathway to a subset of such structures, but general chemical methods for the preparation of skipped polyenes that contain varied stereochemistries and substitution patterns are lacking. Here, we describe a metal-promoted reductive cross-coupling reaction between vinylcyclopropanes and alkynes (or vinylsilanes) that provides stereoselective access to a diverse array of skipped polyenes through a process that establishes one C-C bond, generates up to three stereodefined alkenes, and can be used to introduce stereogenic centres at the central positions of the skipped polyene motif. We also demonstrate the significance of the present bond construction by preparing substituted and stereodefined polyunsaturated synthetic fatty acids.

  1. Eye movements and word skipping during reading: Effects of word length and predictability

    Science.gov (United States)

    Rayner, Keith; Slattery, Timothy J.; Drieghe, Denis; Liversedge, Simon P.

    2012-01-01

    The extent to which target words were predictable from prior context was varied: half of the target words were predictable and the other half were unpredictable. In addition, the length of the target word varied: the target words were short (4–6 letters), medium (7–9 letters), or long (10–12 letters). Length and predictability both yielded strong effects on the probability of skipping the target words and on the amount of time readers fixated the target words (when they were not skipped). However, there was no interaction in any of the measures examined for either skipping or fixation time. The results demonstrate that word predictability (due to contextual constraint) and word length have strong and independent influences on word skipping and fixation durations. Furthermore, since the long words extended beyond the word identification span, the data indicate that skipping can occur on the basis of partial information in relation to word identity. PMID:21463086

  2. Breakfast Skipping and Its Associated Factors among Undergraduates in a Public University in Kuala Lumpur.

    Science.gov (United States)

    Moy, F M; Johari, S; Ismail, Y; Mahad, R; Tie, F H; Wan Ismail, Wm A

    2009-09-01

    An analytical cross-sectional study was conducted in a public university in Kuala Lumpur among a random sample of 2665 undergraduates. The objective was to study the prevalence of breakfast skipping and its associated factors. Data collection was conducted via a self-administered pre-tested questionnaire. There were 43.5% male respondents, with Malays being the majority (58.3%). The prevalence of breakfast skipping was 29.2 (95% CI: 27.3 - 30.3)%. The factors significantly associated with breakfast skipping (pskipping dinner. As the respondents' age increased, their risk of breakfast skipping was lower (OR: 0.95; 0.89 - 0.99). Malays (OR: 1.94; 1.48 - 2.54), Indians (OR: 1.70; 1.08 - 2.66), and students from the Sabah and Sarawak indigenous communities (OR: 2.13; 1.37 - 3.33) were more likely to skip breakfast compared to their Chinese counterparts. Respondents who stayed in their own houses were also less likely to skip breakfast compared to those staying in hostel with meals catered (OR: 2.32; 1.39 - 3.84), hostel with cafeteria (OR: 2.92; 1.74 - 4.91) or in rented houses (OR: 2.08; 1.25 - 3.46). Respondents majoring in Arts and Economics had 1.40 (1.07 - 1.82) times risk of breakfast skipping compared to those majoring in Life Sciences. Those who skipped dinner too had twice the odds (1.47 - 2.77) of breakfast skipping. In conclusion the prevalence of breakfast skipping among the undergraduates of this university was moderately high. Health awareness campaigns or introduction of healthy eating guidelines should be initiated for the undergraduates as well as food caterers in campus. The policy and pricing of catered food in campus should also be reviewed.

  3. Skipping Posterior Dynamic Transpedicular Stabilization for Distant Segment Degenerative Disease

    Directory of Open Access Journals (Sweden)

    Bilgehan Solmaz

    2012-01-01

    Full Text Available Objective. To date, there is still no consensus on the treatment of spinal degenerative disease. Current surgical techniques to manage painful spinal disorders are imperfect. In this paper, we aimed to evaluate the prospective results of posterior transpedicular dynamic stabilization, a novel surgical approach that skips the segments that do not produce pain. This technique has been proven biomechanically and radiologically in spinal degenerative diseases. Methods. A prospective study of 18 patients averaging 54.94 years of age with distant spinal segment degenerative disease. Indications consisted of degenerative disc disease (57%, herniated nucleus pulposus (50%, spinal stenosis (14.28%, degenerative spondylolisthesis (14.28%, and foraminal stenosis (7.1%. The Oswestry Low-Back Pain Disability Questionnaire and visual analog scale (VAS for pain were recorded preoperatively and at the third and twelfth postoperative months. Results. Both the Oswestry and VAS scores showed significant improvement postoperatively (P<0.05. We observed complications in one patient who had spinal epidural hematoma. Conclusion. We recommend skipping posterior transpedicular dynamic stabilization for surgical treatment of distant segment spinal degenerative disease.

  4. Velocity Building by Reflection Waveform Inversion without Cycle-skipping

    KAUST Repository

    Guo, Q.

    2017-05-26

    Reflection waveform inversion (RWI) provides estimation of low wavenumber model components using reflections generated from a migration/demigration process. The resulting model tends to be a good initial model for FWI. In fact, the optimization images to combine the migration velocity analysis (MVA) objectives (given here by RWI) and the FWI ones. However, RWI may still encounter cycle-skipping at far offsets if the velocity model is highly inaccurate. Similar to MVA, RWI is devoted to focusing reflection data to its true image positions, yet because of the cycle skipping potential we tend to initially use only near offsets. To make the inversion procedure more robust, we introduce the extended image into our RWI. Extending the model perturbations (or image) allows us to better fit the data at larger offsets even with an inaccurate velocity. Thus, we implement a nested approach to optimize the velocity and extended image simultaneously using the objective function of RWI. We slowly reduce the extension, as the image becomes focused, to allow wavepath updates from far offsets to near as a natural progression from long wavelength updates to shorter ones. Applications on synthetic data demonstrate the effectiveness of our method without much additional cost to RWI.

  5. Dynamics of Leading-strand Lesion Skipping by the Replisome

    Science.gov (United States)

    Yeeles, Joseph T.P.; Marians, Kenneth J.

    2013-01-01

    SUMMARY The E. coli replisome stalls transiently when it encounters a lesion in the leading-strand template, skipping over the damage by reinitiating replication at a new primer synthesized downstream by the primase. We report here that template unwinding and lagging-strand synthesis continue downstream of the lesion at a reduced rate after replisome stalling, that one replisome is capable of skipping multiple lesions, and that the rate limiting steps of replication restart involve the synthesis and activation of the new primer downstream. We also find little support for the concept that polymerase uncoupling, where extensive lagging-strand synthesis proceeds downstream in the absence of leading-strand synthesis, involves physical separation of the leading-strand polymerase from the replisome. Instead, our data indicate that extensive uncoupled replication likely results from a failure of the leading-strand polymerase still associated with the DNA helicase and the lagging-strand polymerase that are proceeding downstream to reinitiate synthesis. PMID:24268579

  6. The Detector System for the Stratospheric Kinetic Inductance Polarimeter (SKIP)

    CERN Document Server

    Johnson, B R; Araujo, D; Bradford, K J; Chapman, D; Didier, J; Doyle, S; Eriksen, H K; Flanigan, D; Groppi, C; Hillbrand, S; Jones, G; Limon, M; Mauskopf, P; McCarrick, H; Miller, A; Mroczkowski, T; Reichborn-Kjennerud, B; Smiley, B; Sobrin, J; Wehus, I K; Zmuidzinas, J

    2013-01-01

    We discuss the detector system for the Stratospheric Kinetic Inductance Polarimeter (SKIP). SKIP is a proposed balloon-borne experiment designed to study the cosmic microwave background, the cosmic infrared background and Galactic dust emission by observing 1133 square degrees of sky in the Northern Hemisphere with launches from Kiruna, Sweden. The instrument contains 2317 single-polarization, horn-coupled, aluminum lumped-element kinetic inductance detectors (LEKIDs). The LEKIDs will be maintained at 100 mK with an adiabatic demagnetization refrigerator. The polarimeter operates in two configurations, one sensitive to a spectral band centered on 150 GHz and the other sensitive to 260 and 350 GHz bands. The detector readout system is based on the ROACH-1 board, and the detectors will be biased below 300 MHz. The detector array is fed by an F/2.4 crossed-Dragone telescope with a 500 mm aperture yielding a 15 arcmin FWHM beam at 150 GHz. To minimize detector loading and maximize sensitivity, the entire optical ...

  7. The "alternative" choice of constitutive exons throughout evolution.

    Directory of Open Access Journals (Sweden)

    Galit Lev-Maor

    2007-11-01

    Full Text Available Alternative cassette exons are known to originate from two processes-exonization of intronic sequences and exon shuffling. Herein, we suggest an additional mechanism by which constitutively spliced exons become alternative cassette exons during evolution. We compiled a dataset of orthologous exons from human and mouse that are constitutively spliced in one species but alternatively spliced in the other. Examination of these exons suggests that the common ancestors were constitutively spliced. We show that relaxation of the 5' splice site during evolution is one of the molecular mechanisms by which exons shift from constitutive to alternative splicing. This shift is associated with the fixation of exonic splicing regulatory sequences (ESRs that are essential for exon definition and control the inclusion level only after the transition to alternative splicing. The effect of each ESR on splicing and the combinatorial effects between two ESRs are conserved from fish to human. Our results uncover an evolutionary pathway that increases transcriptome diversity by shifting exons from constitutive to alternative splicing.

  8. Transposable elements in disease-associated cryptic exons.

    Science.gov (United States)

    Vorechovsky, Igor

    2010-02-01

    Transposable elements (TEs) make up a half of the human genome, but the extent of their contribution to cryptic exon activation that results in genetic disease is unknown. Here, a comprehensive survey of 78 mutation-induced cryptic exons previously identified in 51 disease genes revealed the presence of TEs in 40 cases (51%). Most TE-containing exons were derived from short interspersed nuclear elements (SINEs), with Alus and mammalian interspersed repeats (MIRs) covering >18 and >16% of the exonized sequences, respectively. The majority of SINE-derived cryptic exons had splice sites at the same positions of the Alu/MIR consensus as existing SINE exons and their inclusion in the mRNA was facilitated by phylogenetically conserved changes that improved both traditional and auxiliary splicing signals, thus marking intronic TEs amenable for pathogenic exonization. The overrepresentation of MIRs among TE exons is likely to result from their high average exon inclusion levels, which reflect their strong splice sites, a lack of splicing silencers and a high density of enhancers, particularly (G)AA(G) motifs. These elements were markedly depleted in antisense Alu exons, had the most prominent position on the exon-intron gradient scale and are proposed to promote exon definition through enhanced tertiary RNA interactions involving unpaired (di)adenosines. The identification of common mechanisms by which the most dynamic parts of the genome contribute both to new exon creation and genetic disease will facilitate detection of intronic mutations and the development of computational tools that predict TE hot-spots of cryptic exon activation.

  9. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III)

    Science.gov (United States)

    Asao, Keiko; Marekani, Amandine Sambira; VanCleave, Jessica; Rothberg, Amy E.

    2016-01-01

    Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988–1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%–12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles. PMID:26927164

  10. Lifestyle and socioeconomic correlates of breakfast skipping in Hong Kong primary 4 schoolchildren.

    Science.gov (United States)

    Tin, Sze Pui Pamela; Ho, Sai Yin; Mak, Kwok Hang; Wan, Ka Leung; Lam, Tai Hing

    2011-01-01

    Although breakfast is associated with different benefits, breakfast skipping is increasingly common among children. This study aimed to identify lifestyle and socioeconomic correlates of breakfast skipping in Hong Kong schoolchildren. 68,606 primary 4 participants of the Department of Health Student Health Service in 1998-2000 reported breakfast habit and other lifestyle characteristics using a standardized questionnaire. Height and weight were measured by trained SHS nurses. Socioeconomic data were reported by parents. In cross-sectional analysis, multivariate logistic regression was used to identify lifestyle and socioeconomic correlates of breakfast skipping. 3,598 subjects (5.2%) usually skipped breakfast. Breakfast skipping was associated with being overweight (Odds ratio=1.59, 95% CI: 1.46 to 1.73) and obese (2.06, 1.80 to 2.36), and unhealthy dietary habits including more frequent junk food (1.23, 1.14 to 1.33) but less frequent fruit/vegetable (1.23, 1.13 to 1.34) and milk (1.98, 1.80 to 2.16) intake. Breakfast skippers tended to skip lunch, do less extra-curricular physical activity, watch more television and have less educated parents. Breakfast skipping was significantly related to various health-compromising lifestyle characteristics and lower parental education. Breakfast habit can be a potential lifestyle indicator. Education programmes aimed at specific target groups should encourage regular breakfast consumption. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III).

    Science.gov (United States)

    Asao, Keiko; Marekani, Amandine Sambira; VanCleave, Jessica; Rothberg, Amy E

    2016-02-25

    Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988-1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%-12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles.

  12. Leptin Level and Skipping Breakfast: The National Health and Nutrition Examination Survey III (NHANES III

    Directory of Open Access Journals (Sweden)

    Keiko Asao

    2016-02-01

    Full Text Available Skipping breakfast is a common dietary habit considered to be unhealthy. However, the mechanisms underlying skipping breakfast have not been fully explored. Leptin is a hormone that regulates food intake and energy storage and secretes in a diurnal rhythm with lowest levels in the morning. We examined the association between the serum leptin level and skipping breakfast in 5714 adults in the U.S. National Health and Nutrition Examination Survey III, 1988–1994. We defined breakfast as any food or beverage consumed between 5:00 a.m. and 10:00 a.m. using a single 24-h recall. Skipped breakfast was seen in 13.1%. In the logistic regression models with and without adjusting for adiposity and sex, leptin levels were not associated with skipping breakfast. After adjusting for age, race/ethnicity, and time of venipuncture, the association remained insignificant. After further adjusting for potential confounders: physical activity, alcohol intake, smoking and diabetes and after further adjusting for: dietary factors, insulin and glucose levels, there was a 9% and 11%–12%, respectively, statistically significantly higher likelihood of skipping breakfast if the leptin level was more than 50% greater. Further investigation into the biological reasons for skipping breakfast may be useful for promoting healthy lifestyles.

  13. Effect of breakfast skipping on diurnal variation of energy metabolism and blood glucose.

    Science.gov (United States)

    Kobayashi, Fumi; Ogata, Hitomi; Omi, Naomi; Nagasaka, Shoichiro; Yamaguchi, Sachiko; Hibi, Masanobu; Tokuyama, Kumpei

    2014-01-01

    Epidemiological studies suggest an association between breakfast skipping and body weight gain, insulin resistance or type 2 diabetes. Time when meal is consumed affects postprandial increase in energy expenditure and blood glucose, and breakfast skipping may reduce 24 h energy expenditure and elevate blood glucose level. The present study evaluated the effect of breakfast skipping on diurnal variation of energy metabolism and blood glucose. The skipped breakfast was compensated by following big meals at lunch and supper. In a randomized repeated-measure design with or without breakfast, eight males stayed twice in a room-size respiratory chamber. Blood glucose was recorded with a continuous glucose monitoring system. Breakfast skipping did not affect 24 h energy expenditure, fat oxidation and thermic effect of food, but increased overall 24 h average of blood glucose (83 ± 3 vs 89 ± 2 mg/dl, P breakfast skipping. These observations suggest that changes in glucose homeostasis precede that of energy balance, in the potential sequence caused by breakfast skipping, if this dietary habit has any effect on energy balance.:

  14. Associations between perceived friends' support of healthy eating and meal skipping in adolescence.

    Science.gov (United States)

    Rosenrauch, Sharon; Ball, Kylie; Lamb, Karen E

    2017-09-07

    Meal skipping is a relatively common behaviour during adolescence. As peer influence increases during adolescence, friendship groups may play a role in determining eating patterns such as meal skipping. The current study examined cross-sectional and longitudinal associations between perceived friends' support of healthy eating and breakfast and lunch skipping among adolescents. Survey of intrapersonal, social and environmental factors that may influence eating patterns at baseline (2004/05) and follow-up (2006/07). Thirty-seven secondary schools in Victoria, Australia. Sample of 1785 students aged 12-15 years at baseline. Adolescents who reported that their friends sometimes or often ate healthy foods with them were less likely (adjusted OR; 95 % CI) to skip breakfast (sometimes: 0·71; 0·57, 0·90; often: 0·54; 0·38, 0·76) or lunch (sometimes: 0·61; 0·41, 0·89; often: 0·59; 0·37, 0·94) at baseline than those who reported their friends never or rarely displayed this behaviour. Although this variable was associated with lunch skipping at follow-up, there was no evidence of an association with breakfast skipping at follow-up. There was no evidence of an association between perceived encouragement of healthy eating, and an inconsistent relationship between perceived discouragement of junk food consumption, and meal skipping. Friends eating healthy foods together may serve to reduce meal skipping during early adolescence, possibly due to the influence of directly observable behaviour and shared beliefs held by those in the same friendship group. Verbal encouragement or discouragement from friends may be less impactful an influence on meal skipping (than directly observable behaviours) in adolescents.

  15. Exonic splicing regulatory elements skew synonymous codon usage near intron-exon boundaries in mammals.

    NARCIS (Netherlands)

    Parmley, J.L.; Hurst, L.D.

    2007-01-01

    In mammals there is a bias in amino acid usage near splice sites that is explained, in large part, by the high density of exonic splicing enhancers (ESEs) in these regions. Is there a similar bias for the relative use of synonymous codons, and can any such bias be predicted by their abundance in ESE

  16. Analysis of factors influencing skip lymphatic metastasis in pN2 non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    Gui-Long Li; Yong Zhu; Wei Zheng; Chao-Hui Guo; Chun Chen

    2012-01-01

    Objective:Although many clinical studies on skip lymphatic metastasis in non-small cell lung cancer have been reported,the risk factors for skip lymphatic metastasis are still controversy and debatable.This study investigated,by multivariate logistic regression analysis,the clinical features of skip metastasis to mediastinal lymph nodes (N2) in non-small cell lung cancer (NSCLC) patients.Methods:We collected the clinicopathological data of 256 pN2-NSCLC patients who underwent lobectomy plus systemic lymph node dissection in Fujian Medical University Union Hospital.The cases in the present study were divided into two groups:skip metastasis (N2 skip+) and non-skip metastasis (N2 skip-).A retrospective analysis of clinical pathological features of two groups was performed.To determine an independent factor,multivariate logistic regression analysis was used to identify possible risk factors.Results:A total of 256 pN2-NSCLC patients were recruited.The analysis results showed that gender,pathologic types,surgery,pleural involvement,smoking history,age,tumor stages,and differentiation were not statistical significant factors impacting on skip metastasis in pN2-NSCLC (P>0.05),whereas tumor size was an independent factor for skip metastasis (P=0.02).Conclusions:The rate of skip lymphatic metastasis increases in pN2-NSCLC patients,in accompany with an increased tumor size.

  17. Species-Specific Exon Loss in Human Transcriptomes

    OpenAIRE

    Wang, Jinkai; Lu, Zhi-xiang; Tokheim, Collin J.; Miller, Sara E.; Xing, Yi

    2014-01-01

    Changes in exon–intron structures and splicing patterns represent an important mechanism for the evolution of gene functions and species-specific regulatory networks. Although exon creation is widespread during primate and human evolution and has been studied extensively, much less is known about the scope and potential impact of human-specific exon loss events. Historically, transcriptome data and exon annotations are significantly biased toward humans over nonhuman primates. This ascertainm...

  18. Many U.S. Travelers Skip Measles Shots, Despite Infection Risk

    Science.gov (United States)

    ... news/fullstory_165583.html Many U.S. Travelers Skip Measles Shots, Despite Infection Risk Though the disease was ... eligible Americans traveling abroad don't get a measles vaccine, and a key reason is lack of ...

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

    Institute of Scientific and Technical Information of China (English)

    王涛; 梁直厚; 孙圣刚; 曹学兵; 彭海; 刘红进; 童萼塘

    2004-01-01

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

  20. Characteristics of transposable element exonization within human and mouse.

    Directory of Open Access Journals (Sweden)

    Noa Sela

    Full Text Available Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.

  1. Palladium-catalyzed 1,4-difunctionalization of butadiene to form skipped polyenes.

    Science.gov (United States)

    McCammant, Matthew S; Liao, Longyan; Sigman, Matthew S

    2013-03-20

    A palladium-catalyzed 1,4-addition across the commodity chemical 1,3-butadiene to afford skipped polyene products is reported. Through a palladium σ → π → σ allyl isomerization, two new carbon-carbon bonds are formed with high regioselectivity and trans stereoselectivity of the newly formed alkene. The utility of this method is highlighted by the successful synthesis of the ripostatin A skipped triene core.

  2. Lifestyle and socioeconomic correlates of breakfast skipping in Hong Kong primary 4 schoolchildren

    OpenAIRE

    Tin, SPP; Ho, SY; Mak, KH; Wan, KL; Lam, Th

    2011-01-01

    Objective: Although breakfast is associated with different benefits, breakfast skipping is increasingly common among children. This study aimed to identify lifestyle and socioeconomic correlates of breakfast skipping in Hong Kong schoolchildren. Methods: 68 606 primary 4 participants of the Department of Health Student Health Service in 1998-2000 reported breakfast habit and other lifestyle characteristics using a standardized questionnaire. Height and weight were measured by trained SHS nurs...

  3. The relationship between breakfast skipping, chronotype, and glycemic control in type 2 diabetes.

    Science.gov (United States)

    Reutrakul, Sirimon; Hood, Megan M; Crowley, Stephanie J; Morgan, Mary K; Teodori, Marsha; Knutson, Kristen L

    2014-02-01

    Breakfast skipping is associated with obesity and an increased risk of type 2 diabetes. Later chronotypes, individuals who have a preference for later bed and wake times, often skip breakfast. The aim of the study was to explore the relationships among breakfast skipping, chronotype, and glycemic control in type 2 diabetes patients. We collected sleep timing and 24-h dietary recall from 194 non-shift-working type 2 diabetes patients who were being followed in outpatient clinics. Mid-sleep time on free days (MSF) was used as an indicator of chronotype. Hemoglobin A1C (HbA1C) values were obtained from medical records. Hierarchical linear regression analyses controlling for demographic, sleep, and dietary variables were computed to determine whether breakfast skipping was associated with HbA1C. Additional regression analyses were performed to test if this association was mediated by chronotype. There were 22 participants (11.3%) who self-reported missing breakfast. Breakfast skippers had significantly higher HbA1C levels, higher body mass indices (BMI), and later MSF than breakfast eaters. Breakfast skipping was significantly associated with higher HbA1C values (B = 0.108, p = 0.01), even after adjusting for age, sex, race, BMI, number of diabetes complications, insulin use, depressive symptoms, perceived sleep debt, and percentage of daily caloric intake at dinner. The relationship between breakfast skipping and HbA1C was partially mediated by chronotype. In summary, breakfast skipping is associated with a later chronotype. Later chronotype and breakfast skipping both contribute to poorer glycemic control, as indicated by higher HbA1C levels. Future studies are needed to confirm these findings and determine whether behavioral interventions targeting breakfast eating or sleep timing may improve glycemic control in patients with type 2 diabetes.

  4. Skipping of the very-high-frequency structural particle de () in Chinese reading.

    Science.gov (United States)

    Zang, Chuanli; Zhang, Manman; Bai, Xuejun; Yan, Guoli; Angele, Bernhard; Liversedge, Simon P

    2017-01-16

    How do readers decide whether to skip or fixate a word? Angele and Rayner [2013. Processing the in the parafovea: Are articles skipped automatically? Journal of Experimental Psychology: Learning, Memory, and Cognition, 39, 649-662] showed that English readers base skipping decisions on the parafoveal information available, but not the sentential context. Due to the increased visual density of the language, Chinese readers may be able to process a parafoveal word and integrate it with the sentence context to a greater extent than English readers. Consequently, influences on skipping decisions in Chinese may differ from those in English. In a boundary paradigm experiment, participants read sentences containing a single-character target verb (e.g., meaning get) whose preview was manipulated in three conditions: identity preview; a preview consisting of the syntactically anomalous high-frequency structural particle de (), or a pseudocharacter preview. The results showed that Chinese readers were more likely to skip the target when the preview was de than in either of the other conditions, suggesting that de-skipping is triggered by the parafoveal preview of a highly frequent particle word rather than on the likelihood of the upcoming word given the sentential context..

  5. Scanning for genes in large genomic regions: cosmid-based exon trapping of multiple exons in a single product.

    Science.gov (United States)

    Datson, N A; van de Vosse, E; Dauwerse, H G; Bout, M; van Ommen, G J; den Dunnen, J T

    1996-03-15

    To facilitate the scanning of large genomic regions for the presence of exonic gene segments we have constructed a cosmid-based exon trap vector. The vector serves a dual purpose since it is also suitable for contig construction and physical mapping. The exon trap cassette of vector sCOGH1 consists of the human growth hormone gene driven by the mouse mettallothionein-1 promoter. Inserts are cloned in the multicloning site located in intron 2 of the hGH gene. The efficiency of the system is demonstrated with cosmids containing multiple exons of the Duchenne Muscular Dystrophy gene. All exons present in the inserts were successfully retrieved and no cryptic products were detected. Up to seven exons were isolated simultaneously in a single spliced product. The system has been extended by a transcription-translation-test protocol to determine the presence of large open reading frames in the trapped products, using a combination of tailed PCR primers directing protein synthesis in three different reading frames, followed by in vitro transcription-translation. Having larger stretches of coding sequence in a single exon trap product rather than small single exons greatly facilitates further analysis of potential genes and offers new possibilities for direct mutation analysis of exon trap material.

  6. The effect of high- and low-frequency previews and sentential fit on word skipping during reading

    Science.gov (United States)

    Angele, Bernhard; Laishley, Abby; Rayner, Keith; Liversedge, Simon P.

    2014-01-01

    In a previous gaze-contingent boundary experiment, Angele and Rayner (2012) found that readers are likely to skip a word that appears to be the definite article the even when syntactic constraints do not allow for articles to occur in that position. In the present study, we investigated whether the word frequency of the preview of a three-letter target word influences a reader’s decision to fixate or skip that word. We found that the word frequency rather than the felicitousness (syntactic fit) of the preview affected how often the upcoming word was skipped. These results indicate that visual information about the upcoming word trumps information from the sentence context when it comes to making a skipping decision. Skipping parafoveal instances of the therefore may simply be an extreme case of skipping high-frequency words. PMID:24707791

  7. Deletion of the Chd6 exon 12 affects motor coordination.

    Science.gov (United States)

    Lathrop, Melissa J; Chakrabarti, Lisa; Eng, Jeremiah; Rhodes, C Harker; Lutz, Thomas; Nieto, Amelia; Liggitt, H Denny; Warner, Sandra; Fields, Jennifer; Stöger, Reinhard; Fiering, Steven

    2010-04-01

    Members of the CHD protein family play key roles in gene regulation through ATP-dependent chromatin remodeling. This is facilitated by chromodomains that bind histone tails, and by the SWI2/SNF2-like ATPase/helicase domain that remodels chromatin by moving histones. Chd6 is ubiquitously expressed in both mouse and human, with the highest levels of expression in the brain. The Chd6 gene contains 37 exons, of which exons 12-19 encode the highly conserved ATPase domain. To determine the biological role of Chd6, we generated mouse lines with a deletion of exon 12. Chd6 without exon 12 is expressed at normal levels in mice, and Chd6 Exon 12 -/- mice are viable, fertile, and exhibit no obvious morphological or pathological phenotype. Chd6 Exon 12 -/- mice lack coordination as revealed by sensorimotor analysis. Further behavioral testing revealed that the coordination impairment was not due to muscle weakness or bradykinesia. Histological analysis of brain morphology revealed no differences between Chd6 Exon 12 -/- mice and wild-type (WT) controls. The location of CHD6 on human chromosome 20q12 is overlapped by the linkage map regions of several human ataxias, including autosomal recessive infantile cerebellar ataxia (SCAR6), a nonprogressive cerebrospinal ataxia. The genomic location, expression pattern, and ataxic phenotype of Chd6 Exon 12 -/- mice indicate that mutations within CHD6 may be responsible for one of these ataxias.

  8. Relationships between bullying victimization psychological distress and breakfast skipping among boys and girls.

    Science.gov (United States)

    Sampasa-Kanyinga, Hugues; Willmore, Jacqueline

    2015-06-01

    The purpose of this study was to further explore the association between bullying victimization and breakfast skipping in children and adolescents. Compared to the previous study, we have used a larger and representative sample of middle and high school students, examined the effect of gender, different forms (physical, verbal, theft/vandalism and cyber) and severity of bullying on breakfast eating behaviour. Data from students (2286 boys and 2859 girls) aged 11 to 19 years (mean ± SD age: 14.6 ± 1.9 years) from the 2013 Ontario Student Drug Use and Health Survey (OSDUHS) were analysed using self-reports of being bullied, diet, psychological distress, demographics, socio-economic status, weight status, and substance use. Results revealed greater odds of breakfast skipping in girl victims of physical, verbal, and cyber bullying, and in boy victims of verbal and cyber bullying. There was a dose-response relationship between experience of both school and cyber bullying victimization and breakfast skipping behaviour for both genders. Mediation analysis indicated that psychological distress fully mediated the relationship between both verbal and physical bullying victimization and breakfast skipping in girls, and partially mediated the relationship between verbal bullying victimization and breakfast skipping in boys. Psychological distress also partially mediated the link between cyber bullying victimization and breakfast skipping in both boys and girls. These results corroborate previous findings on the association between bullying victimization and breakfast skipping in children and adolescents. The strong and consistent associations with different forms of bullying victimization, the dose-response relationship, and the mediating role of psychological distress suggest a causal relationship. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Skip the trip: air travelers' behavioral responses to pandemic influenza.

    Directory of Open Access Journals (Sweden)

    Eli P Fenichel

    Full Text Available Theory suggests that human behavior has implications for disease spread. We examine the hypothesis that individuals engage in voluntary defensive behavior during an epidemic. We estimate the number of passengers missing previously purchased flights as a function of concern for swine flu or A/H1N1 influenza using 1.7 million detailed flight records, Google Trends, and the World Health Organization's FluNet data. We estimate that concern over "swine flu," as measured by Google Trends, accounted for 0.34% of missed flights during the epidemic. The Google Trends data correlates strongly with media attention, but poorly (at times negatively with reported cases in FluNet. Passengers show no response to reported cases. Passengers skipping their purchased trips forwent at least $50 M in travel related benefits. Responding to actual cases would have cut this estimate in half. Thus, people appear to respond to an epidemic by voluntarily engaging in self-protection behavior, but this behavior may not be responsive to objective measures of risk. Clearer risk communication could substantially reduce epidemic costs. People undertaking costly risk reduction behavior, for example, forgoing nonrefundable flights, suggests they may also make less costly behavior adjustments to avoid infection. Accounting for defensive behaviors may be important for forecasting epidemics, but linking behavior with epidemics likely requires consideration of risk communication.

  10. Why do some adult birds skip breeding? A hormonal investigation in a long-lived bird.

    Science.gov (United States)

    Goutte, Aurélie; Kriloff, Marion; Weimerskirch, Henri; Chastel, Olivier

    2011-10-23

    Skipping reproduction is often observed in long-lived organisms, but proximate mechanisms remain poorly understood. Since young and/or very old snow petrels (Pagodroma nivea) commonly skip breeding, we tested whether they are physiologically able to breed during the pre-laying stage. To do so, we measured the ability of known-age (11-45 years old) petrels to release luteinizing hormone (LH, a crucial driver for breeding), by injecting exogenous gonadotropin-releasing hormone (GnRH). Although young petrels exhibited low baseline LH levels, they were able to elevate LH levels after a GnRH challenge. Moreover, young and very old petrels showed a stronger decrease in LH levels after the 10 min post-GnRH injection compared with middle-aged petrels. Birds that skipped breeding were as able as breeders to release LH after a GnRH challenge, indicating that they had functional pituitaries. However, the decision to skip reproduction was linked to a strong LH decrease after the 10 min post-GnRH injection. Our result suggests that the youngest and the oldest petrels fail to maintain elevated baseline LH levels, thereby do not initiate reproductive activities. Skipping reproduction in long-lived birds probably results from age-related changes in the dynamics of the hypothalamic-pituitary-gonadal (HPG) axis function.

  11. Health, behavioral, cognitive, and social correlates of breakfast skipping among women living in socioeconomically disadvantaged neighborhoods.

    Science.gov (United States)

    Smith, Kylie J; McNaughton, Sarah A; Cleland, Verity J; Crawford, David; Ball, Kylie

    2013-11-01

    Breakfast skipping is a potentially modifiable behavior that has negative effects on health and is socioeconomically patterned. This study aimed to examine the intrapersonal (health, behavioral, and cognitive) and social factors associated with breakfast skipping. Nonpregnant women (n = 4123) aged 18-45 y from socioeconomically disadvantaged neighborhoods throughout Victoria, Australia, completed a postal questionnaire. Sociodemographic characteristics, diet, physical activity, sedentary behaviors, and cognitive and social factors were assessed by self-report. Breakfast skipping was defined in 2 ways: 1) "rarely/never" eating breakfast (n = 498) and 2) eating breakfast ≤2 d/wk (includes those who rarely/never ate breakfast; n = 865). Poisson regression was used to calculate prevalence ratios and linear trends, adjusting for covariates. The P values for linear trends are reported below. Compared with breakfast consumers, women who reported rarely/never eating breakfast tended to have poorer self-rated health (P-trend breakfast skipping was defined as eating breakfast ≤2 d/wk, additional associations were found for having lower leisure-time physical activity (P-trend = 0.012) and less self-efficacy for eating a healthy diet (P-trend breakfast skipping among women living in socioeconomically disadvantaged areas. Acknowledging the cross-sectional design and need for causal confirmation, programs that aim to promote breakfast consumption in this population group should consider targeting family-related barriers to healthy eating and nutrition knowledge.

  12. Sequence Analysis of Hoxc8 Exon-1 and Exon-2 of Multi-Vertebrae Mongolia Sheep%多脊椎蒙古羊Hoxc8 exon-1和exon-2的序列分析

    Institute of Scientific and Technical Information of China (English)

    陈琦; 赵静; 张立岭; 马月辉

    2011-01-01

    参考牛的Hoxc8基因序列设计引物,扩增正常蒙古羊(胸椎数13)和多脊椎蒙古羊(胸椎数14)Hoxc8的exon-1和exon-2基因,对得到的序列进行生物信息学分析。结果表明,经序列比对二者的DNA序列,除两侧个别碱基有差异外,中间序列完全一致。蒙古羊Hoxc8的exon-1和exon-2序列分别与其他物种进行同源性比对,蒙古羊Hoxc8 exon-1与人、小鼠、大鼠、犬的同源性达到96%以上,与斑马鱼的同源性为75.8%;exon-2与大猩猩、犬、人、小鼠、大鼠的同源性达到91%以上,与斑马鱼的同源性%In our study,according to the Hoxc8 sequence of cow,the specific primers were designed,and the sequences of Hoxc8 exon-1(432 bp)and exon-2(273 bp)of normal and multi-thoracic vertebrae mongolia sheep were obtained(Genebank accession number: EU817489 and FJ905472).Alignment results of them indicated that the sequences were conformity except a little difference in two sides of sequences.Hoxc8 exon-1 and exon-2 were aligned with other species and the results showed that compared with other mammals(human,dog,mouse,rat and chimpanzee),the homology were above 96%(exon-1) and 91%(exon-2);compared with zebra fish,the homology were 75.8% and 74%.

  13. Potential Association between Breakfast Skipping and Concomitant Late-Night-Dinner Eating with Metabolic Syndrome and Proteinuria in the Japanese Population

    OpenAIRE

    Ayano Kutsuma; Kei Nakajima; Kaname Suwa

    2014-01-01

    Skipping breakfast is considered to be an unhealthy eating habit linked to predispositions to obesity and type 2 diabetes. Because eating dinner late at night can elicit subsequent breakfast skipping, we investigated if skipping breakfast concomitant with late-night-dinner eating (LNDE) was associated with metabolic syndrome (MetS) and proteinuria in the general Japanese population. We examined self-reported habitual breakfast skipping and LNDE, MetS (modified ATP-III criteria), and proteinur...

  14. Adolescents' unhealthy eating habits are associated with meal skipping.

    Science.gov (United States)

    Rodrigues, Paulo Rogério Melo; Luiz, Ronir Raggio; Monteiro, Luana Silva; Ferreira, Márcia Gonçalves; Gonçalves-Silva, Regina Maria Veras; Pereira, Rosangela Alves

    2017-10-01

    Meal consumption and diet quality are important for healthy development during adolescence. The aim of this study was to determine the association between meal habits and diet quality in Brazilian adolescents. A school-based, cross-sectional study was conducted in 2008 with a probabilistic sample of adolescents ages 14 to 19 y (N = 1139) from high schools in central-western Brazil. Consumption of breakfast, morning snack, lunch, afternoon snack, and dinner was assessed to evaluate adolescents' meal profile. The Brazilian Healthy Eating Index-Revised (BHEI-R) was calculated to evaluate diet quality. The association between meal profile and BHEI-R (global estimates and components) was assessed using multivariate linear regression models. Diet was characterized by unhealthy eating: a low consumption of fruits, vegetables, and milk/dairy, and a high consumption of fats and sodium. An unsatisfactory meal profile was observed in 14% of adolescents, whereas daily consumption of breakfast, lunch, and dinner was reported by 47%, 78%, and 52% of adolescents, respectively. Meal profile was positively associated with diet quality. Daily consumption of breakfast was associated with higher BHEI-R scores, lower sodium intake, and greater consumption of fruits and milk/dairy. Daily consumption of lunch was associated with greater consumption of vegetables and "meats, eggs, and legumes," whereas consumption of dinner was associated with an increased consumption of "whole fruits." This study showed a parallelism between daily consumption of meals with healthier eating and greater adherence to traditional Brazilian food habits. Skipping meals was associated with a low-quality diet, especially concerning to the low consumption of fruits and vegetables and a high intake of sodium and calories from solid fats, added sugars, and alcoholic beverages. Therefore, the adoption of regular meal habits may help adolescents improve their diet quality. Copyright © 2017 Elsevier Inc. All

  15. Skipping breakfast and overweight in 2-and 5-year-old Dutch children-the GECKO Drenthe cohort

    NARCIS (Netherlands)

    Kupers, L. K.; de Pijper, J. J.; Sauer, P. J. J.; Stolk, R. P.; Corpeleijn, E.

    2014-01-01

    Skipping breakfast is associated with higher BMI in children aged 5 years and older. However, not much is known about this association in younger children. In the Dutch GECKO Drenthe birth cohort we examined the association between breakfast skipping and objectively measured overweight at the age of

  16. Skipping breakfast and overweight in 2-and 5-year-old Dutch children-the GECKO Drenthe cohort

    NARCIS (Netherlands)

    Kupers, L. K.; de Pijper, J. J.; Sauer, P. J. J.; Stolk, R. P.; Corpeleijn, E.

    Skipping breakfast is associated with higher BMI in children aged 5 years and older. However, not much is known about this association in younger children. In the Dutch GECKO Drenthe birth cohort we examined the association between breakfast skipping and objectively measured overweight at the age of

  17. Forward recursion for Markov decision processes with skip-free-to-the-right transitions - Part II : Non-standard applications

    NARCIS (Netherlands)

    Wijngaard, J.; Stidham, S.

    2000-01-01

    This paper is the sequel to Wijngaard and Stidham (1986). The topic is a countable state, average reward semi-Markov decision process with a transition mechanism that is skip-free to the right. The applications are controlled GI/M/1 queues. Skip-free to the right means that state n cannot be reached

  18. Grade Skipping from the Perspective of Teachers in Germany: The Links between Teachers' Decisions, Acceptance, and Perceived Knowledge

    Science.gov (United States)

    Westphal, Andrea; Vock, Miriam; Stubbe, Tobias

    2017-01-01

    The present study explored teachers' perspectives on one specific type of acceleration, namely, grade skipping. In addition, we investigated the extent to which teachers' beliefs about students' academic, motivational, and social development after grade skipping may explain teachers' acceptance of this accelerative strategy. Moreover, we examined…

  19. 76 FR 70340 - Generation-Skipping Transfers (GST) Section 6011 Regulations and Amendments to the Section 6112...

    Science.gov (United States)

    2011-11-14

    ... Internal Revenue Service 26 CFR Parts 26 and 301 RIN 1545-BG89 Generation-Skipping Transfers (GST) Section 6011 Regulations and Amendments to the Section 6112 Regulations AGENCY: Internal Revenue Service (IRS... generation-skipping transfer tax under section 6011 of the Internal Revenue Code (Code), conforming...

  20. An Adaptive Frame Skipping and VOP Interpolation Algorithm for Video Object Segmentation

    Institute of Scientific and Technical Information of China (English)

    YANGGaobo; ZHANGZhaoyang

    2004-01-01

    Video object segmentation is a key step for the successful use of MPEG-4. However, most of the current available segmentation algorithms are still far away from real-time performance. In order to improve the processing speed, an adaptive frame skipping and VOP interpolation algorithm is proposed in this paper. It adaptively determines the number of skipped frames based on the rigidity and motion complexity of video object. To interpolate the VOPs for skipped frames, a hi-directional projection scheme is adopted. Its principle is to perform a classification of those regions obtained by spatial segmentation for every frame in the sequence. It is valid for both rigid object and non-rigid object and can get good localization of object boundaries. Experimental results show that the proposed approach can improve the processing speed greatly while maintaining visually pleasant results.

  1. Skip-webs: Efficient distributed data structures for multi-dimensional data sets

    DEFF Research Database (Denmark)

    Arge, Lars; Eppstein, David; Goodrich, Michael T.

    2005-01-01

    We present a framework for designing efficient distributed data structures for multi-dimensional data. Our structures, which we call skip-webs, extend and improve previous randomized distributed data structures, including skipnets and skip graphs. Our framework applies to a general class of data...... querying scenarios, which include linear (one-dimensional) data, such as sorted sets, as well as multi-dimensional data, such as d-dimensional octrees and digital tries of character strings defined over a fixed alphabet. We show how to perform a query over such a set of n items spread among n hosts using O......, and O(log n / log log n) messages for one-dimensional data. Finally, we show how to apply a blocking strategy to skip-webs to further improve message complexity for one-dimensional data when hosts can store more data....

  2. Family factors for child meal skipping in low-income families in Korea.

    Science.gov (United States)

    Bae, Hwa-ok; Kim, Meesook; Hong, Soon-Myung

    2010-04-01

    The present study proposed to examine whether family factors are associated with child meal skipping in Korea. Family factors were divided into risk factors and protective factors on conceptual and theoretical bases. The sample was obtained from the Survey of Meal Service for Poor Children conducted by the Korea Institute for Health and Social Affairs in 2007. A final sample was composed of 944 children in low-income families who are served by the public meal program. Child meal skipping was positively associated with risk factors and negatively associated with protective factors, as hypothesized. Single-father family, middle or small urban area, presence of caretaker after school, health level of caretaker, caretaker's concern about child's diet, and degree of family cohesion significantly predicted child meal skipping. The authors suggest a few implications for practice based on the study findings.

  3. Scanning for genes in large genomic regions: cosmid-based exon trapping of multiple exons in a single product.

    OpenAIRE

    Datson, N.A.; Vosse, E van de; Dauwerse, H.G.; Bout, M; van Ommen, G J; J T den Dunnen

    1996-01-01

    To facilitate the scanning of large genomic regions for the presence of exonic gene segments we have constructed a cosmid-based exon trap vector. The vector serves a dual purpose since it is also suitable for contig construction and physical mapping. The exon trap cassette of vector sCOGH1 consists of the human growth hormone gene driven by the mouse mettallothionein-1 promoter. Inserts are cloned in the multicloning site located in intron 2 of the hGH gene. The efficiency of the system is de...

  4. Does Skipping Breakfast and Being Overweight Influence Academic Achievement Among Korean Adolescents?

    Science.gov (United States)

    Kang, Yang Wha; Park, Jong-Hyock

    2016-08-01

    Health status and health behaviors are associated with academic achievement in children and adolescents. The purpose of this study was to investigate whether skipping breakfast and being overweight are related to academic achievement of Korean adolescents. Cross-sectional data on a sample of 1,652 high-school seniors (942 males and 710 females) drawn from the 2004 Korea Education Employment Panel were analyzed. A higher proportion of males (15.3%) than females (6.1%) was overweight (p < 0.001); 37% of males and 41% of females reported skipping breakfast. Overall test scores were significantly higher for females than males (p < 0.05), and in language and foreign language subjects. However, both males and females who reported skipping breakfast had significantly lower scores in language, mathematics, and foreign language than those who did not report skipping breakfast. Overweight males had a lower probability than normal-weight males of having the highest language scores (OR = 0.52, p < 0.05), but there was no difference among females. Females who skipped breakfast had a lower probability of having the highest scores in language (OR = 0.41, p < 0.05), mathematics (OR = 0.24, p < 0.01), or foreign language (OR = 0.18, p < 0.01), while males had a lower probability of having the highest scores in language only (OR = 0.46, p < 0.05). Skipping breakfast and being overweight are associated with poor academic achievement in Korean adolescents. Eating breakfast and weight control is being discussed as the overlooked factors that may influence better academic achievement.

  5. Factors associated with skipping breakfast among Inner Mongolia Medical students in China

    Directory of Open Access Journals (Sweden)

    Sun Juan

    2013-01-01

    Full Text Available Abstract Background Few studies on the breakfast consumption habits of medical students in China have been carried out. The aim of the present study was to determine the prevalence of skipping breakfast and factors associated with skipping breakfast among medical students in Inner Mongolia of China, and to assist in the design of interventions to improve breakfast consumption habits of medical college students in this region. Methods From December 2010 to January 2011 a cross-sectional survey was conducted among medical students in the Inner Mongolia Medical College using a self-administered questionnaire. The prevalence of skipping breakfast in relation to lifestyle habits was described and factors associated with breakfast consumption were identified using multiple logistic regression analysis. Results The overall prevalence of skipping breakfast was 41.7% and 23.5% for males and females, respectively. The Faculty of Medicine Information Management had the highest breakfast skipping prevalence. Logistic regression models found that the main factors associated with breakfast consumption habits among medical students were gender, class years of education, monthly expenses, faculty, appetite, sleeping quality, and the learning process; monthly expenses, sleeping quality, and the learning process showed a dose-dependent relationship. Conclusions Breakfast consumption was associated with many factors, most importantly monthly expenses, sleeping quality and the learning process. The prevalence of skipping breakfast is significantly higher compared recently reported figures for medical students in western countries and other areas of China. Improvement of breakfast education should be considered for students in which higher monthly expenses, poor sleeping quality, or a laborious learning process have been identified.

  6. Differentiated evolutionary rates in alternative exons and the implications for splicing regulation

    Directory of Open Access Journals (Sweden)

    Eyras Eduardo

    2006-06-01

    Full Text Available Abstract Background Alternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences. Results We find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS and non-synonymous (dN substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for

  7. 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...

  8. 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...

  9. Lampe1: an ENU-germline mutation causing spontaneous hepatosteatosis identified through targeted exon-enrichment and next-generation sequencing.

    Directory of Open Access Journals (Sweden)

    Rachel Sheridan

    Full Text Available Using a small scale ENU mutagenesis approach we identified a recessive germline mutant, designated Lampe1 that exhibited growth retardation and spontaneous hepatosteatosis. Low resolution mapping based on 20 intercrossed Lampe1 mice revealed linkage to a ∼14 Mb interval on the distal site of chromosome 11 containing a total of 285 genes. Exons and 50 bp flanking sequences within the critical region were enriched with sequence capture microarrays and subsequently analyzed by next-generation sequencing. Using this approach 98.1 percent of the targeted DNA was covered with a depth of 10 or more reads per nucleotide and 3 homozygote mutations were identified. Two mutations represented intronic nucleotide changes whereas one mutation affected a splice donor site in intron 11-12 of Palmitoyl Acetyl-coenzyme A oxygenase-1 (Acox1, causing skipping of exon 12. Phenotyping of Acox1(Lampe1 mutants revealed a progression from hepatosteatosis to steatohepatitis, and ultimately hepatocellular carcinoma. The current approach provides a highly efficient and affordable method to identify causative mutations induced by ENU mutagenesis and animal models relevant to human pathology.

  10. Media use as a reason for meal skipping and fast eating in secondary school children.

    Science.gov (United States)

    Van den Bulck, J; Eggermont, S

    2006-04-01

    This study examined self-reported meal skipping and eating faster than usual with the goal of watching television or playing computer games. Respondents reported their media use and indicated how often they skipped a meal to watch a favourite television programme or to play a computer game, and how often they ate faster than usual in order to watch television or play a computer game. Respondents were 2546 adolescents of 13 (first year of secondary school) and 16 years (fourth year of secondary school) of age. About one respondent in 10 skipped at least one meal every week for either television viewing or computer game playing. Weekly meal skipping for television viewing occurs more regularly in boys and first-year students, but particularly in teenagers who view 5 h or more daily (15% of the sample). The category of teenagers who play computer games four times a week or more (25.3% of the sample) is at increased risk of meal skipping; those who play more than four times a week are 10 times more likely weekly to skip a meal. A quarter of the adolescents eat faster at least once a week to be able to watch television or play a computer game. Regardless of gender and school year, teenagers' risk of eating faster progressively increases with their use of the media. Those who watch 4 h or more daily are about seven times more likely to skip a meal for television and those who play computer games at least four times a week are nine times more likely weekly to skip a meal. Unhealthy eating habits can be a side effect of heavy or excessive media use. Teenagers' use of television or game computers during nonworking or out-of-school hours partly displaces the amount of time that needs to be spent at meals. Practitioners and educators may try to encourage or restore a pattern of healthful meal consumption habits by reducing the amount of media use, and by supporting parental rule-making regarding children's eating habits and media use.

  11. Fault Tolerant Variable Block Carry Skip Logic (VBCSL) using Parity Preserving Reversible Gates

    CERN Document Server

    Islam, Md Saiful; Begum, Zerina; Hafiz, Mohd Zulfiquar

    2010-01-01

    Reversible logic design has become one of the promising research directions in low power dissipating circuit design in the past few years and has found its application in low power CMOS design, digital signal processing and nanotechnology. This paper presents the efficient design approaches of fault tolerant carry skip adders (FTCSAs) and compares those designs with the existing ones. Variable block carry skip logic (VBCSL) using the fault tolerant full adders (FTFAs) has also been developed. The designs are minimized in terms of hardware complexity, gate count, constant inputs and garbage outputs. Besides of it, technology independent evaluation of the proposed designs clearly demonstrates its superiority with the existing counterparts.

  12. Tdp-43 cryptic exons are highly variable between cell types.

    Science.gov (United States)

    Jeong, Yun Ha; Ling, Jonathan P; Lin, Sophie Z; Donde, Aneesh N; Braunstein, Kerstin E; Majounie, Elisa; Traynor, Bryan J; LaClair, Katherine D; Lloyd, Thomas E; Wong, Philip C

    2017-02-02

    TDP-43 proteinopathy is a prominent pathological feature that occurs in a number of human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myositis (IBM). Our recent finding that TDP-43 represses nonconserved cryptic exons led us to ask whether cell type-specific cryptic exons could exist to impact unique molecular pathways in brain or muscle. In the present work, we investigated TDP-43's function in various mouse tissues to model disease pathogenesis. We generated mice to conditionally delete TDP-43 in excitatory neurons or skeletal myocytes and identified the cell type-specific cryptic exons associated with TDP-43 loss of function. Comparative analysis of nonconserved cryptic exons in various mouse cell types revealed that only some cryptic exons were common amongst stem cells, neurons, and myocytes; the majority of these nonconserved cryptic exons were cell type-specific. Our results suggest that in human disease, TDP-43 loss of function may impair cell type-specific pathways.

  13. Intron phase correlations and the evolution of the intron/exon structure of genes.

    Science.gov (United States)

    Long, M; Rosenberg, C; Gilbert, W

    1995-01-01

    Two issues in the evolution of the intron/exon structure of genes are the role of exon shuffling and the origin of introns. Using a large data base of eukaryotic intron-containing genes, we have found that there are correlations between intron phases leading to an excess of symmetric exons and symmetric exon sets. We interpret these excesses as manifestations of exon shuffling and make a conservative estimate that at least 19% of the exons in the data base were involved in exon shuffling, suggesting an important role for exon shuffling in evolution. Furthermore, these excesses of symmetric exons appear also in those regions of eukaryotic genes that are homologous to prokaryotic genes: the ancient conserved regions. This last fact cannot be explained in terms of the insertional theory of introns but rather supports the concept that some of the introns were ancient, the exon theory of genes. PMID:8618928

  14. Potential Association between Breakfast Skipping and Concomitant Late-Night-Dinner Eating with Metabolic Syndrome and Proteinuria in the Japanese Population

    Directory of Open Access Journals (Sweden)

    Ayano Kutsuma

    2014-01-01

    Full Text Available Skipping breakfast is considered to be an unhealthy eating habit linked to predispositions to obesity and type 2 diabetes. Because eating dinner late at night can elicit subsequent breakfast skipping, we investigated if skipping breakfast concomitant with late-night-dinner eating (LNDE was associated with metabolic syndrome (MetS and proteinuria in the general Japanese population. We examined self-reported habitual breakfast skipping and LNDE, MetS (modified ATP-III criteria, and proteinuria in a cross-sectional study of 60,800 Japanese adults aged 20–75 years. A total of 14,068 subjects (23.1% skipped breakfast, of whom approximately half (52.8% skipped breakfast alone (without LNDE. The percentages of subjects who skipped breakfast showed a J-shaped relationship with body mass index (BMI. Multivariate logistic regression analysis showed that skipping breakfast concomitant with LNDE (n = 6,645 was significantly associated with MetS and proteinuria, even after adjusting for relevant confounders (odds ratio (95% CI, 1.17 (1.08–1.28, P=0.0003, and 1.37 (1.24–1.52, P<0.0001, resp.. Skipping breakfast alone and LNDE alone were not associated with MetS and proteinuria, respectively. In conclusion, habitual breakfast skipping concomitant with LNDE may represent poorer eating behavior than skipping breakfast alone, associated with MetS, asymptomatic proteinuria, obesity, and low body weight in the general Japanese population.

  15. Potential Association between Breakfast Skipping and Concomitant Late-Night-Dinner Eating with Metabolic Syndrome and Proteinuria in the Japanese Population.

    Science.gov (United States)

    Kutsuma, Ayano; Nakajima, Kei; Suwa, Kaname

    2014-01-01

    Skipping breakfast is considered to be an unhealthy eating habit linked to predispositions to obesity and type 2 diabetes. Because eating dinner late at night can elicit subsequent breakfast skipping, we investigated if skipping breakfast concomitant with late-night-dinner eating (LNDE) was associated with metabolic syndrome (MetS) and proteinuria in the general Japanese population. We examined self-reported habitual breakfast skipping and LNDE, MetS (modified ATP-III criteria), and proteinuria in a cross-sectional study of 60,800 Japanese adults aged 20-75 years. A total of 14,068 subjects (23.1%) skipped breakfast, of whom approximately half (52.8%) skipped breakfast alone (without LNDE). The percentages of subjects who skipped breakfast showed a J-shaped relationship with body mass index (BMI). Multivariate logistic regression analysis showed that skipping breakfast concomitant with LNDE (n = 6,645) was significantly associated with MetS and proteinuria, even after adjusting for relevant confounders (odds ratio (95% CI), 1.17 (1.08-1.28), P = 0.0003, and 1.37 (1.24-1.52), P Skipping breakfast alone and LNDE alone were not associated with MetS and proteinuria, respectively. In conclusion, habitual breakfast skipping concomitant with LNDE may represent poorer eating behavior than skipping breakfast alone, associated with MetS, asymptomatic proteinuria, obesity, and low body weight in the general Japanese population.

  16. strong>TAT> gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping

    DEFF Research Database (Denmark)

    Maydan, G; Andresen, Brage Storstein; Madsen, Pia Pinholt

    2006-01-01

    Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II or Richner-Hanhart syndrome). Parents may...

  17. Effects of social determinants on food choice and skipping meals among Turkish adolescents.

    Science.gov (United States)

    Soyer, Meral Turk; Ergin, Isil; Gursoy, Safak Taner

    2008-01-01

    To present data that contributes to understanding factors that influence food choice and skipping meals in adolescents. A cross sectional study is carried in selected high schools in Bornova. Study sample compromises of 527 students chosen randomly by class from a population of 2410 first year in high school students. Self-administered questionnaires containing sociodemographic determinants, self reported weight and height, food choices and meal patterns were used. A psychosocial factor that affects almost all of the students is the "taste and sensory perception of food". The second noticable factor is the "health and nutritious value of food". The time conserved and the convenience in the preparation of food is one of the lifestyle factors that affect more than half of the students. The cost of the food was also found to have an effect. Among the third group of factors categorized as "media", the leading factor is advertisement, effective in one third of the students. Among boys and girls, there was no statistical difference in the type of meal skipped. Living in Izmir for more than 10 years compared to less than ten years, being in a nuclear family to extended family, and belonging to the "owner" social class to "wage laborer" class also do not statistically differ with regard to skipping meals. However, the mother's and father's education level and having a working mother are associated with skipping meals. These results provide important evidence to support opportunities to positively influence the adoption of healthful eating.

  18. Meal-Skipping Behaviors and Body Fat in 6-Year-Old Children

    NARCIS (Netherlands)

    A.I. Wijtzes (Anne); W. Jansen (Wilma); S.H. Bouthoorn (Selma); F.J. van Lenthe (Frank); O.H. Franco (Oscar); A. Hofman (Albert); V.W.V. Jaddoe (Vincent W. V.); H. Raat (Hein)

    2016-01-01

    textabstractObjective To assess the prospective associations of breakfast, lunch, and dinner skipping at age 4 years with body fat (ie, percent fat mass, body mass index [BMI], and weight status) at age 6 years. Study design Data were analyzed from 5913 children participating in the Generation R Stu

  19. Skipping breakfast is associated with lower physical activity energy expenditure in young healthy women

    Science.gov (United States)

    Objective: According to recent NHANES data, the prevalence of breakfast consumption has decreased in adults from 89% to 82% between 1971 and 2002. Skipping breakfast has been negatively correlated with physical activity but positively correlated with body weight and risk factors associated with obes...

  20. Breakfast-skipping in children and young adolescents in the Netherlands

    NARCIS (Netherlands)

    Brugman, E.; Meulmeester, J.F.; Spee-Wekke, A. van der; Verloove-Vanhorick, S.P.

    1998-01-01

    Background: The objective of this study was to provide national figures on the prevalence of breakfast-skipping and the association with sociodemographic variables in 4-15 year old children. Methods: Data of 4,377 children were collected. A food questionnaire (24 h recall) was completed by the paren

  1. Breakfast skipping is associated with cyberbullying and school bullying victimization. A school-based cross-sectional study.

    Science.gov (United States)

    Sampasa-Kanyinga, Hugues; Roumeliotis, Paul; Farrow, Claire V; Shi, Yuanfeng F

    2014-08-01

    Breakfast skipping is a health concern that has well-known negative consequences physically and psychologically. It is therefore important to understand why children skip breakfast. The purpose of this study was to establish whether the experience of bullying and cyberbullying impacts upon breakfast skipping and to further evaluate whether the inability for youths to cope with bullying victimization affects their mental health (depression), and in turn predicts breakfast skipping. Data were obtained from the Eastern Ontario 2011 Youth Risk Behaviour Survey, a cross-sectional regional school-based survey of middle and high school students (11-20 years old) across the five counties of Eastern Ontario, Canada (N = 3035). Self-reported data about children's experiences of bullying victimization, breakfast eating habits, socio-economical status, depression, and other risk behaviours were analysed. Approximately half of the participants (50.4%) reported not eating breakfast on a regular basis: 26.3% and 24.1% reported often (usually eat breakfast three times or more per week) and frequent (usually eat breakfast twice a week or less) breakfast skipping behaviour, respectively. Victims of both cyberbullying and school bullying presented greater likelihood of often (adjusted relative risk ratio (RR) = 1.55; 95% confidence interval (CI) = 1.17-2.06) and frequent (RR = 1.97; 95% CI = 1.28-3.03) breakfast skipping. Mediation analysis further showed that depression fully mediated the relationship between school bullying victimization and frequent breakfast skipping. Moreover, depression partially mediated the associations between both cyberbullying and school bullying with frequent breakfast skipping. These findings highlight the potential interrelationships between cyberbullying, school bullying and depression in predicting unhealthy breakfast skipping behaviour in children.

  2. The combined unhealthy behaviors of breakfast skipping and smoking are associated with the prevalence of diabetes mellitus.

    Science.gov (United States)

    Nishiyama, Midori; Muto, Takashi; Minakawa, Toshihiro; Shibata, Toshie

    2009-08-01

    Skipping breakfast has been considered a representative unhealthy behavior, but there is little information about the combined effects of breakfast skipping and other unhealthy health habits, especially smoking. First this cross-sectional study investigated unhealthy behaviors among breakfast skippers, and then examined the impact of the combined association of skipping breakfast and smoking on health. A total of 1,200 adults living in one Japanese community were sent questionnaires to elicit data on age, gender, breakfast-eating frequency, and other lifestyle habits. A total 603 of people returned their questionnaires (response rate: 50.3%), and 493 (230 men and 263 women) questionnaires were considered appropriate for analysis. Smoking rate in men (mean age, 53.7 years) and women (mean age, 50.4 years) was 41.3%, and 9.5%, respectively. Skipping breakfast was more prevalent in people under age 50 years (p breakfast skipping (3.10, 95%CI 1.50-6.39). Other factors included, age younger than 50 years (3.04, 95%CI 1.31-7.06) and poor sleeping quality (2.06, 95%CI 1.00-4.25). After examining the combined impact of skipping breakfast and smoking, the highest odds ratio for a diagnosis of diabetes mellitus was found among those who smoked and skipped breakfast (4.68, 95% CI: 1.46-15.05). Moreover, skipping breakfast among non-smokers showed a high association with perceived stress (2.83, 95% CI: 1.05-7.61). In conclusion, the combined unhealthy behaviors of skipping breakfast and smoking are associated with the prevalence of diabetes mellitus.

  3. SparseLeap: Efficient Empty Space Skipping for Large-Scale Volume Rendering

    KAUST Repository

    Hadwiger, Markus

    2017-08-28

    Recent advances in data acquisition produce volume data of very high resolution and large size, such as terabyte-sized microscopy volumes. These data often contain many fine and intricate structures, which pose huge challenges for volume rendering, and make it particularly important to efficiently skip empty space. This paper addresses two major challenges: (1) The complexity of large volumes containing fine structures often leads to highly fragmented space subdivisions that make empty regions hard to skip efficiently. (2) The classification of space into empty and non-empty regions changes frequently, because the user or the evaluation of an interactive query activate a different set of objects, which makes it unfeasible to pre-compute a well-adapted space subdivision. We describe the novel SparseLeap method for efficient empty space skipping in very large volumes, even around fine structures. The main performance characteristic of SparseLeap is that it moves the major cost of empty space skipping out of the ray-casting stage. We achieve this via a hybrid strategy that balances the computational load between determining empty ray segments in a rasterization (object-order) stage, and sampling non-empty volume data in the ray-casting (image-order) stage. Before ray-casting, we exploit the fast hardware rasterization of GPUs to create a ray segment list for each pixel, which identifies non-empty regions along the ray. The ray-casting stage then leaps over empty space without hierarchy traversal. Ray segment lists are created by rasterizing a set of fine-grained, view-independent bounding boxes. Frame coherence is exploited by re-using the same bounding boxes unless the set of active objects changes. We show that SparseLeap scales better to large, sparse data than standard octree empty space skipping.

  4. 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.

  5. 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.

  6. Recombinant Exon-Encoded Resilins for Elastomeric Biomaterials

    Science.gov (United States)

    Qin, Guokui; Rivkin, Amit; Lapidot, Shaul; Hu, Xiao; Arinus, Shira B.; Dgany, Or; Shoseyov, Oded; Kaplan, David L.

    2011-01-01

    Resilin is an elastomeric protein found in specialized regions of the cuticle of most insects, providing outstanding material properties including high resilience and fatigue lifetime for insect flight and jumping needs. Two exons (1 and 3) from the resilin gene in Drosophila melanogaster were cloned and the encoded proteins expressed as soluble products in Escherichia coli. A heat and salt precipitation method was used for efficient purification of the recombinant proteins. The proteins were solution cast from water and formed into rubber-like biomaterials via horseradish peroxidase-mediated cross-linking. Comparative studies of the two proteins expressed from the two different exons were investigated by Fourier Transform Infrared Spectroscopy (FTIR) and Circular Dichrosim (CD) for structural features. Little structural organization was found, suggesting structural order was not induced by the enzyme-mediateed dityrosine cross-links. Atomic Force Microscopy (AFM) was used to study the elastomeric properties of the uncross-linked and cross-linked proteins. The protein from exon 1 exhibited 90% resilience in comparison to 63% for the protein from exon 3, and therefore may be the more critical domain for functional materials to mimic native resilin. Further, the cross-linking of the recombinant exon 1 via the citrate-modified photo-Fenton reaction was explored as an alternative dityrosine mediated polymerization method and resulted in both highly elastic and adhesive materials. The citrate-modified photo-Fenton system may be suitable for in-vivo applications of resilin biomaterials. PMID:21963157

  7. Large-scale remodeling of a repressed exon ribonucleoprotein to an exon definition complex active for splicing.

    Science.gov (United States)

    Wongpalee, Somsakul Pop; Vashisht, Ajay; Sharma, Shalini; Chui, Darryl; Wohlschlegel, James A; Black, Douglas L

    2016-11-24

    Polypyrimidine-tract binding protein PTBP1 can repress splicing during the exon definition phase of spliceosome assembly, but the assembly steps leading to an exon definition complex (EDC) and how PTBP1 might modulate them are not clear. We found that PTBP1 binding in the flanking introns allowed normal U2AF and U1 snRNP binding to the target exon splice sites but blocked U2 snRNP assembly in HeLa nuclear extract. Characterizing a purified PTBP1-repressed complex, as well as an active early complex and the final EDC by SILAC-MS, we identified extensive PTBP1-modulated changes in exon RNP composition. The active early complex formed in the absence of PTBP1 proceeded to assemble an EDC with the eviction of hnRNP proteins, the late recruitment of SR proteins, and binding of the U2 snRNP. These results demonstrate that during early stages of splicing, exon RNP complexes are highly dynamic with many proteins failing to bind during PTBP1 arrest.

  8. Automatic detection of exonic splicing enhancers (ESEs using SVMs

    Directory of Open Access Journals (Sweden)

    Suhai Sándor

    2008-09-01

    Full Text Available Abstract Background Exonic splicing enhancers (ESEs activate nearby splice sites and promote the inclusion (vs. exclusion of exons in which they reside, while being a binding site for SR proteins. To study the impact of ESEs on alternative splicing it would be useful to have a possibility to detect them in exons. Identifying SR protein-binding sites in human DNA sequences by machine learning techniques is a formidable task, since the exon sequences are also constrained by their functional role in coding for proteins. Results The choice of training examples needed for machine learning approaches is difficult since there are only few exact locations of human ESEs described in the literature which could be considered as positive examples. Additionally, it is unclear which sequences are suitable as negative examples. Therefore, we developed a motif-oriented data-extraction method that extracts exon sequences around experimentally or theoretically determined ESE patterns. Positive examples are restricted by heuristics based on known properties of ESEs, e.g. location in the vicinity of a splice site, whereas negative examples are taken in the same way from the middle of long exons. We show that a suitably chosen SVM using optimized sequence kernels (e.g., combined oligo kernel can extract meaningful properties from these training examples. Once the classifier is trained, every potential ESE sequence can be passed to the SVM for verification. Using SVMs with the combined oligo kernel yields a high accuracy of about 90 percent and well interpretable parameters. Conclusion The motif-oriented data-extraction method seems to produce consistent training and test data leading to good classification rates and thus allows verification of potential ESE motifs. The best results were obtained using an SVM with the combined oligo kernel, while oligo kernels with oligomers of a certain length could be used to extract relevant features.

  9. Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Victor Villar

    2013-01-01

    Full Text Available Purpose. To determine whether Ski-interacting protein (SKIP regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA, matrix metalloproteinase-9 (MMP-9, and uPA Inhibitor (PAI-1 in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment.

  10. Breakfast skipping as a risk correlate of overweight and obesity in school-going ethnic Fijian adolescent girls.

    Science.gov (United States)

    Thompson-McCormick, Jonas J; Thomas, Jennifer J; Bainivualiku, Asenaca; Khan, A Nisha; Becker, Anne E

    2010-01-01

    The prevalence of overweight and obesity has increased globally, and population data suggest that it is also increasing among ethnic Fijian youth. Among numerous behavioural changes contributing to overweight in youth residing in nations undergoing rapid economic and social change, meal skipping has not been examined as a potential risk factor. The study objectives were to assess the prevalence of overweight, obesity, and breakfast skipping and examine their cross-sectional association in a community sample of school-going ethnic Fijian adolescent girls (N=523). We measured height and weight, and assessed dietary patterns, eating pathology, dimensions of acculturation, and other socio-demographic and cultural data by self-report. We observed a high prevalence of both overweight (41%, including 15% who were obese) and breakfast skipping (68%). In addition, in multivariable analyses unadjusted for eating pathology, we found that more frequent breakfast skipping was associated with greater odds of overweight (odds ratio (OR)=1.15, confidence interval (CI)=1.06, 1.26, pbreakfast skipping, eating pathology, and overweight in ethnic Fijian girls, and to identify whether breakfast skipping may be a modifiable risk factor for overweight in this population.

  11. Skipping breakfast and overweight in 2- and 5-year-old Dutch children-the GECKO Drenthe cohort.

    Science.gov (United States)

    Küpers, L K; de Pijper, J J; Sauer, P J J; Stolk, R P; Corpeleijn, E

    2014-04-01

    Skipping breakfast is associated with higher BMI in children aged 5 years and older. However, not much is known about this association in younger children. In the Dutch GECKO Drenthe birth cohort we examined the association between breakfast skipping and objectively measured overweight at the age of 2 (n=1488) and 5 (n=1366) years. At 2 years, 124 (8.3%) children were overweight and 44 (3.0%) did not eat breakfast daily. At 5 years, 180 (13.2%) children were overweight and 73 (5.3%) did not eat breakfast daily. Children belonging to families of non-Dutch origin, those with lower educated parents and those with single parents skipped breakfast more often. Breakfast skipping in 2- and 5-year-olds is rare in the Netherlands. We found no association between skipping breakfast and overweight, neither at age 2 (odds ratio (OR): 1.85 (95% confidence interval (CI): 0.61-5.64)) nor at age 5 (OR: 0.46 (95% CI: 0.19-1.11)). Also the type of breakfast was not related to overweight at 5 years. An explanation for this finding might be that skipping breakfast is not (yet) an issue in these children.

  12. Meal skipping and variables related to energy balance in adults: a brief review, with emphasis on the breakfast meal.

    Science.gov (United States)

    McCrory, Megan A

    2014-07-01

    A popular notion regarding habitual meal skipping is that it leads to weight gain; however, there is little support for this idea in the scientific literature. Here we review the evidence both for and against this notion in adults (≥18 years), with, out of practicality, a primary focus on the breakfast meal. To date, few randomized controlled trials and prospective studies have been conducted on breakfast skipping and energy balance. Three acute feeding studies have been published which show equivocal results and do not strongly support an effect of breakfast skipping on variables related to energy balance. Four longer-term experimental studies lasting 2-3 weeks have been published and are consistent with the acute feeding trials in that breakfast skipping or eating treatments did not materially impact weight change. Four prospective studies in which participants were followed-up for over 3.7-10 years do suggest a potential role of skipping breakfast in weight gain. However, observational studies do not imply causality; therefore, longer term experimental trials are needed before a definitive conclusion can be made concerning the role of breakfast skipping in weight change.

  13. Polymorphism of exon 3 of the HLA-G gene

    DEFF Research Database (Denmark)

    Hviid, T V; Meldgaard, Michael; Sørensen, S

    1997-01-01

    populations have only revealed a limited polymorphism. We investigated the polymorphism of the exon 3 of HLA-G by means of Polymerase Chain Reaction (PCR)-Single Strand Conformation Polymorphism (SSCP)- and DNA sequencing analysis in a Danish population. We detected four single-base substitutions in exon 3...... rate of embryos. HLA-G seems to play an important role in the feto-maternal relationship. The polymorphism of the HLA-G locus is not fully clarified. One study has shown extensive nucleotide sequence variation in the exon 3 (alpha-2 domain) in healthy African Americans. A few studies in other...... compared to the sequence of HLA-6.0 (G*01011); one of these has not been reported before. We also found a deletion of the first base of codon 130 or the third of codon 129 in a heterozygous individual. This study, together with previous results, suggests that the polymorphism of exon 3 of the HLA-G gene...

  14. Exon duplications in the ATP7A gene

    DEFF Research Database (Denmark)

    Mogensen, Mie; Skjørringe, Tina; Kodama, Hiroko

    2011-01-01

    BACKGROUND: Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the ATP7A gene...

  15. Packet Skipping and Network Coding for Delay-Sensitive Network Communication

    CERN Document Server

    Aoun, Marc; Argyriou, Antonios; Denteneer, Dee; van der Stok, Peter

    2012-01-01

    We provide an analytical study of the impact of packet skipping and opportunistic network coding on the timely communication of messages through a single network element. In a first step, we consider a single-server queueing system with Poisson arrivals, exponential service times, and a single buffer position. Packets arriving at a network node have a fixed deadline before which they should reach the destination. To preserve server capacity, we introduce a thresholding policy, based on remaining time until deadline expiration, to decide whether to serve a packet or skip its service. The obtained goodput improvement of the system is derived, as well as the operating conditions under which thresholding can enhance performance. Subsequently, we focus our analysis on a system that supports network coding instead of thresholding. We characterize the impact of network coding at a router node on the delivery of packets associated with deadlines. We model the router node as a queueing system where packets arrive from...

  16. Redox-mediated bypass of restriction point via skipping of G1pm

    Directory of Open Access Journals (Sweden)

    Greene James J

    2006-07-01

    Full Text Available Abstract Background It is well known that cancer cells bypass the restriction point, R, and undergo uncontrolled cell proliferation. Hypothesis and evidence We suggest here that fibrosarcoma cells enter G1ps directly from M, skipping G1pm, hence bypassing R, in response to redox modulation. Evidence is presented from the published literature that demonstrate a shortening of the cycle period of transformed fibroblasts (SV-3T3 compared to the nontransformed 3T3 fibroblasts, corresponding to the duration of G1pm in the 3T3 fibroblasts. Evidence is also presented that demonstrate that redox modulation can induce the CUA-4 fibroblasts to bypass R, resulting in a cycle period closely corresponding to the cycle period of fibrosarcoma cells (HT1080. Conclusion The evidence supports our hypothesis that a low internal redox potential can cause fibrosarcoma cells to skip the G1pm phase of the cell cycle.

  17. An Improved Artificial Bee Colony Algorithm for Solving Hybrid Flexible Flowshop With Dynamic Operation Skipping.

    Science.gov (United States)

    Li, Jun-Qing; Pan, Quan-Ke; Duan, Pei-Yong

    2016-06-01

    In this paper, we propose an improved discrete artificial bee colony (DABC) algorithm to solve the hybrid flexible flowshop scheduling problem with dynamic operation skipping features in molten iron systems. First, each solution is represented by a two-vector-based solution representation, and a dynamic encoding mechanism is developed. Second, a flexible decoding strategy is designed. Next, a right-shift strategy considering the problem characteristics is developed, which can clearly improve the solution quality. In addition, several skipping and scheduling neighborhood structures are presented to balance the exploration and exploitation ability. Finally, an enhanced local search is embedded in the proposed algorithm to further improve the exploitation ability. The proposed algorithm is tested on sets of the instances that are generated based on the realistic production. Through comprehensive computational comparisons and statistical analysis, the highly effective performance of the proposed DABC algorithm is favorably compared against several presented algorithms, both in solution quality and efficiency.

  18. Optimized design of BCD adder and Carry skip BCD adder using reversible logic gates

    OpenAIRE

    H.R.Bhagyalakshmi,; M K Venkatesha

    2011-01-01

    Reversible logic is very essential for the construction of low power, low loss computational structures which are very essential for the construction of arithmetic circuits used in quantum computation, nano technology and other low power digital circuits. In the present paper an optimized and low quantum cost one digit BCD adder and an optimized one digit carry skip BCD adder using new reversible logic gates are proposed. The proposed work is best compared to the other existing circuits.

  19. Optimized design of Carry Skip BCD adder using new FHNG reversible logic gates

    Directory of Open Access Journals (Sweden)

    Md.Belayet Ali

    2012-07-01

    Full Text Available Reversible logic is very essential for the construction of low power, low loss computational structures which are very essential for the construction of arithmetic circuits used in quantum computation, nanotechnology and other low power digital circuits. In the present paper an optimized and low quantum cost one digit carry skip BCD adder using new reversible logic gates are proposed. The proposed work is best compared to the other existing circuits.

  20. Optimized design of BCD adder and Carry skip BCD adder using reversible logic gates

    Directory of Open Access Journals (Sweden)

    H.R.Bhagyalakshmi,

    2011-04-01

    Full Text Available Reversible logic is very essential for the construction of low power, low loss computational structures which are very essential for the construction of arithmetic circuits used in quantum computation, nano technology and other low power digital circuits. In the present paper an optimized and low quantum cost one digit BCD adder and an optimized one digit carry skip BCD adder using new reversible logic gates are proposed. The proposed work is best compared to the other existing circuits.

  1. The B-Skip-List: A Simpler Uniquely Represented Alternative to B-Trees

    CERN Document Server

    Golovin, Daniel

    2010-01-01

    In previous work, the author introduced the B-treap, a uniquely represented B-tree analogue, and proved strong performance guarantees for it. However, the B-treap maintains complex invariants and is very complex to implement. In this paper we introduce the B-skip-list, which has most of the guarantees of the B-treap, but is vastly simpler and easier to implement. Like the B-treap, the B-skip-list may be used to construct strongly history-independent index structures and filesystems; such constructions reveal no information about the historical sequence of operations that led to the current logical state. For example, a uniquely represented filesystem would support the deletion of a file in a way that, in a strong information-theoretic sense, provably removes all evidence that the file ever existed. Like the B-tree, the B-skip-list has depth O(log_B (n)) where B is the block transfer size of the external memory, uses linear space with high probability, and supports efficient one-dimensional range queries.

  2. Skipping Selected Steps of DWT Computation in Lossless JPEG 2000 for Improved Bitrates.

    Science.gov (United States)

    Starosolski, Roman

    2016-01-01

    In order to improve bitrates of lossless JPEG 2000, we propose to modify the discrete wavelet transform (DWT) by skipping selected steps of its computation. We employ a heuristic to construct the skipped steps DWT (SS-DWT) in an image-adaptive way and define fixed SS-DWT variants. For a large and diverse set of images, we find that SS-DWT significantly improves bitrates of non-photographic images. From a practical standpoint, the most interesting results are obtained by applying entropy estimation of coding effects for selecting among the fixed SS-DWT variants. This way we get the compression scheme that, as opposed to the general SS-DWT case, is compliant with the JPEG 2000 part 2 standard. It provides average bitrate improvement of roughly 5% for the entire test-set, whereas the overall compression time becomes only 3% greater than that of the unmodified JPEG 2000. Bitrates of photographic and non-photographic images are improved by roughly 0.5% and 14%, respectively. At a significantly increased cost of exploiting a heuristic, selecting the steps to be skipped based on the actual bitrate instead of an estimated one, and by applying reversible denoising and lifting steps to SS-DWT, we have attained greater bitrate improvements of up to about 17.5% for non-photographic images.

  3. Handover Management in 5G and Beyond: A Topology Aware Skipping Approach

    KAUST Repository

    Arshad, Rabe

    2016-12-21

    Network densification is foreseen as a potential solution to fulfill the 5G spectral efficiency requirements. The spectral efficiency is improved by shrinking base stations’ (BSs) footprints, thus improving the spatial frequency reuse and reducing the number of users sharing the resources of each BS. However, the foreseen densification gains are achieved at the expense of increasing handover (HO) rates. Hence, HO rate is a key performance limiting factor that should be carefully considered in densification planning. This paper sheds light on the HO problem that appears in dense 5G networks and proposes an effective solution via topology aware HO skipping. Different skipping techniques are considered and compared with the conventional best connected scheme. To this end, the proposed schemes are validated via the average user rate in downlink single-tier and two-tier cellular networks, which are modeled using the Poisson point process and the Poisson cluster process, respectively. The proposed skipping schemes show up to 47% gains in the average throughput, which would maximize the benefit of network densification.

  4. SKIP:an efficient search mechanism in unstructured P2P networks

    Institute of Scientific and Technical Information of China (English)

    SHEN Wen-wu; SU Sen; SHUANG Kai; YANG Fang-chun

    2010-01-01

    Search efficiency and accuracy of resource are important considerations for search algorithm in peer-to-peer(P2P)network.Most search algorithms use flooding among neighbor nodes to search relevant resource.However,this usually causes great amount of redundant messages,which results in high search costs and low search precision.In this paper,we use vector space model(VSM)and relevance ranking algorithms to construct overlay network,and a novel search mechanism search with K-iteration preference(SKIP)based on semantic group for P2P networks is proposed to efficiently solve these problems.The key idea of SKIP is to reorder the semantic neighbors of nodes according to relevant scores and to utilize preference selection during the process of query.We analysis and implement the scheme and reveal that the SKIP provides a low overhead on topology maintenance,which can be effectively used in P2P searching and verify it outperformanee in higher precision and lower search cost by comparing with current semantic-based searching mechanism gnutella-like efficient searching system(GES).

  5. Deep RNA sequencing reveals the smallest known mitochondrial micro exon in animals: The placozoan cox1 single base pair exon.

    Science.gov (United States)

    Osigus, Hans-Jürgen; Eitel, Michael; Schierwater, Bernd

    2017-01-01

    The phylum Placozoa holds a key position for our understanding of the evolution of mitochondrial genomes in Metazoa. Placozoans possess large mitochondrial genomes which harbor several remarkable characteristics such as a fragmented cox1 gene and trans-splicing cox1 introns. A previous study also suggested the existence of cox1 mRNA editing in Trichoplax adhaerens, yet the only formally described species in the phylum Placozoa. We have analyzed RNA-seq data of the undescribed sister species, Placozoa sp. H2 ("Panama" clone), with special focus on the mitochondrial mRNA. While we did not find support for a previously postulated cox1 mRNA editing mechanism, we surprisingly found two independent transcripts representing intermediate cox1 mRNA splicing stages. Both transcripts consist of partial cox1 exon as well as overlapping intron fragments. The data suggest that the cox1 gene harbors a single base pair (cytosine) micro exon. Furthermore, conserved group I intron structures flank this unique micro exon also in other placozoans. We discuss the evolutionary origin of this micro exon in the context of a self-splicing intron gain in the cox1 gene of the last common ancestor of extant placozoans.

  6. Enhancement of TGF-β-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP).

    Science.gov (United States)

    Kuki, Kazumasa; Yamaguchi, Noritaka; Iwasawa, Shuto; Takakura, Yuki; Aoyama, Kazumasa; Yuki, Ryuzaburo; Nakayama, Yuji; Kuga, Takahisa; Hashimoto, Yuuki; Tomonaga, Takeshi; Yamaguchi, Naoto

    2017-08-26

    c-Abl is a non-receptor-type tyrosine kinase that plays an important role in cell proliferation, migration, apoptosis, and fibrosis. Furthermore, although c-Abl is involved in transforming growth factor-β (TGF-β) signaling, its molecular functions in TGF-β signaling are not fully understood. Here, we found that c-Abl phosphorylates SKI-interacting protein (SKIP), a nuclear cofactor of the transcription factor Smad3. The c-Abl inhibitor imatinib suppressed TGF-β-induced expression of Smad3 targets as well as SKIP/Smad3 interaction. TGF-β-stimulation induced tyrosine phosphorylation of SKIP, and this phosphorylation was suppressed by imatinib. Tyr(292), Tyr(430), and Tyr(433) residues in SKIP were shown to be involved in c-Abl-mediated phosphorylation. Phosphomimetic glutamic acid substitution at Tyr(292) in SKIP enhanced, whereas its phospho-dead phenylalanine substitution attenuated TGF-β-induced SKIP/Smad3 interaction. Moreover, the phosphomimetic mutant of SKIP augmented transcriptional activity of Smad3. Taken together, these results suggest that c-Abl phosphorylates SKIP mainly at Tyr(292) and promotes SKIP/Smad3 interaction for the full activation of TGF-β/Smad3 signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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.

  8. Evaluating the protein coding potential of exonized transposable element sequences

    Directory of Open Access Journals (Sweden)

    Borodovsky Mark

    2007-11-01

    Full Text Available Abstract Background Transposable element (TE sequences, once thought to be merely selfish or parasitic members of the genomic community, have been shown to contribute a wide variety of functional sequences to their host genomes. Analysis of complete genome sequences have turned up numerous cases where TE sequences have been incorporated as exons into mRNAs, and it is widely assumed that such 'exonized' TEs encode protein sequences. However, the extent to which TE-derived sequences actually encode proteins is unknown and a matter of some controversy. We have tried to address this outstanding issue from two perspectives: i-by evaluating ascertainment biases related to the search methods used to uncover TE-derived protein coding sequences (CDS and ii-through a probabilistic codon-frequency based analysis of the protein coding potential of TE-derived exons. Results We compared the ability of three classes of sequence similarity search methods to detect TE-derived sequences among data sets of experimentally characterized proteins: 1-a profile-based hidden Markov model (HMM approach, 2-BLAST methods and 3-RepeatMasker. Profile based methods are more sensitive and more selective than the other methods evaluated. However, the application of profile-based search methods to the detection of TE-derived sequences among well-curated experimentally characterized protein data sets did not turn up many more cases than had been previously detected and nowhere near as many cases as recent genome-wide searches have. We observed that the different search methods used were complementary in the sense that they yielded largely non-overlapping sets of hits and differed in their ability to recover known cases of TE-derived CDS. The probabilistic analysis of TE-derived exon sequences indicates that these sequences have low protein coding potential on average. In particular, non-autonomous TEs that do not encode protein sequences, such as Alu elements, are frequently

  9. A simple physical model predicts small exon length variations.

    Directory of Open Access Journals (Sweden)

    2006-04-01

    Full Text Available One of the most common splice variations are small exon length variations caused by the use of alternative donor or acceptor splice sites that are in very close proximity on the pre-mRNA. Among these, three-nucleotide variations at so-called NAGNAG tandem acceptor sites have recently attracted considerable attention, and it has been suggested that these variations are regulated and serve to fine-tune protein forms by the addition or removal of a single amino acid. In this paper we first show that in-frame exon length variations are generally overrepresented and that this overrepresentation can be quantitatively explained by the effect of nonsense-mediated decay. Our analysis allows us to estimate that about 50% of frame-shifted coding transcripts are targeted by nonsense-mediated decay. Second, we show that a simple physical model that assumes that the splicing machinery stochastically binds to nearby splice sites in proportion to the affinities of the sites correctly predicts the relative abundances of different small length variations at both boundaries. Finally, using the same simple physical model, we show that for NAGNAG sites, the difference in affinities of the neighboring sites for the splicing machinery accurately predicts whether splicing will occur only at the first site, splicing will occur only at the second site, or three-nucleotide splice variants are likely to occur. Our analysis thus suggests that small exon length variations are the result of stochastic binding of the spliceosome at neighboring splice sites. Small exon length variations occur when there are nearby alternative splice sites that have similar affinity for the splicing machinery.

  10. Detection of an exon 53 polymorphism in the dystrophin gene.

    Science.gov (United States)

    Prior, T W; Papp, A C; Snyder, P J; Sedra, M S

    1993-10-01

    We utilized a heteroduplex method to screen for small mutations in Duchenne muscular dystrophy patients who did not have deletions or duplications. A dystrophin exon 53 heteroduplex band was identified in 14.4% of the affected patients. Direct sequencing of the amplified product from DNA producing the heteroduplex revealed the presence of a polymorphism in the coding region. The codon for asparagine was converted from AAT to AAC.

  11. An Exon-Capture System for the Entire Class Ophiuroidea.

    Science.gov (United States)

    Hugall, Andrew F; O'Hara, Timothy D; Hunjan, Sumitha; Nilsen, Roger; Moussalli, Adnan

    2016-01-01

    Exon-capture studies have typically been restricted to relatively shallow phylogenetic scales due primarily to hybridization constraints. Here, we present an exon-capture system for an entire class of marine invertebrates, the Ophiuroidea, built upon a phylogenetically diverse transcriptome foundation. The system captures approximately 90% of the 1,552 exon target, across all major lineages of the quarter-billion-year-old extant crown group. Key features of our system are 1) basing the target on an alignment of orthologous genes determined from 52 transcriptomes spanning the phylogenetic diversity and trimmed to remove anything difficult to capture, map, or align; 2) use of multiple artificial representatives based on ancestral state reconstructions rather than exemplars to improve capture and mapping of the target; 3) mapping reads to a multi-reference alignment; and 4) using patterns of site polymorphism to distinguish among paralogy, polyploidy, allelic differences, and sample contamination. The resulting data give a well-resolved tree (currently standing at 417 samples, 275,352 sites, 91% data-complete) that will transform our understanding of ophiuroid evolution and biogeography.

  12. 40 CFR 265.1062 - Alternative standards for valves in gas/vapor service or in light liquid service: skip period...

    Science.gov (United States)

    2010-07-01

    ... gas/vapor service or in light liquid service: skip period leak detection and repair. 265.1062 Section... FACILITIES Air Emission Standards for Equipment Leaks § 265.1062 Alternative standards for valves in gas/vapor service or in light liquid service: skip period leak detection and repair. (a) An owner...

  13. 40 CFR 264.1062 - Alternative standards for valves in gas/vapor service or in light liquid service: skip period...

    Science.gov (United States)

    2010-07-01

    ... gas/vapor service or in light liquid service: skip period leak detection and repair. 264.1062 Section... Emission Standards for Equipment Leaks § 264.1062 Alternative standards for valves in gas/vapor service or in light liquid service: skip period leak detection and repair. (a) An owner or operator subject...

  14. Socioeconomic status and dietary habits as predictors of home breakfast skipping in young women.

    Science.gov (United States)

    El Hamid Hussein, Rania Abd

    2014-08-01

    Breakfast skipping is prevalent among adolescents and young women, and deprives the body of important nutrients. This study was conducted to assess the correlation between breakfast eating and sociodemographic and lifestyle criteria. A cross-sectional study was carried out on a convenient sample of 400 female students selected from the female sector of King Abdulaziz University, Jeddah, Saudi Arabia. Home breakfast habit and other lifestyle characteristics were studied using a standardized questionnaire. Logistic regression was used to examine the relationship between home breakfast habit and different predictors. Home breakfast skippers constituted 71.75% of the whole sample. Breakfast eaters had a significantly higher BMI compared with breakfast skippers (22.66±4.88 vs. 21.58±4.09 in home breakfast skippers; P=0.025). Irrespective of other sociodemographic and lifestyle variables, fathers' education lower than university level negatively predicted home breakfast eating [Exp B=0.40, confidence interval (CI)=0.21-0.77], and being employed positively predicted breakfast eating (Exp B=2.31, CI=1.04-5.15). Likewise, consuming less amount of junk food and fewer soft drinks (Exp B=2.57, CI=1.54-4.28, and Exp B=2.59, CI=1.39-4.81, respectively) and consuming more milk and dairy products (Exp B=1.91, CI=1.16-3.15) correlated positively with home breakfast eating. Breakfast skipping was prevalent among adolescents and young women in the studied sample. Unhealthy dietary habits, father's education lower than university level, and father being unemployed positively predicted breakfast skipping of daughters at home. This implies that breakfast eating can be encouraged by approaching parents in addition to their daughters.

  15. 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 < 12% JAK2(V617F) allelic burden. Current WHO guidelines do not recommend further testing once JAK2(V617F) mutation is detected in MPNs. The findings, however, indicate that quantification of JAK2(V617F) allele burden may be clinically relevant in MPNs and in those with low allelic burden additional testing for JAK2 exon-12 and MPL exon-10 mutation should be pursued.

  16. Breakfast Macronutrient Composition Influences Thermic Effect of Feeding and Fat Oxidation in Young Women Who Habitually Skip Breakfast.

    Science.gov (United States)

    Neumann, Brianna L; Dunn, Amy; Johnson, Dallas; Adams, J D; Baum, Jamie I

    2016-08-10

    The purpose of this study was to determine if breakfast macronutrient composition improved thermic effect of feeding (TEF) and appetite after a one-week adaptation in young women who habitually skip breakfast. A randomized, controlled study was conducted in females (24.1 ± 2 years), who skip breakfast (≥5 times/week). Participants were placed into one of three groups for eight days (n = 8 per group): breakfast skipping (SKP; no breakfast), carbohydrate (CHO; 351 kcal; 59 g CHO, 10 g PRO, 8 g fat) or protein (PRO; 350 kcal; 39 g CHO, 30 g PRO, 8 g fat). On days 1 (D1) and 8 (D8), TEF, substrate oxidation, appetite and blood glucose were measured. PRO had higher (p breakfast on appetite response. In addition, CHO had a significant increase (p breakfast for 8 days increased TEF compared to CHO and SKP, while consumption of CHO for one week increased PP hunger response.

  17. Personnel reliability impact on petrochemical facilities monitoring system's failure skipping probability

    Science.gov (United States)

    Kostyukov, V. N.; Naumenko, A. P.

    2017-08-01

    The paper dwells upon urgent issues of evaluating impact of actions conducted by complex technological systems operators on their safe operation considering application of condition monitoring systems for elements and sub-systems of petrochemical production facilities. The main task for the research is to distinguish factors and criteria of monitoring system properties description, which would allow to evaluate impact of errors made by personnel on operation of real-time condition monitoring and diagnostic systems for machinery of petrochemical facilities, and find and objective criteria for monitoring system class, considering a human factor. On the basis of real-time condition monitoring concepts of sudden failure skipping risk, static and dynamic error, monitoring systems, one may solve a task of evaluation of impact that personnel's qualification has on monitoring system operation in terms of error in personnel or operators' actions while receiving information from monitoring systems and operating a technological system. Operator is considered as a part of the technological system. Although, personnel's behavior is usually a combination of the following parameters: input signal - information perceiving, reaction - decision making, response - decision implementing. Based on several researches on behavior of nuclear powers station operators in USA, Italy and other countries, as well as on researches conducted by Russian scientists, required data on operator's reliability were selected for analysis of operator's behavior at technological facilities diagnostics and monitoring systems. The calculations revealed that for the monitoring system selected as an example, the failure skipping risk for the set values of static (less than 0.01) and dynamic (less than 0.001) errors considering all related factors of data on reliability of information perception, decision-making, and reaction fulfilled is 0.037, in case when all the facilities and error probability are under

  18. Breakfast skipping and proposed effects of breakfast on obesity: A school based study in adolescents in Aligarh, India

    Directory of Open Access Journals (Sweden)

    Nafis Faizi

    2014-01-01

    Full Text Available Background: Breakfast is one of the most integral components of an individual′s diet, despite that breakfast skipping is widely prevalent. Proposed effects of breakfast on obesity (PEBO have corroborative evidences from different countries, especially, regarding the effects of breakfast skipping on obesity. Habits and lifestyle factors like breakfast skipping maybe formed, changed or strengthened in the tender age of adolescence and can also serve as an early warning system of threats that may engulf larger populations. The study objectives were to find out the frequency of breakfast skipping in adolescents and PEBO, including associations with body mass index (BMI status. Materials and Methods: This was a cross sectional study conducted in all the 13-15 years students who fulfilled the inclusion criteria in the schools affiliated to Aligarh Muslim University. The study was based on a pretested and validated questionnaire and the nutritional status/anthropometric records were measured by the now recommended World Health Organization multicentric growth reference standards 2007. Result and Conclusion: A total of 1416 students were studied, out of which frequency of breakfast consumption was found to be <2 times/week in 6. 21% of the study population, 3-5 times/week in 27.54% and 6-7 times/week in 66.24%. As far as PEBO is concerned, a decreased frequency of breakfast was found to have an association with obesity and overweight as well. Further, an association of breakfast skipping on the BMI Z scores was also found to be significant on analysis of variance and post-hoc tests. The high prevalence of breakfast skipping in India and PEBO is a big cause of concern for multiple reasons, and an intervention is urged.

  19. 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...

  20. Effects of eating frequency, snacking, and breakfast skipping on energy regulation: symposium overview.

    Science.gov (United States)

    McCrory, Megan A; Campbell, Wayne W

    2011-01-01

    The ASN hosted a symposium entitled "Eating Patterns and Energy Balance: A Look at Eating Frequency, Snacking, and Breakfast Omission" at the Experimental Biology 2009 annual meeting on April 19, 2009, in New Orleans, LA. The symposium was chaired by Megan McCrory and co-chaired by Wayne Campbell, both from Purdue University. The goal of the symposium was to bring together experts to provide an overview of research on the potential role of eating patterns in the development of overweight and obesity. Studies on eating frequency, snacking, and breakfast skipping were highlighted. In particular, evidence both for and against their roles were discussed, methodological issues that underlie controversies were addressed, and suggested future directions for research were outlined. Appetite regulation and hormonal effects were also reviewed. Megan McCrory introduced the session then discussed studies on eating frequency and energy regulation in free-living adults consuming self-selected diets. Heather Leidy summarized the state of the research on eating frequency and energy regulation in adults from controlled feedings studies. Didier Chapelot discussed various usages of "snack" and argued for a physiological basis to distinguish snacks from meals. Mark Pereira presented information on the effects of breakfast skipping and the macronutrient composition of breakfast in energy regulation and mood. A panel discussion/question and answer session ended the symposium. The symposium was videotaped and can be viewed at www.nutrition.org.

  1. Analytic Guidance for the First Entry in a Skip Atmospheric Entry

    Science.gov (United States)

    Garcia-Llama, Eduardo

    2007-01-01

    This paper presents an analytic method to generate a reference drag trajectory for the first entry portion of a skip atmospheric entry. The drag reference, expressed as a polynomial function of the velocity, will meet the conditions necessary to fit the requirements of the complete entry phase. The generic method proposed to generate the drag reference profile is further simplified by thinking of the drag and the velocity as density and cumulative distribution functions respectively. With this notion it will be shown that the reference drag profile can be obtained by solving a linear algebraic system of equations. The resulting drag profile is flown using the feedback linearization method of differential geometric control as guidance law with the error dynamics of a second order homogeneous equation in the form of a damped oscillator. This approach was first proposed as a revisited version of the Space Shuttle Orbiter entry guidance. However, this paper will show that it can be used to fly the first entry in a skip entry trajectory. In doing so, the gains in the error dynamics will be changed at a certain point along the trajectory to improve the tracking performance.

  2. Replisome-mediated Translesion Synthesis and Leading Strand Template Lesion Skipping Are Competing Bypass Mechanisms*

    Science.gov (United States)

    Gabbai, Carolina B.; Yeeles, Joseph T. P.; Marians, Kenneth J.

    2014-01-01

    A number of different enzymatic pathways have evolved to ensure that DNA replication can proceed past template base damage. These pathways include lesion skipping by the replisome, replication fork regression followed by either correction of the damage and origin-independent replication restart or homologous recombination-mediated restart of replication downstream of the lesion, and bypass of the damage by a translesion synthesis DNA polymerase. We report here that of two translesion synthesis polymerases tested, only DNA polymerase IV, not DNA polymerase II, could engage productively with the Escherichia coli replisome to bypass leading strand template damage, despite the fact that both enzymes are shown to be interacting with the replicase. Inactivation of the 3′ → 5′ proofreading exonuclease of DNA polymerase II did not enable bypass. Bypass by DNA polymerase IV required its ability to interact with the β clamp and act as a translesion polymerase but did not require its “little finger” domain, a secondary region of interaction with the β clamp. Bypass by DNA polymerase IV came at the expense of the inherent leading strand lesion skipping activity of the replisome, indicating that they are competing reactions. PMID:25301949

  3. Impact of breakfast skipping on the health status of the population

    Directory of Open Access Journals (Sweden)

    Raksha Goyal

    2014-01-01

    Full Text Available Background: Obesity has become a worldwide epidemic and its prevalence continues to increase at a rapid rate in various populations and across all age-group. The effect of meal skipping, both behaviorally and physiologically, may have an impact on the outcome of weight-loss efforts. Aims and Objectives: Therefore, the aim of this study was to examine the prevalence of breakfast skipping and obesity in subjects. Materials and Methods: A retrospective analysis of the patients visited to a metabolic clinic of the city was done. Results: One hundred and eighty-six eligible subjects were included for the study. A questionnaire was used for data collection which included information regarding dietary factors and exercise schedule/physical activity. A 24-hour dietary recall method was used to assess the amount of food consumed. Anthropometric measurements were taken. Results: Overweight is generally higherin females than males. The prevalence of overweight was higher among those who consumed more than recommended calories than those who were taking recommended or fewer calories per day. The average intake of fat and protein by the study subjects was quite different than the recommended intake of these food items. There was positive association between fat (oil intake and overweight status and a negative association between protein intake and overweight status which was statistically significant. Conclusion: The higher prevalence of overweight and obesity in the present study could be because of imbalance in the diet and faulty food habits prevalent in the region.

  4. Skipping breakfast is associated with diet quality and metabolic syndrome risk factors of adults.

    Science.gov (United States)

    Min, Chanyang; Noh, Hwayoung; Kang, Yun-Sook; Sim, Hea Jin; Baik, Hyun Wook; Song, Won O; Yoon, Jihyun; Park, Young-Hee; Joung, Hyojee

    2011-10-01

    The aim of the present study was to assess the effects of skipping breakfast on diet quality and metabolic disease risk factors in healthy Korean adults. Subjects included 415 employees (118 men, 297 women; 30-50 years old) of Jaesang Hospital in Korea and their acquaintances. Data collected from each subject included anthropometric measurements, 3-day dietary intake, blood pressure, and blood analyses. The subjects were classified into three groups based on the number of days they skipped breakfast: 'Regular breakfast eater', 'Often breakfast eater', or 'Rare breakfast eater'. Participants in the 'Rare breakfast eater' group consumed less rice, potatoes, kimchi, vegetables, fish and shellfish, milk and dairy products, and sweets than did participants in the other two groups (P for trend breakfast eater' group consumed less daily energy, fat, dietary fiber, calcium, and potassium than did participants in the other groups (P for trend breakfast eater' group than in the other groups (P for trend breakfast eater' group consumed more energy from fat compared with the other two groups (P breakfast eater' group than in the other two groups (P breakfast eater' group (OR, 0.3 [0.1-1.0], P for trend = 0.0232). We conclude that eating breakfast regularly enhances diet quality, but may increase the risk of elevated serum triglycerides.

  5. Evidence for a novel exon in the coding region of the adenomatous polyposis coli (APC) gene

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Ling; St. Denis, K.A.; Bapat, B. [Univ. of Toronto (Canada)

    1995-08-10

    Germline mutations of the tumor suppressor gene APC cause familial adenomatous polyposis. Somatic APC alterations are involved in several sporadic neoplasma, including colorectal, duodenal, gastric, and esophageal carcinoma. The APC mRNA is encoded by 15 exons. Additional transcripts have been reported, due to alternative splicing of coding as well as noncoding regions. Two mRNA isoforms occur due to a deletion of exon 7 or a partial deletion of exon 9. We have identified a novel exon, flanked by APC exons 10 and 11, which is expressed as an alternatively transcribed product of the gene. Further, we have shown that the novel exon consists of a heptad repeat motif and is conserved across species. 18 refs., 2 figs.

  6. Polymorphisms of exon 5, exon 7 and intron 10 of MMP2 gene and their association with wool density in Rex rabbits

    Directory of Open Access Journals (Sweden)

    S.J. Chen

    2017-06-01

    Full Text Available Wool density is an important index that influences Rex rabbit fur quality. In our earlier studies, we found some important differentially expressed genes in different wool density of Rex rabbit by cDNA microarray. Based on the outcome, we conducted an association study to identify single nucleotide polymorphisms (SNPs of exon 1, 5, 7 and 10 of matrix metalloproteinase-2 (MMP2 gene and their ligands associated with wool density. The results showed that exon 1 and exon 10 of MMP2 gene did not occur mutation in 100 Rex rabbits, meanwhile 3 SNPs were identified in exon 5, exon 7 and intron 10 of MMP2 gene sequence respectively, the 3 mutation sites were as follows: MMP2-exon 5-26C/G, MMP2-exon 7-101C/T and MMP2-intron 10-6C/T. The 3 SNPs were all in Hardy-Weinberg equilibrium. Phenotypic correlation analysis results showed the 3 mutations lacked significant associations (P>0.05 with the wool density.

  7. Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy.

    Science.gov (United States)

    Yamashita, Yoshihiro; Matsuura, Tohru; Shinmi, Jun; Amakusa, Yoshinobu; Masuda, Akio; Ito, Mikako; Kinoshita, Masanobu; Furuya, Hirokazu; Abe, Koji; Ibi, Tohru; Sahashi, Ko; Sahashi, Koo; Ohno, Kinji

    2012-06-01

    Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value=0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data.

  8. 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.

  9. 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.

  10. 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).

  11. Single nucleotide polymorphism-based validation of exonic splicing enhancers.

    Directory of Open Access Journals (Sweden)

    William G Fairbrother

    2004-09-01

    Full Text Available Because deleterious alleles arising from mutation are filtered by natural selection, mutations that create such alleles will be underrepresented in the set of common genetic variation existing in a population at any given time. Here, we describe an approach based on this idea called VERIFY (variant elimination reinforces functionality, which can be used to assess the extent of natural selection acting on an oligonucleotide motif or set of motifs predicted to have biological activity. As an application of this approach, we analyzed a set of 238 hexanucleotides previously predicted to have exonic splicing enhancer (ESE activity in human exons using the relative enhancer and silencer classification by unanimous enrichment (RESCUE-ESE method. Aligning the single nucleotide polymorphisms (SNPs from the public human SNP database to the chimpanzee genome allowed inference of the direction of the mutations that created present-day SNPs. Analyzing the set of SNPs that overlap RESCUE-ESE hexamers, we conclude that nearly one-fifth of the mutations that disrupt predicted ESEs have been eliminated by natural selection (odds ratio = 0.82 +/- 0.05. This selection is strongest for the predicted ESEs that are located near splice sites. Our results demonstrate a novel approach for quantifying the extent of natural selection acting on candidate functional motifs and also suggest certain features of mutations/SNPs, such as proximity to the splice site and disruption or alteration of predicted ESEs, that should be useful in identifying variants that might cause a biological phenotype.

  12. 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.

  13. Exon Shuffling and Origin of Scorpion Venom Biodiversity

    Directory of Open Access Journals (Sweden)

    Xueli Wang

    2016-12-01

    Full Text Available Scorpion venom is a complex combinatorial library of peptides and proteins with multiple biological functions. A combination of transcriptomic and proteomic techniques has revealed its enormous molecular diversity, as identified by the presence of a large number of ion channel-targeted neurotoxins with different folds, membrane-active antimicrobial peptides, proteases, and protease inhibitors. Although the biodiversity of scorpion venom has long been known, how it arises remains unsolved. In this work, we analyzed the exon-intron structures of an array of scorpion venom protein-encoding genes and unexpectedly found that nearly all of these genes possess a phase-1 intron (one intron located between the first and second nucleotides of a codon near the cleavage site of a signal sequence despite their mature peptides remarkably differ. This observation matches a theory of exon shuffling in the origin of new genes and suggests that recruitment of different folds into scorpion venom might be achieved via shuffling between body protein-coding genes and ancestral venom gland-specific genes that presumably contributed tissue-specific regulatory elements and secretory signal sequences.

  14. Evolutionary characteristics of exons expressed at different abundance levels in mammals

    Institute of Scientific and Technical Information of China (English)

    YU HaiJing; FANG Lin; LI Xin; ZHANG XiaoYan; YE Jia; LI Jie; HU WeiHong; ZHENG BingRong; XIAO ChunJie

    2009-01-01

    With comparative genomics approaches, we evaluated the evolutionary characteristics of conservation of exons which are expressed abundantly, moderately or lowly in mammals. Using non-coding regions and pseudogenes as controls, sequence identity, phastCons and Ka/Ks analyses were carried out and our results showed that as the exons of high abundance are highly conserved, the minor and low exons also showed conservative characteristics in evolution. Our findings suggested that the exons with less abundance which constitute a large proportion of distinct species in transcriptome of organisms are under functional constraint and might play certain roles in enriching biological complexity in the evolution of organisms.

  15. Skipping the Baltic : the emergence of a dichotomy of alternative spring migration strategies in Russian barnacle geese

    NARCIS (Netherlands)

    Eichhorn, Goetz; Drent, Rudolf H.; Stahl, Julia; Leito, Aivar; Alerstam, Thomas

    2009-01-01

    Since the early 1990s, an increasing proportion of barnacle geese, Branta leucopsis, bound for breeding sites in the Russian Arctic delay their departure from the wintering quarters in the Wadden Sea by 4 weeks. These late-migrating geese skip spring stopover sites in the Baltic traditionally used b

  16. The Effect of High- and Low-Frequency Previews and Sentential Fit on Word Skipping during Reading

    Science.gov (United States)

    Angele, Bernhard; Laishley, Abby E.; Rayner, Keith; Liversedge, Simon P.

    2014-01-01

    In a previous gaze-contingent boundary experiment, Angele and Rayner (2013) found that readers are likely to skip a word that appears to be the definite article "the" even when syntactic constraints do not allow for articles to occur in that position. In the present study, we investigated whether the word frequency of the preview of a…

  17. Risk factors for overweight in urban and rural school girls in Iran: skipping breakfast and early menarche.

    Science.gov (United States)

    Maddah, Mohsen

    2009-08-14

    This study aimed to investigate the predictors of overweight among Iranian 14-17 years adolescent girls in urban and rural areas in Guilan, Iran. Between December 2005 and March 2006 a cross-sectional survey on 2090 high-school girls (1054 in urban and 1036 in rural areas) in Guilan, northern Iran was performed. Data on age, mother's education, age at menarche, physical activity, hours of TV viewing, birth weight, duration of any breast feeding and skipping breakfast were collected using questionnaire and body weight and height of the girls were measured. Logistic regression analysis showed that in urban residents, low age group (14 years) OR=13.9 (1.15-1.61), lower menarcheal age OR=0.76 (0.61-0.95) and skipping breakfast OR=1.96 (1.52-2.35) were independently related to overweight and obesity. In rural residents, low menarcheal age, OR=0.82 (0.69-0.98), skipping breakfast OR=2.23 (1.37-3.65), and high maternal education OR=2.01 (1.62-2.85) were predictors of overweight/obesity. In conclusion, these data indicated that skipping breakfast is a potential risk factor for overweight/obesity in both urban and rural girls. High maternal education as a risk factor for overweight in the rural girls is notable.

  18. Rice cyclophilin OsCYP18-2 is translocated to the nucleus by an interaction with SKIP and enhances drought tolerance in rice and Arabidopsis.

    Science.gov (United States)

    Lee, Sang Sook; Park, Hyun Ji; Yoon, Dae Hwa; Kim, Beom-Gi; Ahn, Jun Cheul; Luan, Sheng; Cho, Hye Sun

    2015-10-01

    Cyclophilin 18-2 (CYP18-2) genes, homologues of human peptidyl-prolyl isomerase-like 1 (PPiL1), are conserved across multicellular organisms and Schizosaccharomyces pombe. Although PPiL1 is known to interact with ski-interacting protein (SKIP), a transcriptional co-regulator and spliceosomal component, there have been no functional analyses of PPiL1 homologues in plants. Rice cyclophilin 18-2 (OsCYP18-2) bound directly to amino acids 56-95 of OsSKIP and its binding was independent of cyclosporin A, a cyclophilin-binding drug. Moreover, OsCYP18-2 exhibited PPIase activity regardless of its interaction with OsSKIP. Therefore, the binding site for OsCYP18-2's interaction with SKIP was distinct from the PPIase active site. OsCYP18-2's interaction with SKIP full-length protein enabled OsCYP18-2's translocation from the cytoplasm into the nucleus and AtSKIP interacted in planta with both AtCYP18-2 and OsCYP18-2. Drought and salt stress induced similar expression of OsCYP18-2 and OsSKIP. Overexpression of OsCYP18-2 in transgenic rice and Arabidopsis thaliana plants enhanced drought tolerance and altered expression and pre-mRNA splicing patterns of stress-related genes in Arabidopsis under drought conditions. Furthermore, OsCYP18-2 caused transcriptional activation with/without OsSKIP in the GAL4 system of yeast; thus the OsSKIP-OsCYP18-2 interaction has an important role in the transcriptional and post-transcriptional regulation of stress-related genes and increases tolerance to drought stress.

  19. 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

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

    DEFF Research Database (Denmark)

    Baldi, Pierre; Brunak, Søren; Chauvin, Yves;

    1996-01-01

    alignments of internal exon and intron sequences corresponds to a periodic "in phase" bending potential towards the major groove of the DNA. The nucleosome positioning data show that the consensus triplets (and their complements) have a preference for locations on a bent double helix where the major groove...... of roughly ten nucleotides. The periodic pattern is also present in intron sequences, although the strength per nucleotide is weaker. Using two independent profile methods based on triplet bendability parameters from DNase I experiments and nucleosome positioning data, we show that the pattern in multiple...... faces inward and is compressed. The in-phase triplets are located adjacent to GCC/GGC triplets known to have the strongest bias in their positioning on the nucleosome. Analysis of mRNA sequences encoding proteins with known tertiary structure exclude the possibility that the pattern is a consequence...

  1. EVEN-SKIPPED HOMEOBOX 1 controls human ES cell differentiation by directly repressing GOOSECOID expression

    DEFF Research Database (Denmark)

    Kalisz, Mark; Winzi, Maria Karin; Bisgaard, Hanne Cathrine;

    2012-01-01

    TGFß signaling patterns the primitive streak, yet little is known about transcriptional effectors that mediate the cell fate choices during streak-like development in mammalian embryos and in embryonic stem (ES) cells. Here we demonstrate that cross-antagonistic actions of EVEN-SKIPPED HOMEOBOX 1...... (EVX1) and GOOSECOID (GSC) regulate cell fate decisions in streak-like progenitors derived from human ES cells exposed to BMP4 and/or activin. We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1...... expression and was required for development of anterior streak-like progeny in response to activin. Chromatin immunoprecipitation assays showed that EVX1 bound to the GSC 5'-flanking region in BMP4 treated human ES cells, and band shift assays identified two EVX1 binding sites in the GSC 5'-region...

  2. Efficient Approaches for Designing Fault Tolerant Reversible Carry Look-Ahead and Carry-Skip Adders

    CERN Document Server

    Islam, Md Saiful; begum, Zerina; Hafiz, Mohd Zulfiquar

    2010-01-01

    Combinational or Classical logic circuits dissipate heat for every bit of information that is lost. Information is lost when the input vector cannot be recovered from its corresponding output vector. Reversible logic circuit implements only the functions having one-to-one mapping between its input and output vectors and therefore naturally takes care of heating. Reversible logic design becomes one of the promising research directions in low power dissipating circuit design in the past few years and has found its application in low power CMOS design, digital signal processing and nanotechnology. This paper presents the efficient approaches for designing fault tolerant reversible fast adders that implement carry look-ahead and carry-skip logic. The proposed high speed reversible adders include MIG gates for the realization of its basic building block. The MIG gate is universal and parity preserving. It allows any fault that affects no more than a single signal readily detectable at the circuit's primary outputs...

  3. Absolute flatness testing of skip-flat interferometry by matrix analysis in polar coordinates.

    Science.gov (United States)

    Han, Zhi-Gang; Yin, Lu; Chen, Lei; Zhu, Ri-Hong

    2016-03-20

    A new method utilizing matrix analysis in polar coordinates has been presented for absolute testing of skip-flat interferometry. The retrieval of the absolute profile mainly includes three steps: (1) transform the wavefront maps of the two cavity measurements into data in polar coordinates; (2) retrieve the profile of the reflective flat in polar coordinates by matrix analysis; and (3) transform the profile of the reflective flat back into data in Cartesian coordinates and retrieve the profile of the sample. Simulation of synthetic surface data has been provided, showing the capability of the approach to achieve an accuracy of the order of 0.01 nm RMS. The absolute profile can be retrieved by a set of closed mathematical formulas without polynomial fitting of wavefront maps or the iterative evaluation of an error function, making the new method more efficient for absolute testing.

  4. Study on Pulse Skip Modulation Mode in Smart Power Integrated Circuits and Its Test Technology

    Institute of Scientific and Technical Information of China (English)

    LUO Ping

    2005-01-01

    @@ Up to now, the popular control modes for smart power integrated circuit (SPIC) are PWM and PFM.PWM bases on constant frequency variable width (CFVW) control pulse, whereas, PFM bases on constant width variable frequency (CWVF) control pulse. PWM converter has low efficiency with light loads and high amplitude harmonic. On the other hand,the control circuit and filter for PFM are much complex. This dissertation proposes a novel modulation mode named pulse skip modulation (PSM)for SPIC converter, which bases on constant width constant frequency (CWCF) control pulse. It is shown that PSM converter would improve its efficiency and suppress EMI. It also has quick response speed, good interfere rejection and strong robust. Furthermore, it is easy to realize PSM control circuit. The modulating theories of PSM are firstly studied in the world according to the author's investigation.

  5. Skip areas of retained melanin: A clue to the histopathological diagnosis of idiopathic guttate hypomelanosis

    Directory of Open Access Journals (Sweden)

    Rajiv Joshi

    2014-01-01

    Full Text Available Biopsy findings in 55 cases of idiopathic guttate hypomelanosis (IGH are reported. Most cases had a flat epidermis with loss of the rete pattern and a thickened orthokeratotic basket weave stratum corneum. The epidermis had markedly decreased to absent melanin in the basal layer and reduced numbers of melanocytes at the dermoepidermal junction. One-third of patients had a sparse perivascular lymphocytic infiltrate, whereas the rest had no significant dermal inflammation. These findings are in concordance with current literature.However, small foci of retained melanin in the basal layer (skip areas alternating with larger areas of melanin loss were present in almost 80% of cases. This finding has not been reported earlier and appears to be quite specific to IGH and may be used as a clue to differentiate IGH from other similar conditions such as vitiligo and guttate morphea.

  6. 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.

  7. Novel exon of mammalian ADAR2 extends open reading frame.

    Directory of Open Access Journals (Sweden)

    Stefan Maas

    Full Text Available BACKGROUND: The post-transcriptional processing of pre-mRNAs by RNA editing contributes significantly to the complexity of the mammalian transcriptome. RNA editing by site-selective A-to-I modification also regulates protein function through recoding of genomically specified sequences. The adenosine deaminase ADAR2 is the main enzyme responsible for recoding editing and loss of ADAR2 function in mice leads to a phenotype of epilepsy and premature death. Although A-to-I RNA editing is known to be subject to developmental and cell-type specific regulation, there is little knowledge regarding the mechanisms that regulate RNA editing in vivo. Therefore, the characterization of ADAR expression and identification of alternative ADAR variants is an important prerequisite for understanding the mechanisms for regulation of RNA editing and the causes for deregulation in disease. METHODOLOGY/PRINCIPAL FINDINGS: Here we present evidence for a new ADAR2 splice variant that extends the open reading frame of ADAR2 by 49 amino acids through the utilization of an exon located 18 kilobases upstream of the previously annotated first coding exon and driven by a candidate alternative promoter. Interestingly, the 49 amino acid extension harbors a sequence motif that is closely related to the R-domain of ADAR3 where it has been shown to function as a basic, single-stranded RNA binding domain. Quantitative expression analysis shows that expression of the novel ADAR2 splice variant is tissue specific being highest in the cerebellum. CONCLUSIONS/SIGNIFICANCE: The strong sequence conservation of the ADAR2 R-domain between human, mouse and rat ADAR2 genes suggests a conserved function for this isoform of the RNA editing enzyme.

  8. 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.

  9. JAK2 exon 12 mutations in patients with Philadelphia(Ph) chromosome-negative myeloproliferative neoplasms

    Institute of Scientific and Technical Information of China (English)

    王婕妤

    2012-01-01

    Objective To investigate JAK2 exon 12 mutations in patients with Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPN) and the clinical characteristics of patients with JAK2 exon 12 mutants. Methods Allele-specific PCR(AS-PCR) was applied to identify JAK2 V617F mutation.

  10. Nutrition-related practices and attitudes of Kansas skipped-generation(s) caregivers and their grandchildren.

    Science.gov (United States)

    Higgins, Mary Meck; Murray, Bethany J

    2010-12-01

    Despite growing numbers, the nutrition practices and attitudes of skipped-generation(s) kinship caregivers regarding feeding the dependent children in their care have not been examined. In this qualitative study, transcriptions of semi-structured interviews with 19 female and four male skipped-generation(s) Kansas caregivers (ages 47 to 80, 92% non-Hispanic whites, 83% female, 78% grandparents and 22% great-aunt or great-grandparent caregivers; caring for a range of one to four children, ages three to 18, for an average of nine years) were content analyzed for how their nutrition-related practices and attitudes had changed since parenting the first time. Sub-themes regarding practices included: being more nutrition and food safety conscious now, and shifting their child feeding style. The children seemed to be adversely affected by an on-the-go lifestyle and the use of more electronics. Caregivers described their sources for child feeding advice as being based mostly on information from their mothers, physicians, and their past parenting experiences. Sub-themes for attitudes included opinions that nutrition and safe food handling are important and that nutritious food is expensive. They preferred printed or video nutrition education materials and wanted to receive information through organizations they trusted. This population could benefit from education on: infant, child, adolescent, and sports nutrition; feeding "picky eaters"; healthful recipes, "fast foods" and packaged foods; quick, inexpensive meals and snacks low in fat, sugar, and salt; limiting sedentary time; family meals; using food thermometers; and intergenerational gardening and cooking.

  11. Fourier Power Spectrum Analysis of Exons for the Period-3 Behavior

    Institute of Scientific and Technical Information of China (English)

    Yuan Xin TIAN; Chao CHEN; Xiao Yong ZOU; Jian Ding QIU; Pei Xiang CAI; Jin Yuan MO

    2005-01-01

    The period-3 behaviors of 105 exons from 20 genes in human were studied by Fourier power spectrum. The results indicated that not all exons show the period-3 behavior. The exons were adjusted in order to make them accord with the order of the protein translated, and we found that the period-3 character is relation to the length of exons and the bases distribution in the three codon position. Furthermore, as long as the exons with period-3 behavior accord with the order of protein translated, they would exhibit the synonymous codons usage preference, and the codons with g/c at the third position are used in higher frequency. The results are significant to the gene prediction and the research on the introns.

  12. Exon 44 nonsense mutation in two-Duchenne muscular dystrophy brothers detected by heteroduplex analysis.

    Science.gov (United States)

    Prior, T W; Papp, A C; Snyder, P J; Burghes, A H; Sedra, M S; Western, L M; Bartolo, C; Mendell, J R

    1993-01-01

    Utilizing a heteroduplex method, we screened the dystrophin exon 43-45 region for point mutations, including small deletions and insertions. The method depends upon the formation of a heteroduplex between wild-type and mutant DNA PCR products. DNA specimens from one hundred and four DMD patients without detected deletions or duplications were multiplexed amplified for exons 43, 44, and 45. The PCR products were mixed with the PCR products from nonaffected controls, electrophoresed, and examined for the presence of altered mobility heteroduplex bands. An exon 44 nonsense mutation in two DMD brothers and a common intron 44 polymorphism were identified using this approach. Although the exon 44-45 region is a hotspot for deletion breakpoints, it does not appear to be prone to point mutations. The technique is extremely useful for screening several exons simultaneously and it allowed us to screen a large number of patients.

  13. CoNVaDING: Single Exon Variation Detection in Targeted NGS Data.

    Science.gov (United States)

    Johansson, Lennart F; van Dijk, Freerk; de Boer, Eddy N; van Dijk-Bos, Krista K; Jongbloed, Jan D H; van der Hout, Annemieke H; Westers, Helga; Sinke, Richard J; Swertz, Morris A; Sijmons, Rolf H; Sikkema-Raddatz, Birgit

    2016-05-01

    We have developed a tool for detecting single exon copy-number variations (CNVs) in targeted next-generation sequencing data: CoNVaDING (Copy Number Variation Detection In Next-generation sequencing Gene panels). CoNVaDING includes a stringent quality control (QC) metric, that excludes or flags low-quality exons. Since this QC shows exactly which exons can be reliably analyzed and which exons are in need of an alternative analysis method, CoNVaDING is not only useful for CNV detection in a research setting, but also in clinical diagnostics. During the validation phase, CoNVaDING detected all known CNVs in high-quality targets in 320 samples analyzed, giving 100% sensitivity and 99.998% specificity for 308,574 exons. CoNVaDING outperforms existing tools by exhibiting a higher sensitivity and specificity and by precisely identifying low-quality samples and regions.

  14. Effects of eating breakfast compared with skipping breakfast on ratings of appetite and intake at subsequent meals in 8- to 10-y-old children123

    OpenAIRE

    Kral, Tanja VE; Whiteford, Linda M; Heo, Moonseong; Faith, Myles S

    2010-01-01

    Background: Cross-sectional data indicate an inverse relation between breakfast consumption and child weight. It has been suggested that skipping breakfast may adversely affect appetite in children, which could lead to overeating later in the day.

  15. Characterization of porcine SKIP gene in skeletal muscle development: polymorphisms, association analysis, expression and regulation of cell growth in C2C12 cells.

    Science.gov (United States)

    Xiong, Qi; Chai, Jin; Deng, Changyan; Jiang, Siwen; Liu, Yang; Huang, Tao; Suo, Xiaojun; Zhang, Nian; Li, Xiaofeng; Yang, Qianping; Chen, Mingxin; Zheng, Rong

    2012-12-01

    Skeletal muscle and kidney-enriched inositol phosphatase (SKIP) was identified as a 5'-inositol phosphatase that hydrolyzes phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) to PI(3,4)P2 and negatively regulates insulin-induced phosphatidylinositol 3-kinase signaling in skeletal muscle. In this study, two new single nucleotide polymorphisms (SNPs) in porcine SKIP introns 1 and 6 were detected. The C1092T locus in intron 1 showed significant associations with some meat traits, whereas the A17G locus in intron 6 showed significant associations with some carcass traits. Expression analysis showed that porcine SKIP is upregulated at d 65 of gestation and Meishan fetuses have higher and prolonged expression of SKIP compared to Large White at d 100 of gestation. Ectopic expression of porcine SKIP decreased insulin-induced cell proliferation and promoted serum starvation-induced cell cycle arrest in G0/G1 phase in C2C12. Our results suggest that SKIP plays a negative regulatory role in skeletal muscle development partly by preventing cell proliferation.

  16. 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.

  17. Evolutionary constraint helps unmask a splicing regulatory region in BRCA1 exon 11.

    Directory of Open Access Journals (Sweden)

    Michela Raponi

    Full Text Available BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence in a critical region of BRCA1 exon 11 has been reported to be associated with the necessity to maintain regulatory sequences. METHODOLOGY/PRINCIPAL FINDINGS: Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the BRCA1 alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of BRCA1 exon 11. CONCLUSIONS/SIGNIFICANCE: Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of BRCA1 exon 11. Identification of the trans-acting factors involved in regulating exon 11 alternative splicing will be important in understanding BRCA1-associated tumorigenesis.

  18. The evolutionary fate of alternatively spliced homologous exons after gene duplication.

    Science.gov (United States)

    Abascal, Federico; Tress, Michael L; Valencia, Alfonso

    2015-04-29

    Alternative splicing and gene duplication are the two main processes responsible for expanding protein functional diversity. Although gene duplication can generate new genes and alternative splicing can introduce variation through alternative gene products, the interplay between the two processes is complex and poorly understood. Here, we have carried out a study of the evolution of alternatively spliced exons after gene duplication to better understand the interaction between the two processes. We created a manually curated set of 97 human genes with mutually exclusively spliced homologous exons and analyzed the evolution of these exons across five distantly related vertebrates (lamprey, spotted gar, zebrafish, fugu, and coelacanth). Most of these exons had an ancient origin (more than 400 Ma). We found examples supporting two extreme evolutionary models for the behaviour of homologous axons after gene duplication. We observed 11 events in which gene duplication was accompanied by splice isoform separation, that is, each paralog specifically conserved just one distinct ancestral homologous exon. At other extreme, we identified genes in which the homologous exons were always conserved within paralogs, suggesting that the alternative splicing event cannot easily be separated from the function in these genes. That many homologous exons fall in between these two extremes highlights the diversity of biological systems and suggests that the subtle balance between alternative splicing and gene duplication is adjusted to the specific cellular context of each gene. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  19. Genome-wide survey of ds exonization to enrich transcriptomes and proteomes in plants.

    Science.gov (United States)

    Liu, Li-Yu Daisy; Charng, Yuh-Chyang

    2012-01-01

    Insertion of transposable elements (TEs) into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization which can enrich the complexity of transcriptomes and proteomes. Previously, we performed the first experimental assessment of TE exonization by inserting a Ds element into each intron of the rice epsps gene. Exonization of Ds in plants was biased toward providing splice donor sites from the beginning of the inserted Ds sequence. Additionally, Ds inserted in the reverse direction resulted in a continuous splice donor consensus region by offering 4 donor sites in the same intron. The current study involved genome-wide computational analysis of Ds exonization events in the dicot Arabidopsis thaliana and the monocot Oryza sativa (rice). Up to 71% of the exonized transcripts were putative targets for the nonsense-mediated decay (NMD) pathway. The insertion patterns of Ds and the polymorphic splice donor sites increased the transcripts and subsequent protein isoforms. Protein isoforms contain protein sequence due to unspliced intron-TE region and/or a shift of the reading frame. The number of interior protein isoforms would be twice that of C-terminal isoforms, on average. TE exonization provides a promising way for functional expansion of the plant proteome.

  20. Identification, characterization and expression of novel Sex Hormone Binding Globulin alternative first exons in the human prostate

    Directory of Open Access Journals (Sweden)

    de Torres Inés

    2009-06-01

    Full Text Available Abstract Background The human Sex Hormone Binding Globulin (SHBG gene, located at 17p13.1, comprises, at least, two different transcription units regulated by two different promoters. The first transcription unit begins with the exon 1 sequence and is responsible for the production of plasma SHBG by the hepatocytes, while the second begins with an alternative exon 1 sequence, which replaces the exon 1 present in liver transcripts. Alternative exon 1 transcription and translation has only been demonstrated in the testis of transgenic mice containing an 11-kb human SHBG transgene and in the human testis. Our goal has been to further characterize the 5' end of the SHBG gene and analyze the presence of the SHBG alternative transcripts in human prostate tissue and derived cell lines. Results Using a combination of in silico and in vitro studies, we have demonstrated that the SHBG gene, along with exon 1 and alternative exon 1 (renamed here exon 1A, contains four additional alternative first exons: the novel exons 1B, 1C, and 1E, and a previously identified exon 1N, which has been further characterized and renamed as exon 1D. We have shown that these four alternative first exons are all spliced to the same 3' splice site of SHBG exon 2, and that exon 1A and the novel exon 1B can be spliced to exon 1. We have also demonstrated the presence of SHBG transcripts beginning with exons 1B, 1C and 1D in prostate tissues and cell lines, as well as in several non-prostatic cell lines. Finally, the alignment of the SHBG mammalian sequences revealed that, while exons 1C, 1D and 1E are very well conserved phylogenetically through non-primate mammal species, exon 1B probably aroused in apes due to a single nucleotide change that generated a new 5' splice site in exon 1B. Conclusion The identification of multiple transcription start sites (TSS upstream of the annotated first exon of human SHBG, and the detection of the alternative transcripts in human prostate

  1. Functional analysis of splicing mutations in exon 7 of NF1 gene

    Directory of Open Access Journals (Sweden)

    Calvieri Stefano

    2007-02-01

    Full Text Available Abstract Background Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries, and is particularly prone to missplicing. Methods In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X, c.945G>A/c.946C>A (Q315Q/L316M, c.1005T>C (N335N] identified in exon 7 of three different NF1 patients. Results Our results detected the presence of three exonic splicing enhancers (ESEs and one putative exonic splicing silencer (ESS element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1ΔE7. Both the wild type and the mutated constructs shared NF1ΔE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1ΔE7, while in the presence of N335N variant, the NF1ΔE7 expression is abolished. Conclusion In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.

  2. 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

  3. 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

  4. Impact of Breakfast Skipping and Breakfast Choice on the Nutrient Intake and Body Mass Index of Australian Children

    OpenAIRE

    Flavia Fayet-Moore; Jean Kim; Nilani Sritharan; Peter Petocz

    2016-01-01

    Recent data on breakfast consumption among Australian children are limited. This study examined the impact of breakfast skipping and breakfast type (cereal or non-cereal) on nutrient intakes, likelihood of meeting nutrient targets and anthropometric measures. A secondary analysis of two 24-h recall data from the 2007 Australian National Children’s Nutrition and Physical Activity Survey was conducted (2–16 years; n = 4487) to identify (a) breakfast skippers and (b) breakfast consumers, with br...

  5. Molecular analysis of contiguous exons of the phenylalanine hydroxylase gene: identification of a new PKU mutation.

    OpenAIRE

    Dianzani, I; Camaschella, C.; Saglio, G; Ferrero, G B; Ramus, S; Ponzone, A; Cotton, R G

    1993-01-01

    A modified application of the chemical cleavage of mismatch (CCM) method has been used to screen three contiguous exons (exons 9, 10, and 11) of the phenylalanine hydroxylase gene in 17 Italian PKU patients. A new nonsense heterozygous C-->G transversion within exon 11 (S359X) was identified in a single patient. Only one of the four mutations previously reported in this DNA region in Caucasians was found. This lesion, IVS X-546, was detected in five of the 34 PKU alleles examined. Our results...

  6. Gastrointestinal malignancies harbor actionable MET exon 14 deletions

    Science.gov (United States)

    Hong, Mineui; Kim, Sun Young; Jang, Jiryeon; Ahn, Soomin; Kang, So Young; Lee, Sujin; Kim, Seung Tae; Kim, Bogyou; Choi, Jaehyun; Kim, Kyung-Ah; Lee, Jiyun; Park, Charny; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Keunchil; Park, Young Suk; Kim, Kyoung-Mee

    2015-01-01

    Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies. PMID:26375439

  7. Analytic Development of a Reference Profile for the First Entry in a Skip Atmospheric Entry

    Science.gov (United States)

    Garcia-Llama, Eduardo

    2010-01-01

    This note shows that a feasible reference drag profile for the first entry portion of a skip entry can be generated as a polynomial expression of the velocity. The coefficients of that polynomial are found through the resolution of a system composed of m + 1 equations, where m is the degree of the drag polynomial. It has been shown that a minimum of five equations (m = 4) are required to establish the range and the initial and final conditions on velocity and flight path angle. It has been shown that at least one constraint on the trajectory can be imposed through the addition of one extra equation in the system, which must be accompanied by the increase in the degree of the drag polynomial. In order to simplify the resolution of the system of equations, the drag was considered as being a probability density function of the velocity, with the velocity as a distribution function of the drag. Combining this notion with the introduction of empirically derived constants, it has been shown that the system of equations required to generate the drag profile can be successfully reduced to a system of linear algebraic equations. For completeness, the resulting drag profiles have been flown using the feedback linearization method of differential geometric control as a guidance law with the error dynamics of a second order homogeneous equation in the form of a damped oscillator. Satisfactory results were achieved when the gains in the error dynamics were changed at a certain point along the trajectory that is dependent on the velocity and the curvature of the drag as a function of the velocity. Future work should study the capacity to update the drag profile in flight when dispersions are introduced. Also, future studies should attempt to link the first entry, as presented and controlled in this note, with a more standard control concept for the second entry, such as the Apollo entry guidance, to try to assess the overall skip entry performance. A guidance law that includes

  8. Variants Within TSC2 Exons 25 and 31 Are Very Unlikely to Cause Clinically Diagnosable Tuberous Sclerosis.

    Science.gov (United States)

    Ekong, Rosemary; Nellist, Mark; Hoogeveen-Westerveld, Marianne; Wentink, Marjolein; Panzer, Jessica; Sparagana, Steven; Emmett, Warren; Dawson, Natalie L; Malinge, Marie Claire; Nabbout, Rima; Carbonara, Caterina; Barberis, Marco; Padovan, Sergio; Futema, Marta; Plagnol, Vincent; Humphries, Steve E; Migone, Nicola; Povey, Sue

    2016-04-01

    Inactivating mutations in TSC1 and TSC2 cause tuberous sclerosis complex (TSC). The 2012 international consensus meeting on TSC diagnosis and management agreed that the identification of a pathogenic TSC1 or TSC2 variant establishes a diagnosis of TSC, even in the absence of clinical signs. However, exons 25 and 31 of TSC2 are subject to alternative splicing. No variants causing clinically diagnosed TSC have been reported in these exons, raising the possibility that such variants would not cause TSC. We present truncating and in-frame variants in exons 25 and 31 in three individuals unlikely to fulfil TSC diagnostic criteria and examine the importance of these exons in TSC using different approaches. Amino acid conservation analysis suggests significantly less conservation in these exons compared with the majority of TSC2 exons, and TSC2 expression data demonstrates that the majority of TSC2 transcripts lack exons 25 and/or 31 in many human adult tissues. In vitro assay of both exons shows that neither exon is essential for TSC complex function. Our evidence suggests that variants in TSC2 exons 25 or 31 are very unlikely to cause classical TSC, although a role for these exons in tissue/stage specific development cannot be excluded.

  9. 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.

  10. Functional evaluation of targeted exon deletion reveals prospect for dystrophic epidermolysis bullosa therapy

    NARCIS (Netherlands)

    Bornert, Olivier; Kühl, Tobias; Bremer, Jeroen; Van Den Akker, Peter C; Pasmooij, Anna M G; Nyström, Alexander

    2016-01-01

    Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB) - a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therap

  11. Fault tolerant reversible logic synthesis: Carry look-ahead and carry-skip adders

    CERN Document Server

    Islam, Md Saiful; Begum, Zerina; Hafiz, Mohd Zulfiquar; 10.1109/ACTEA.2009.5227871

    2010-01-01

    Irreversible logic circuits dissipate heat for every bit of information that is lost. Information is lost when the input vector cannot be recovered from its corresponding output vector. Reversible logic circuit naturally takes care of heating because it implements only the functions that have one-to-one mapping between its input and output vectors. Therefore reversible logic design becomes one of the promising research directions in low power dissipating circuit design in the past few years and has found its application in low power CMOS design, digital signal processing and nanotechnology. This paper presents the efficient approaches for designing reversible fast adders that implement carry look-ahead and carry-skip logic. The proposed 16-bit high speed reversible adder will include IG gates for the realization of its basic building block. The IG gate is universal in the sense that it can be used to synthesize any arbitrary Boolean-functions. The IG gate is parity preserving, that is, the parity of the input...

  12. Outcomes of the Rope Skipping ‘STAR’ Programme for Schoolchildren

    Directory of Open Access Journals (Sweden)

    Ha Amy S.

    2015-03-01

    Full Text Available Physical activity in children and adolescents is on a decline trend. To this end, we conducted a matched-pair randomized controlled trial to examine the effects of a 4-week STAR (School-based; Train-the-trainer; Accessibility of resources; Recreational skipping programme. 1,386 schoolchildren from 20 primary and secondary schools were recruited. Schools were randomized into the experimental or wait-list control group. Participants self-reported their health-related quality of life using the KIDSCREEN-27. Accelerometers were used to measure the time a subgroup of participants (n = 480 spent in moderate-to-vigorous physical activity during school hours on five consecutive days. Measures were taken at pre- and post-test. At post-test, students in the experimental group, compared to those in the control group, engaged in less moderate-to-vigorous physical activity during school hours. Health-related quality of life from two groups of students was similar, but the experimental group reported higher levels of autonomy and parent relationships. Results suggested that although the intervention did not increase students’ physical activity levels, it slightly improved their health-related quality of life. Future studies should explore personal factors that might mediate the effect of the intervention.

  13. Fibrin/platelet plug counteracts cutaneous wound contraction: the hypothesis of "skipping stone".

    Science.gov (United States)

    Farahani, Ramin Mostofi Zadeh

    2007-01-01

    Cutaneous wound contraction and epithelialization act collaboratively to minimize the exposed wound surface. However excessive wound contraction is undesirable due to the resultant disfigurement and scarring. Fibrin clot has greater stiffness than surrounding tissue and mechanical strain further enhances its stiffness. On the contrary, skin exhibits diminished stiffness when affected by high strain rates. Therefore during early stages of wound healing, the contractile wound border is confronted by fibrin clot forming a high strain region in the interface of contractile tissue and fibrin clot--which is evidenced by computer simulation. Due to the stress relaxation property of skin, the contractile strain is partly neutralized. Meanwhile, gradually the stiffness of fibrin clot decreases which is followed by another cycle of wound contraction. This cyclic pattern of contraction resembles the movement of a stone over water or "skipping stone". The stone bounces repeatedly when thrown across the surface of water with reduction of jumping altitude with each bounce till the stone stops completely. This hypothesis is further supported by the observed initial delay in wound contraction and the chronological correlation of enhanced wound contraction with loss of superficial eschar and substitution of fibrin clot with granulation tissue. Also there is evidence that fibrin inhibits fibroblast-mediated contraction of collagen. Furthermore, modest increase in wound contraction rate in fibrinogen deficient mice and fibrin-mediated diminished wound contraction are agreement with the proposed hypothesis.

  14. Expression of Multiple Taenia Solium Immunogens in Plant Cells Through a Ribosomal Skip Mechanism.

    Science.gov (United States)

    Monreal-Escalante, Elizabeth; Bañuelos-Hernández, Bernardo; Hernández, Marisela; Fragoso, Gladis; Garate, Teresa; Sciutto, Edda; Rosales-Mendoza, Sergio

    2015-07-01

    Taenia solium cysticercosis is a major parasitic disease that affects the human health and the economy in underdeveloped countries. Porcine cysticercosis, an obligatory stage in the parasite life cycle, is a suitable target for vaccination. While several recombinant and synthetic antigens proved to be effective as vaccines, the cost and logistic difficulties have prevented their massive use. Taking this into account, a novel strategy for developing a multi-epitope low-cost vaccine is herein explored. The S3Pvac vaccine components (KETc1, KETc12, KETc7, and GK1 [KETc7]) and the protective HP6/TSOL18 antigen were expressed in a Helios2A polyprotein system, based on the 'ribosomal skip' mechanism mediated by the 2A sequence (LLNFDLLKLAGDVESNPG-P) derived from the Foot-and-mouth disease virus, which induces self-cleavage events at a translational level. This protein arrangement was expressed in transgenic tobacco cells. The inserted sequence and its transcript were detected in several Helios2A lines, with some lines showing recombinant protein accumulation levels up to 1.3 µg/g of fresh weight in leaf tissues. The plant-derived Helios2A vaccine was recognized by antibodies in the cerebral spinal fluid from neurocysticercosis patients and elicited specific antibodies in BALB/c immunized mice. These evidences point to the Helios2A polyprotein as a promising system for expressing multiple antigens of interest for vaccination and diagnosis in one single construction.

  15. Single skip metastasis in sentinel lymph node: In an early gastric cancer.

    Science.gov (United States)

    Bara, Tivadar; Gurzu, Simona; Jung, Ioan; Kadar, Zoltan; Sugimura, Haruhiko; Bara, Tivadar

    2015-09-01

    Lymph node status is considered a key prognostic and predictive factor in patients with gastric cancer (GC). Although there is a practical approach to the intraoperative detection of sentinel lymph nodes (SLNs), such a procedure is not included in the European surgical protocol. In this report, we present a practical approach to SLN mapping in a representative case with early gastric cancer (EGC). A 74-year-old female was hospitalized with an endoscopically observed, superficially ulcerated tumor located in the antral region. Subtotal gastrectomy with D2 lymphadenectomy and SLN mapping was performed by injecting methylene blue dye into the peritumoral submucosal layer. An incidentally detected blue-stained lymph node located along the middle colic artery was also removed. This was detected 40 min after injection of the methylene blue. Histopathologic examination showed a pT1b-staged well-differentiated HER-2-negative adenocarcinoma. All of the 41 LNs located at the first, third, and fifth station of the regional LN compartments were found to be free of tumor cells. The only lymph node with metastasis was located along the middle colic artery and was considered a non-regional lymph node. This incidentally identified skip metastasis indicated stage IV GC. A classic chemotherapy regimen was given, and no recurrences were observed six months after surgery. In this representative case, low-cost SLN mapping, with a longer intraoperative waiting time, totally changed the stage of the tumor in a patient with EGC.

  16. Cellular resolution models for even skipped regulation in the entire Drosophila embryo

    Science.gov (United States)

    Ilsley, Garth R; Fisher, Jasmin; Apweiler, Rolf; DePace, Angela H; Luscombe, Nicholas M

    2013-01-01

    Transcriptional control ensures genes are expressed in the right amounts at the correct times and locations. Understanding quantitatively how regulatory systems convert input signals to appropriate outputs remains a challenge. For the first time, we successfully model even skipped (eve) stripes 2 and 3+7 across the entire fly embryo at cellular resolution. A straightforward statistical relationship explains how transcription factor (TF) concentrations define eve’s complex spatial expression, without the need for pairwise interactions or cross-regulatory dynamics. Simulating thousands of TF combinations, we recover known regulators and suggest new candidates. Finally, we accurately predict the intricate effects of perturbations including TF mutations and misexpression. Our approach imposes minimal assumptions about regulatory function; instead we infer underlying mechanisms from models that best fit the data, like the lack of TF-specific thresholds and the positional value of homotypic interactions. Our study provides a general and quantitative method for elucidating the regulation of diverse biological systems. DOI: http://dx.doi.org/10.7554/eLife.00522.001 PMID:23930223

  17. Motif finding in DNA sequences based on skipping nonconserved positions in background Markov chains.

    Science.gov (United States)

    Zhao, Xiaoyan; Sze, Sing-Hoi

    2011-05-01

    One strategy to identify transcription factor binding sites is through motif finding in upstream DNA sequences of potentially co-regulated genes. Despite extensive efforts, none of the existing algorithms perform very well. We consider a string representation that allows arbitrary ignored positions within the nonconserved portion of single motifs, and use O(2(l)) Markov chains to model the background distributions of motifs of length l while skipping these positions within each Markov chain. By focusing initially on positions that have fixed nucleotides to define core occurrences, we develop an algorithm to identify motifs of moderate lengths. We compare the performance of our algorithm to other motif finding algorithms on a few benchmark data sets, and show that significant improvement in accuracy can be obtained when the sites are sufficiently conserved within a given sample, while comparable performance is obtained when the site conservation rate is low. A software program (PosMotif ) and detailed results are available online at http://faculty.cse.tamu.edu/shsze/posmotif.

  18. Fast hybrid CPU- and GPU-based CT reconstruction algorithm using air skipping technique.

    Science.gov (United States)

    Lee, Byeonghun; Lee, Ho; Shin, Yeong Gil

    2010-01-01

    This paper presents a fast hybrid CPU- and GPU-based CT reconstruction algorithm to reduce the amount of back-projection operation using air skipping involving polygon clipping. The algorithm easily and rapidly selects air areas that have significantly higher contrast in each projection image by applying K-means clustering method on CPU, and then generates boundary tables for verifying valid region using segmented air areas. Based on these boundary tables of each projection image, clipped polygon that indicates active region when back-projection operation is performed on GPU is determined on each volume slice. This polygon clipping process makes it possible to use smaller number of voxels to be back-projected, which leads to a faster GPU-based reconstruction method. This approach has been applied to a clinical data set and Shepp-Logan phantom data sets having various ratio of air region for quantitative and qualitative comparison and analysis of our and conventional GPU-based reconstruction methods. The algorithm has been proved to reduce computational time to half without losing any diagnostic information, compared to conventional GPU-based approaches.

  19. Skipping breakfast: morningness-eveningness preference is differentially related to state and trait food cravings.

    Science.gov (United States)

    Meule, A; Roeser, K; Randler, C; Kübler, A

    2012-12-01

    Eveningness preference is associated with unhealthy eating behaviors. We measured state and trait food cravings in chronotypes in the morning and in the evening. Less Evening (E)- than Morning (M)-types reported to have had breakfast. Accordingly, hours that had elapsed since the last meal were higher in E- than M-types in the morning, but did not differ between groups in the evening. E-types reported higher anticipation of positive reinforcement that may result from eating than M-types in the morning, but both had the same hunger levels. On a trait level, M-types reported more feelings of guilt for giving into cravings compared to E-types. Results suggest that E-types skip breakfast more often than M-types, but this eating pattern does not inevitably lead to more food cravings in the evening or more pronounced habitual cravings. Furthermore, E-types did not experience more hunger in the morning although they had not been eating for a longer time period. Results support findings about a different lifestyle in E-types compared to M-types.

  20. Nutritional Status Associated to Skipping Breakfast in Brazilian Health Service Patients.

    Science.gov (United States)

    Batista-Jorge, Gislaine Cândida; Barcala-Jorge, Antônio Sérgio; Oliveira Dias, Anderson Frederico; Silveira, Marise Fagundes; de Farias Lelis, Deborah; Oliveira Andrade, João Marcus; Claro, Rafael Moreira; de Paula, Alfredo Mauricio Batista; Guimaraes, Andre Luiz Sena; Ferreira, Adaliene Versiane; Santos, Sérgio Henrique Sousa

    2016-01-01

    Recent studies show that skipping breakfast is associated with an increased risk of obesity, diabetes and cardiovascular diseases. In this context, this study evaluated 400 patients from the Brazilian health service who had their nutritional status defined based on the body mass index and were classified as physically active or insufficient active. The energy intake and macronutrients was also assessed by a 24-hour dietary recall where the association of overweight/obesity with the investigated variables was evaluated using chi-square, Student's t test and multivariate analysis (p breakfast (55.8%), and among those, 81.2% were overweight/obese (p breakfast had a higher chance of being overweight compared with those who had this habit (OR 2.20; 95% CI 1.40-3.60) and the chance of the physically insufficient active individuals to be overweight/obese was 2.9 times higher when compared to the active individuals (p breakfast consumption may decrease overweight and obesity risk.

  1. Combined eating behaviors and overweight: Eating quickly, late evening meals, and skipping breakfast.

    Science.gov (United States)

    Lee, Jung Su; Mishra, Gita; Hayashi, Kunihiko; Watanabe, Etsuko; Mori, Katsumi; Kawakubo, Kiyoshi

    2016-04-01

    Various eating behaviors have been linked with body weight management. However, combined effects of major eating behaviors are not fully understood. This study aimed to clarify the association of the combination of eating quickly (EQ), late evening meals (LEM), and skipping breakfast (SB) with being overweight. A cross-sectional study with standardized questions for EQ, LEM, and SB was conducted. Stratified random sampling of 5% of residents aged 20 to 80years was surveyed in a city in northeast Japan in 2011, and 4249 (84.9%) residents were analyzed. Association of combinations of eating behaviors on being overweight (BMI (kg/m(2)≥25.0)) was estimated by using logistic analysis, and odds ratio (OR) and 95% confidential interval were calculated after adjustment for potential covariates. LEM, SB, or a combination of LEM and SB was not significantly associated with being overweight. However, the combination of EQ or only EQ was significantly associated with being overweight. As the number of eating behavior practices increased, there was a linear increase in OR for being overweight. The OR of all three combined eating behaviors was higher than that of any combined two behaviors or of each behavior. This study result supports the evidence that EQ increases the risk of being overweight whether by itself or in combinations with LEM and/or SB. However, only LEM or only SB did not increase the risk of being overweight. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. 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.

  3. Intersubtype Genetic Variation of HIV-1 Tat Exon 1.

    Science.gov (United States)

    Roy, Chandra Nath; Khandaker, Irona; Oshitani, Hitoshi

    2015-06-01

    HIV-1 Tat is a regulatory protein that plays a pivotal role in viral transcription and replication. Our study aims to investigate the genetic variation of Tat exon 1 in all subtypes of HIV-1: A, B, C, D, F, G, H, J, and K. We performed phylogenetic, mutation, and selection pressure analyses on a total of 1,179 sequences of different subtypes of HIV-1 Tat obtained from the Los Alamos National Laboratory (LANL). The mean nucleotide divergences (%) among the analyzed sequences of subtypes A, B, C, D, F, G, H, J, and K were 88, 89, 90, 88, 86, 89, 88, 97, and 97, respectively. We revealed that subtype B evolved relatively faster than other subtypes. The second and fifth domains were found comparatively more variable among all subtypes. Site-by-site tests of positive selection revealed that several positions in all subtypes were under significant positive selection. Positively selected sites were found in the acidic domain at positions 3, 4, and 19, in the cysteine-rich domains at positions 24, 29, 32, and 36, in the core domain at position 40, and in the basic domain for the rest of the positions for all subtypes. Positions 58 and 68 in the basic domain were positively selected in subtypes A, B, C and B, C, F, respectively. We also observed high variability within positively selected sites in amino acid positions. Our study findings on HIV-1 Tat genetic variability may contribute to a better understanding of HIV-1 evolution as well as to the development of effective Tat-targeted therapeutics and vaccines.

  4. Molecular characterization of exon 3 of caprine myostatin gene in Marwari goat

    Directory of Open Access Journals (Sweden)

    Jai Prakash Khichar

    2016-06-01

    Full Text Available Aim: To estimate genetic variability in exon 3 of caprine myostatin gene in Marwari goats. Materials and Methods: A total of 120 blood samples from unrelated Marwari goats were randomly collected from different villages of Bikaner (Rajasthan, India. Genomic DNA was extracted from whole blood using blood DNA isolation kit (Himedia Ltd. as per manufacturer’s protocol. The quality of extracted genomic DNA was checked on 0.8% agarose gel. Specifically designed a primer set for caprine myostatin (MSTN gene (Genebank accession no. DQ167575 was used to amplify the exon 3 region of MSTN gene in Marwari goat. The genetic variability in exon 3 of MSTN gene in Marwari goat was assessed on 8% polyacrylamide gel electrophoresis to detect single strand conformation polymorphism (SSCP pattern. Results: The exon 3 of MSTN gene in Marwari goat showed two types of conformation patterns on 8% polyacrylamide gel. One of the patterns showed only two bands and was considered as genotype AA, whereas another pattern having an extra band was designated as genotype AB. The frequencies of AA and AB genotype for exon 3 region of MSTN gene were calculated as 0.90 and 0.10, respectively. Conclusion: Low level of polymorphism was observed at exon 3 region of MSTN gene in Marwari goat through SSCP analysis. This information could be utilized in future breeding plan to exploit the unique characteristics of Marwari goat of Rajasthan.

  5. Compensatory relationship between splice sites and exonic splicing signals depending on the length of vertebrate introns

    Directory of Open Access Journals (Sweden)

    Rogozin Igor B

    2006-12-01

    Full Text Available Abstract Background The signals that determine the specificity and efficiency of splicing are multiple and complex, and are not fully understood. Among other factors, the relative contributions of different mechanisms appear to depend on intron size inasmuch as long introns might hinder the activity of the spliceosome through interference with the proper positioning of the intron-exon junctions. Indeed, it has been shown that the information content of splice sites positively correlates with intron length in the nematode, Drosophila, and fungi. We explored the connections between the length of vertebrate introns, the strength of splice sites, exonic splicing signals, and evolution of flanking exons. Results A compensatory relationship is shown to exist between different types of signals, namely, the splice sites and the exonic splicing enhancers (ESEs. In the range of relatively short introns (approximately, Conclusion Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals. Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

  6. Menzerath-Altmann law in mammalian exons reflects the dynamics of gene structure evolution.

    Science.gov (United States)

    Nikolaou, Christoforos

    2014-12-01

    Genomic sequences exhibit self-organization properties at various hierarchical levels. One such is the gene structure of higher eukaryotes with its complex exon/intron arrangement. Exon sizes and exon numbers in genes have been shown to conform to a law derived from statistical linguistics and formulated by Menzerath and Altmann, according to which the mean size of the constituents of an entity is inversely related to the number of these constituents. We herein perform a detailed analysis of this property in the complete exon set of the mouse genome in correlation to the sequence conservation of each exon and the transcriptional complexity of each gene locus. We show that extensive linear fits, representative of accordance to Menzerath-Altmann law are restricted to a particular subset of genes that are formed by exons under low or intermediate sequence constraints and have a small number of alternative transcripts. Based on this observation we propose a hypothesis for the law of Menzerath-Altmann in mammalian genes being predominantly due to genes that are more versatile in function and thus, more prone to undergo changes in their structure. To this end we demonstrate one test case where gene categories of different functionality also show differences in the extent of conformity to Menzerath-Altmann law. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Alternative splicing of anciently exonized 5S rRNA regulates plant transcription factor TFIIIA.

    Science.gov (United States)

    Fu, Yan; Bannach, Oliver; Chen, Hao; Teune, Jan-Hendrik; Schmitz, Axel; Steger, Gerhard; Xiong, Liming; Barbazuk, W Brad

    2009-05-01

    Identifying conserved alternative splicing (AS) events among evolutionarily distant species can prioritize AS events for functional characterization and help uncover relevant cis- and trans-regulatory factors. A genome-wide search for conserved cassette exon AS events in higher plants revealed the exonization of 5S ribosomal RNA (5S rRNA) within the gene of its own transcription regulator, TFIIIA (transcription factor for polymerase III A). The 5S rRNA-derived exon in TFIIIA gene exists in all representative land plant species but not in green algae and nonplant species, suggesting it is specific to land plants. TFIIIA is essential for RNA polymerase III-based transcription of 5S rRNA in eukaryotes. Integrating comparative genomics and molecular biology revealed that the conserved cassette exon derived from 5S rRNA is coupled with nonsense-mediated mRNA decay. Utilizing multiple independent Arabidopsis overexpressing TFIIIA transgenic lines under osmotic and salt stress, strong accordance between phenotypic and molecular evidence reveals the biological relevance of AS of the exonized 5S rRNA in quantitative autoregulation of TFIIIA homeostasis. Most significantly, this study provides the first evidence of ancient exaptation of 5S rRNA in plants, suggesting a novel gene regulation model mediated by the AS of an anciently exonized noncoding element.

  8. 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

    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.

  9. NF1 single and multi-exons copy number variations in neurofibromatosis type 1.

    Science.gov (United States)

    Imbard, Apolline; Pasmant, Eric; Sabbagh, Audrey; Luscan, Armelle; Soares, Magali; Goussard, Philippe; Blanché, Hélène; Laurendeau, Ingrid; Ferkal, Salah; Vidaud, Michel; Pinson, Stéphane; Bellanne-Chantelot, Christine; Vidaud, Dominique; Wolkenstein, Pierre; Parfait, Béatrice

    2015-04-01

    Neurofibromatosis type 1 (NF1) is caused by dominant loss-of-function mutations of the tumor suppressor NF1 containing 57 constitutive coding exons. A huge number of different pathogenic NF1 alterations has been reported. The aim of the present study was to evaluate the usefulness of a multiplex ligation-dependent probe amplification (MLPA) approach in NF1 patients to detect single and multi-exon NF1 gene copy number variations. A genotype-phenotype correlation was then performed in NF1 patients carrying these types of genetic alterations. Among 565 NF1 index cases from the French NF1 cohort, single and multi-exon deletions/duplications screening identified NF1 partial deletions/duplications in 22 patients (~4%) using MLPA analysis. Eight single exon deletions, 11 multiple exons deletions, 1 complex rearrangement and 2 duplications were identified. All results were confirmed using a custom array-CGH. MLPA and custom array-CGH allowed the identification of rearrangements that were missed by cDNA/DNA sequencing or microsatellite analysis. We then performed a targeted next-generation sequencing of NF1 that allowed confirmation of all 22 rearrangements. No clear genotype-phenotype correlations were found for the most clinically significant disease features of NF1 in patients with single and multi-exons NF1 gene copy number changes.

  10. Systematic dissection of coding exons at single nucleotide resolution supports an additional role in cell-specific transcriptional regulation.

    Directory of Open Access Journals (Sweden)

    Ramon Y Birnbaum

    2014-10-01

    Full Text Available In addition to their protein coding function, exons can also serve as transcriptional enhancers. Mutations in these exonic-enhancers (eExons could alter both protein function and transcription. However, the functional consequence of eExon mutations is not well known. Here, using massively parallel reporter assays, we dissect the enhancer activity of three liver eExons (SORL1 exon 17, TRAF3IP2 exon 2, PPARG exon 6 at single nucleotide resolution in the mouse liver. We find that both synonymous and non-synonymous mutations have similar effects on enhancer activity and many of the deleterious mutation clusters overlap known liver-associated transcription factor binding sites. Carrying a similar massively parallel reporter assay in HeLa cells with these three eExons found differences in their mutation profiles compared to the liver, suggesting that enhancers could have distinct operating profiles in different tissues. Our results demonstrate that eExon mutations could lead to multiple phenotypes by disrupting both the protein sequence and enhancer activity and that enhancers can have distinct mutation profiles in different cell types.

  11. Development of Therapeutic Chimeric Uricase by Exon Replacement/Restoration and Site-Directed Mutagenesis

    Directory of Open Access Journals (Sweden)

    Guangrong Xie

    2016-05-01

    Full Text Available The activity of urate oxidase was lost during hominoid evolution, resulting in high susceptibility to hyperuricemia and gout in humans. In order to develop a more “human-like” uricase for therapeutic use, exon replacement/restoration and site-directed mutagenesis were performed to obtain porcine–human uricase with higher homology to deduced human uricase (dHU and increased uricolytic activity. In an exon replacement study, substitution of exon 6 in wild porcine uricase (wPU gene with corresponding exon in dhu totally abolished its activity. Substitutions of exon 5, 3, and 1–2 led to 85%, 60%, and 45% loss of activity, respectively. However, replacement of exon 4 and 7–8 did not significantly change the enzyme activity. When exon 5, 6, and 3 in dhu were replaced by their counterparts in wpu, the resulting chimera H1-2P3H4P5-6H7-8 was active, but only about 28% of wPU. Multiple sequence alignment and homology modeling predicted that mutations of E24D and E83G in H1-2P3H4P5-6H7-8 were favorable for further increase of its activity. After site-directed mutagenesis, H1-2P3H4P5-6H7-8 (E24D & E83G with increased homology (91.45% with dHU and higher activity and catalytic efficiency than the FDA-approved porcine–baboon chimera (PBC was obtained. It showed optimum activity at pH 8.5 and 35 °C and was stable in a pH range of 6.5–11.0 and temperature range of 20–40 °C.

  12. A Brassica exon array for whole-transcript gene expression profiling.

    Directory of Open Access Journals (Sweden)

    Christopher G Love

    Full Text Available Affymetrix GeneChip® arrays are used widely to study transcriptional changes in response to developmental and environmental stimuli. GeneChip® arrays comprise multiple 25-mer oligonucleotide probes per gene and retain certain advantages over direct sequencing. For plants, there are several public GeneChip® arrays whose probes are localised primarily in 3' exons. Plant whole-transcript (WT GeneChip® arrays are not yet publicly available, although WT resolution is needed to study complex crop genomes such as Brassica, which are typified by segmental duplications containing paralogous genes and/or allopolyploidy. Available sequence data were sampled from the Brassica A and C genomes, and 142,997 gene models identified. The assembled gene models were then used to establish a comprehensive public WT exon array for transcriptomics studies. The Affymetrix GeneChip® Brassica Exon 1.0 ST Array is a 5 µM feature size array, containing 2.4 million 25-base oligonucleotide probes representing 135,201 gene models, with 15 probes per gene distributed among exons. Discrimination of the gene models was based on an E-value cut-off of 1E(-5, with ≤98% sequence identity. The 135 k Brassica Exon Array was validated by quantifying transcriptome differences between leaf and root tissue from a reference Brassica rapa line (R-o-18, and categorisation by Gene Ontologies (GO based on gene orthology with Arabidopsis thaliana. Technical validation involved comparison of the exon array with a 60-mer array platform using the same starting RNA samples. The 135 k Brassica Exon Array is a robust platform. All data relating to the array design and probe identities are available in the public domain and are curated within the BrassEnsembl genome viewer at http://www.brassica.info/BrassEnsembl/index.html.

  13. Nutrition-Related Practices and Attitudes of Kansas Skipped-Generation(s Caregivers and Their Grandchildren

    Directory of Open Access Journals (Sweden)

    Mary Meck Higgins

    2010-11-01

    Full Text Available Despite growing numbers, the nutrition practices and attitudes of skipped‑generation(s kinship caregivers regarding feeding the dependent children in their care have not been examined. In this qualitative study, transcriptions of semi-structured interviews with 19 female and four male skipped-generation(s Kansas caregivers (ages 47 to 80, 92% non-Hispanic whites, 83% female, 78% grandparents and 22% great-aunt or great‑grandparent caregivers; caring for a range of one to four children, ages three to 18, for an average of nine years were content analyzed for how their nutrition-related practices and attitudes had changed since parenting the first time. Sub-themes regarding practices included: being more nutrition and food safety conscious now, and shifting their child feeding style. The children seemed to be adversely affected by an on-the-go lifestyle and the use of more electronics. Caregivers described their sources for child feeding advice as being based mostly on information from their mothers, physicians, and their past parenting experiences. Sub-themes for attitudes included opinions that nutrition and safe food handling are important and that nutritious food is expensive. They preferred printed or video nutrition education materials and wanted to receive information through organizations they trusted. This population could benefit from education on: infant, child, adolescent, and sports nutrition; feeding “picky eaters”; healthful recipes, “fast foods” and packaged foods; quick, inexpensive meals and snacks low in fat, sugar, and salt; limiting sedentary time; family meals; using food thermometers; and intergenerational gardening and cooking.

  14. Early nocturnal meal skipping alters the peripheral clock and increases lipogenesis in mice

    Directory of Open Access Journals (Sweden)

    Yoshida Chika

    2012-09-01

    Full Text Available Abstract Background In humans, skipping meals, especially breakfast, has been associated with obesity and other related syndromes. Recent studies in rodents suggest that fasting and feeding times are potential factors that affect the peripheral circadian clocks and metabolism. However, the link between fasting and obesity in rodents has yet to be fully demonstrated. Method We conducted early nocturnal fasting (ENF from zeitgeber time (ZT 12 to 18 for 4 consecutive days in C57B6 mice. The first set of experiments was performed under ad libitum conditions, where ENF and free-feeding (FF control groups were compared. The second set was performed under isocaloric adjustment by restricting the diet to 90% of the basal intake of ENF mice. Calorie-restricted ENF (ENF-CR mice were then compared with isocaloric controls (IC-control. Body weight, food intake, core body temperature, activity, adiposity, and clock-related gene expression levels in the liver and adipose tissues were investigated. A stable isotopic analysis was also conducted to estimate de novo lipogenesis fluxes. Results In the ad libitum condition, the ENF mice ate more during the day, increased their overall daily food intake and gained more weight than FF-control mice. The amplitude of the body core temperature rhythm in ENF mice was also lower than in the FF-controls. Under isocaloric conditions, ENF-CR attenuated the CR-induced body weight loss, compared with the IC-control. ENF-CR also altered the acrophase time of the expression of the clock genes, which is associated with time-shift of genes involved in lipid metabolism and increased lipogenesis, compared with the IC-control. Conclusions ENF in nocturnal mice disturbs the peripheral clock and increases de novo lipid synthesis and results in a predisposition to obesity.

  15. A high-protein breakfast prevents body fat gain, through reductions in daily intake and hunger, in "Breakfast skipping" adolescents.

    Science.gov (United States)

    Leidy, Heather J; Hoertel, Heather A; Douglas, Steve M; Higgins, Kelly A; Shafer, Rebecca S

    2015-09-01

    The purpose of this study was to examine whether the daily consumption of normal-protein (NP) vs. high-protein (HP) breakfast meals improves appetite control, food intake, and body composition in "breakfast skipping" young people with overweight/obesity. Fifty-seven adolescents (age: 19 ± 1 years; BMI: 29.7 ± 4.6 kg m(-2)) completed a 12-week randomized controlled trial in which the adolescents consumed either a 1,464 kJ NP breakfast (13 g protein) or a HP breakfast (35 g protein) or continued to skip breakfast (CON). Pre- and post-study appetite, food intake, body weight, and body composition were assessed. Time-by-group interactions (P fat mass, daily intake, and perceived hunger. Specifically, HP prevented fat mass gains over the 12 weeks (-0.4 ± 0.5 kg) vs. CON (+1.6 ± 0.9 kg; P = 0.02), whereas NP did not (+0.3 ± 0.5 kg). HP led to reductions in daily intake (-1,724 ± 954 kJ) vs. CON (+1,556 ± 745 kJ; P = 0.03), whereas NP did not (+494 ± 213 kJ). Lastly, only the HP group experienced reductions in daily hunger vs. CON (P fat gain, voluntary reductions in daily intake, and reductions in daily hunger in breakfast skipping adolescents with overweight/obesity. © 2015 The Obesity Society.

  16. Breakfast Macronutrient Composition Influences Thermic Effect of Feeding and Fat Oxidation in Young Women Who Habitually Skip Breakfast

    Science.gov (United States)

    Neumann, Brianna L.; Dunn, Amy; Johnson, Dallas; Adams, J. D.; Baum, Jamie I.

    2016-01-01

    The purpose of this study was to determine if breakfast macronutrient composition improved thermic effect of feeding (TEF) and appetite after a one-week adaptation in young women who habitually skip breakfast. A randomized, controlled study was conducted in females (24.1 ± 2 years), who skip breakfast (≥5 times/week). Participants were placed into one of three groups for eight days (n = 8 per group): breakfast skipping (SKP; no breakfast), carbohydrate (CHO; 351 kcal; 59 g CHO, 10 g PRO, 8 g fat) or protein (PRO; 350 kcal; 39 g CHO, 30 g PRO, 8 g fat). On days 1 (D1) and 8 (D8), TEF, substrate oxidation, appetite and blood glucose were measured. PRO had higher (p < 0.05) TEF compared to SKP and CHO on D1 and D8, with PRO having 29% higher TEF than CHO on D8. On D1, PRO had 30.6% higher fat oxidation than CHO and on D8, PRO had 40.6% higher fat oxidation than CHO. SKP had higher (p < 0.05) fat oxidation on D1 and D8 compared to PRO and CHO. There was an interaction (p < 0.0001) of time and breakfast on appetite response. In addition, CHO had a significant increase (p < 0.05) in PP hunger response on D8 vs. D1. CHO and PRO had similar PP (postprandial) glucose responses on D1 and D8. Consumption of PRO breakfast for 8 days increased TEF compared to CHO and SKP, while consumption of CHO for one week increased PP hunger response. PMID:27517958

  17. Meal skipping relates to food choice, understanding of nutrition labeling, and prevalence of obesity in Korean fifth grade children.

    Science.gov (United States)

    Kim, Hye-Young; Lee, Na-Rae; Lee, Jung-Sug; Choi, Young-Sun; Kwak, Tong-Kyung; Chung, Hae Rang; Kwon, Sehyug; Choi, Youn-Ju; Lee, Soon-Kyu; Kang, Myung-Hee

    2012-08-01

    This study was performed to investigate the differences in food choice, nutrition labeling perceptions, and prevalence of obesity due to meal skipping in Korean elementary school children. A national survey was performed in 2010 to collect data on food intake frequency, understanding of nutrition labeling, and body mass index from 2,335 fifth grade students in 118 elementary schools selected from 16 metropolitan local governments by stratified cluster sampling. The data were analyzed using the SAS 9.1 and SUDAAN 10.0 packages. Students who consumed three meals for 6-7 days during the past week were classified into the regular meal eating (RM) group (n = 1,476) and those who did not were placed into the meal skipping (MS) group (n = 859). The daily intake frequency of fruits, vegetables, kimchi, and milk was significantly lower in the MS group compared to that in the RM group (P instant noodles (ramyeon) was significantly higher in the MS group than that in the RM group (P < 0.05). The MS group demonstrated a significantly lower degree of understanding with regard to nutrition labeling and high calorie foods containing low nutritional value than that in the RM group. The distribution of obesity based on the percentile criteria using the Korean growth chart was different between the MS and RM groups. The MS group (8.97%) had a higher percentage of obese subjects than that in the RM group (5.38%). In conclusion, meal skipping was related to poor food choice, low perception of nutrition labeling, and a high prevalence of obesity in Korean fifth grade children.

  18. Breakfast Macronutrient Composition Influences Thermic Effect of Feeding and Fat Oxidation in Young Women Who Habitually Skip Breakfast

    Directory of Open Access Journals (Sweden)

    Brianna L. Neumann

    2016-08-01

    Full Text Available The purpose of this study was to determine if breakfast macronutrient composition improved thermic effect of feeding (TEF and appetite after a one-week adaptation in young women who habitually skip breakfast. A randomized, controlled study was conducted in females (24.1 ± 2 years, who skip breakfast (≥5 times/week. Participants were placed into one of three groups for eight days (n = 8 per group: breakfast skipping (SKP; no breakfast, carbohydrate (CHO; 351 kcal; 59 g CHO, 10 g PRO, 8 g fat or protein (PRO; 350 kcal; 39 g CHO, 30 g PRO, 8 g fat. On days 1 (D1 and 8 (D8, TEF, substrate oxidation, appetite and blood glucose were measured. PRO had higher (p < 0.05 TEF compared to SKP and CHO on D1 and D8, with PRO having 29% higher TEF than CHO on D8. On D1, PRO had 30.6% higher fat oxidation than CHO and on D8, PRO had 40.6% higher fat oxidation than CHO. SKP had higher (p < 0.05 fat oxidation on D1 and D8 compared to PRO and CHO. There was an interaction (p < 0.0001 of time and breakfast on appetite response. In addition, CHO had a significant increase (p < 0.05 in PP hunger response on D8 vs. D1. CHO and PRO had similar PP (postprandial glucose responses on D1 and D8. Consumption of PRO breakfast for 8 days increased TEF compared to CHO and SKP, while consumption of CHO for one week increased PP hunger response.

  19. Outlier Detection in Regression Using an Iterated One-Step Approximation to the Huber-Skip Estimator

    DEFF Research Database (Denmark)

    Johansen, Søren; Nielsen, Bent

    2013-01-01

    In regression we can delete outliers based upon a preliminary estimator and reestimate the parameters by least squares based upon the retained observations. We study the properties of an iteratively defined sequence of estimators based on this idea. We relate the sequence to the Huber......-skip estimator. We provide a stochastic recursion equation for the estimation error in terms of a kernel, the previous estimation error and a uniformly small error term. The main contribution is the analysis of the solution of the stochastic recursion equation as a fixed point, and the results...

  20. [Long-term survival of a patient with lung cancer with skip metastasis to supraclavicular lymph nodes].

    Science.gov (United States)

    Ohta, Y; Nakaizumi, H; Furukawa, S; Ushijima, S; Mori, Y; Sato, H; Kurumaya, H

    1995-04-01

    A case of lung cancer with skip metastasis to supraclavicular lymph nodes is described. The patient had undergone radical resection for gastric cancer about nine years ago. For about one year, chemotherapy had been done by Tegafur (600 mg/day) after operation. Radical resection for lung cancer (p/d squamous cell carcinoma) was performed about seven years ago. Pathologically, mediastinal lymph node metastasis could not be detected. The needle aspiration biopsy of supraclavicular lymph node revealed metastasis. Then, radical neck lymph nodes dissection involving supraclavicular lymph nodes and radiation therapy were added. There has been no sign of recurrence so far.

  1. Association of hyperglycemia in a general Japanese population with late-night-dinner eating alone, but not breakfast skipping alone.

    Science.gov (United States)

    Nakajima, Kei; Suwa, Kaname

    2015-01-01

    The unhealthy habit of late-night-dinner eating (LNDE) is often observed in adults. Since LNDE can lead to breakfast skipping (BS) the next morning, we examined the associations of LNDE and BS with hyperglycemia (HbA1c ≥ 5.7% and/or pharmacotherapy for diabetes), separately and in combination, in 61,364 apparently healthy Japanese adults aged 30-70 years. Although LNDE alone was significantly associated with hyperglycemia, even after adjustment for body mass index, BS alone was not. Our results indicate that hyperglycemia in the general Japanese population is associated with LNDE alone, but not BS alone.

  2. ABNORMAL TYPE-III COLLAGEN PRODUCED BY AN EXON-17-SKIPPING MUTATION OF THE COL3A1 GENE IN EHLERS-DANLOS SYNDROME TYPE-IV IS NOT INCORPORATED INTO THE EXTRACELLULAR-MATRIX

    NARCIS (Netherlands)

    CHIODO, AA; SILLENCE, DO; COLE, WG; BATEMAN, JF

    1995-01-01

    A novel heterozygous mutation of the COL3Al gene that encodes the alpha 1(III) chains of type III collagen was identified in a family with the: acrogeric form of Ehlers-Danlos syndrome type IV (EDS-IV). Cultured dermal fibroblasts produced normal and shortened alpha 1(III) chains. The triple helix o

  3. Live-Cell Imaging Visualizes Frequent Mitotic Skipping During Senescence-Like Growth Arrest in Mammary Carcinoma Cells Exposed to Ionizing Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Masatoshi, E-mail: msuzuki@nagasaki-u.ac.jp [Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan); Yamauchi, Motohiro; Oka, Yasuyoshi; Suzuki, Keiji; Yamashita, Shunichi [Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan)

    2012-06-01

    Purpose: Senescence-like growth arrest in human solid carcinomas is now recognized as the major outcome of radiotherapy. This study was designed to analyze cell cycle during the process of senescence-like growth arrest in mammary carcinoma cells exposed to X-rays. Methods and Materials: Fluorescent ubiquitination-based cell cycle indicators were introduced into the human mammary carcinoma cell line MCF-7. Cell cycle was sequentially monitored by live-cell imaging for up to 5 days after exposure to 10 Gy of X-rays. Results: Live-cell imaging revealed that cell cycle transition from G2 to G1 phase without mitosis, so-called mitotic skipping, was observed in 17.1% and 69.8% of G1- and G2-irradiated cells, respectively. Entry to G1 phase was confirmed by the nuclear accumulation of mKO{sub 2}-hCdt1 as well as cyclin E, which was inversely correlated to the accumulation of G2-specific markers such as mAG-hGeminin and CENP-F. More than 90% of cells skipping mitosis were persistently arrested in G1 phase and showed positive staining for the senescent biochemical marker, which is senescence-associated ss-galactosidase, indicating induction of senescence-like growth arrest accompanied by mitotic skipping. While G2 irradiation with higher doses of X-rays induced mitotic skipping in approximately 80% of cells, transduction of short hairpin RNA (shRNA) for p53 significantly suppressed mitotic skipping, suggesting that ionizing radiation-induced mitotic skipping is associated with p53 function. Conclusions: The present study found the pathway of senescence-like growth arrest in G1 phase without mitotic entry following G2-irradiation.

  4. Mutations of p53 gene exons 4-8 in human esophageal cancer

    Institute of Scientific and Technical Information of China (English)

    Li-Ya Li; Jin-Tian Tang; Li-Qun Jia; Pei-Wen Li

    2005-01-01

    AIM: To characterize the tumor suppressor gene p53 mutations in exon 4, esophageal cancer and adjacent noncancerous tissues.METHODS: We performed p53 (exons 4-8) gene mutation analysis on 24 surgically resected human esophageal cancer specimens by PCR, single-strand conformation polymorphism, and DNA sequencing. RESULTS: p53 gene mutations were detected in 9 of 22 (40.9%) esophageal cancer specimens and 10 of 17 (58.8%) adjacent non-cancerous tissues. Eight of sixteen (50.0%) point mutations detected were G-A transitions and 9 of 18 (50.0%) p53 gene mutations occurred in exon 4 in esophageal cancer specimens. Only 1 of 11 mutations detected was G-A transition and 4 of 11 (36.4%) p53 gene mutations occurred in exon 4 in adjacent non-cancerous tissues.CONCLUSION: Mutation of p53 gene in exon 4 may play an important role in development of esophageal cancer. The observation of p53 gene mutation in adjacent noncancerous tissues suggests that p53 gene mutation may be an early event in esophageal carcinogenesis. Some clinical factors, including age, sex, pre-operation therapy and location of tumors, do not influence p53 gene mutation rates.

  5. Molecular Diagnosis of Duchenne/Becker Muscular Dystrophy: Analysis of Exons Deletion and Carrier Detection

    Directory of Open Access Journals (Sweden)

    Mohammad Taghi Akbari

    2010-01-01

    Full Text Available Objective: Duchenne and Becker Muscular Dystrophy (DMD and BMD are X-linked conditionsresulting from a defect in the dystrophin gene located at Xp21.2. DMD is the mostfrequent neuromuscular disease in humans (1/3500 male newborns. In approximately65% of DMD and BMD patients, deletions in the dystrophin gene have been identified asthe molecular determinant. The frequency and distribution of dystrophin gene deletions inDMD/BMD patients from different populations are different.The aim of this study was to delineate various types of deleted exons and their frequencyin affected male patients and identification of carrier females by linkage analysis.Materials and Methods: In this study 100 unrelated patients with DMD/BMD were studiedfor intragenic deletions in 28 exons and the promoter region of the dystrophin geneusing multiplex PCR. We also performed linkage analysis within the dystrophin gene utilizing8 short tandem repeat markers.Results: Fifty-two (52% patients showed intragenic deletions. A total of 81% of the deletionswere located at the distal hot spot region (44-55 exons and 19% of the deletionswere located at the proximal region (exon 2-19. The most frequent deleted exons were47(16%, 48 and 46 (11%.Most of the STR markers showed heterozygosity in the families studied. The linkageanalysis was useful for detecting carrier status.Conclusion: The present study suggests that intragenic dystrophin gene deletions occurwith the same frequency in Iranian patients compared with other ethnic groups.

  6. Differential splicing of exon 5 of the Wilms tumour (WTI) gene.

    Science.gov (United States)

    Renshaw, J; King-Underwood, L; Pritchard-Jones, K

    1997-08-01

    The WTI gene encodes a developmentally regulated transcription factor whose function is altered by alternative splicing at two sites: the 17 amino acids of exon 5, whose functional effects are ill-defined, and the 3 amino acids (KTS) between exons 9 and 10, which determine sequence-specific DNA binding and nuclear localisation. Germline mutations, which prevent normal KTS splicing, can underlie the Denys-Drash syndrome, and disruptions of splicing of exon 5 may occur in Wilms tumours. We analysed by reverse transcriptase polymerase chain reaction (RT-PCR) amplification the relative ratios of the four splice variants of WTI mRNA in normal and tumour tissues and found tissue-specific, developmental stage-specific, and species-specific differences in the splicing of exon 5 but not of KTS. We found no evidence for disrupted splicing in acute leukaemias or gonadal tumours. The significance of these findings is discussed, and the possibility is raised that WTI may orchestrate the appropriate response to growth and differentiation factor signalling, mediated by alterations in the relative levels of exon 5 containing WTI isoforms.

  7. Huntingtin exon 1 fibrils feature an interdigitated β-hairpin-based polyglutamine core.

    Science.gov (United States)

    Hoop, Cody L; Lin, Hsiang-Kai; Kar, Karunakar; Magyarfalvi, Gábor; Lamley, Jonathan M; Boatz, Jennifer C; Mandal, Abhishek; Lewandowski, Józef R; Wetzel, Ronald; van der Wel, Patrick C A

    2016-02-09

    Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington's disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid-state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intramolecular and intermolecular contacts, backbone and side-chain torsion angles, relaxation measurements, and calculations of chemical shifts. These experiments reveal the presence of β-hairpin-containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand-based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are coassembled from differently structured monomers, which we describe as a type of "intrinsic" polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. We show that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms.

  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. KIT exon 11 deletion-inversions represent complex mutations in gastrointestinal stromal tumors.

    Science.gov (United States)

    Lasota, Jerzy; Miettinen, Markku

    2007-05-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT expression and mutational KIT activation have been documented in a majority of GISTs. Most mutations have been found in KIT juxtamembrane domain encoded by exon 11. Recently, we have identified three, complex KIT exon 11 mutations previously unreported in GISTs. These mutations consisted of several nucleotide deletions accompanied by insertions of inverted complementary DNA strand sequences. All three mutations were found in the 5' part of KIT exon 11. At the protein level, these mutations lead to the same end result: in-frame loss and insertion of a number of amino acids and could be considered examples of deletion-insertion. Although proper description of these mutations at the genomic level is a complex task and requires an individual approach, the uniform name deletion-inversion is suggested for this type of mutation, based on the present study. The frequency of deletion-inversions among KIT exon 11 mutant GISTs was estimated to be <0.5%, based on evaluation of 700 KIT exon 11 mutants. Molecular events leading to formation of deletion-inversions remain elusive and should be studied further.

  10. STUDY OF ECK GENE EXON-3 FROM HUMAN NORMAL TISSUE AND BREAST CANCER CELL LINE

    Institute of Scientific and Technical Information of China (English)

    李瑶琛; 孔令洪; 王一理; 司履生

    2003-01-01

    Objective To establish a method cloning the exon 3 of eck gene from normal tissue and ZR-75-1 cell line (a human breast cancer cell line)and study whether these genes exist mutant. Methods Designed a pair of specific primers and amplified the exon 3 of eck gene fragment from the extracted genomic DNA derived from normal epithelial cells from skin tissue and ZR-75-1 cell line respectively by PCR technique. Transformed the E.coil. JM109 with recombinant plamids constructed by inserting the amplified fragments into medium vector pUCm-T and sequenced these amplified fragments after primary screening of endonuclease restriction digestion and PCR amplification. Results ① Obtained the genomic DNA of human normal epithelial cells and ZR-75-1 cell line respectively. ② Obtained the amplified fragments of human exon 3 of eck gene through PCR technique. ③ Obtained the cloning vectors of exon 3 of eck gene of human normal epithelial cells and ZR-75-1 cell line respectively. ④ ZR-75-1 cell line exists mutation of nucleotides. Conclusion Successfully established the method of cloning the human exon 3 of eck gene and found some mutations in the detected samples. This study lays a foundation for further studying the function of eck gene in tumorgenesis.

  11. Implementation of exon arrays: alternative splicing during T-cell proliferation as determined by whole genome analysis

    Directory of Open Access Journals (Sweden)

    Whistler Toni

    2010-09-01

    Full Text Available Abstract Background The contribution of alternative splicing and isoform expression to cellular response is emerging as an area of considerable interest, and the newly developed exon arrays allow for systematic study of these processes. We use this pilot study to report on the feasibility of exon array implementation looking to replace the 3' in vitro transcription expression arrays in our laboratory. One of the most widely studied models of cellular response is T-cell activation from exogenous stimulation. Microarray studies have contributed to our understanding of key pathways activated during T-cell stimulation. We use this system to examine whole genome transcription and alternate exon usage events that are regulated during lymphocyte proliferation in an attempt to evaluate the exon arrays. Results Peripheral blood mononuclear cells form healthy donors were activated using phytohemagglutinin, IL2 and ionomycin and harvested at 5 points over a 7 day period. Flow cytometry measured cell cycle events and the Affymetrix exon array platform was used to identify the gene expression and alternate exon usage changes. Gene expression changes were noted in a total of 2105 transcripts, and alternate exon usage identified in 472 transcript clusters. There was an overlap of 263 transcripts which showed both differential expression and alternate exon usage over time. Gene ontology enrichment analysis showed a broader range of biological changes in biological processes for the differentially expressed genes, which include cell cycle, cell division, cell proliferation, chromosome segregation, cell death, component organization and biogenesis and metabolic process ontologies. The alternate exon usage ontological enrichments are in metabolism and component organization and biogenesis. We focus on alternate exon usage changes in the transcripts of the spliceosome complex. The real-time PCR validation rates were 86% for transcript expression and 71% for

  12. Catalyst-free synthesis of skipped dienes from phosphorus ylides, allylic carbonates, and aldehydes via a one-pot SN2' allylation-Wittig strategy.

    Science.gov (United States)

    Xu, Silong; Zhu, Shaoying; Shang, Jian; Zhang, Junjie; Tang, Yuhai; Dou, Jianwei

    2014-04-18

    A catalyst-free allylic alkylation of stabilized phosphorus ylides with allylic carbonates via a regioselective SN2' process is presented. Subsequent one-pot Wittig reaction with both aliphatic and aromatic aldehydes as well as ketenes provides structurally diverse skipped dienes (1,4-dienes) in generally high yields and moderate to excellent stereoselectivity with flexible substituent patterns. This one-pot SN2' allylation-Wittig strategy constitutes a convenient and efficient synthetic method for highly functionalized skipped dienes from readily available starting materials.

  13. 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.

  14. AA Amyloidosis and Atypical Familial Mediterranean Fever with Exon 2 and 3 Mutations

    Directory of Open Access Journals (Sweden)

    Junko Yabuuchi

    2017-07-01

    Full Text Available A 54-year-old Japanese man presented with recurrent abdominal pain, fever lasting >5 days, and renal failure. AA amyloidosis was proven by renal and gastric biopsy. Symptoms subsided with the administration of colchicine, but a subsequent recurrence of symptoms did not respond to colchicine. Mediterranean fever gene (MEFV analysis showed that he was heterozygous for mutations in exon 2 (E148Q/R202Q and exon 3 (P369S/R408Q, although he had none of the exon 10 mutations known to be closely related to AA amyloidosis. He did not respond to infliximab, but tocilizumab therapy was successful. The present case is a rare report of AA amyloidosis associated with familial Mediterranean fever in Japan.

  15. Exon-primed intron-crossing (EPIC markers as a tool for ant phylogeography

    Directory of Open Access Journals (Sweden)

    Patrícia R. Ströher

    2013-12-01

    Full Text Available Exon-primed intron-crossing (EPIC markers as a tool for ant phylogeography. Due to their local abundance, diversity of adaptations and worldwide distribution, ants are a classic example of adaptive radiation. Despite this evolutionary and ecological importance, phylogeographical studies on ants have relied largely on mitochondrial markers. In this study we design and test exon-primed intron-crossing (EPIC markers, which can be widely used to uncover ant intraspecific variation. Candidate markers were obtained through screening the available ant genomes for unlinked conserved exonic regions interspersed with introns. A subset of 15 markers was tested in vitro and showed successful amplification in several phylogenetically distant ant species. These markers represent an important step forward in ant phylogeography and population genetics, allowing for more extensive characterization of variation in ant nuclear DNA without the need to develop species-specific markers.

  16. 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.

  17. Benign familial neonatal convulsions caused by mutation in KCNQ3, exon 6: a European case.

    Science.gov (United States)

    Fister, Petja; Soltirovska-Salamon, Aneta; Debeljak, Marusa; Paro-Panjan, Darja

    2013-05-01

    Benign familial neonatal convulsions (BFNC) is a rare, clinically and genetically heterogenous epileptic disorder. Two voltage gated potassium genes, KCNQ2 and KCNQ3, have been identified as genes responsible for BFNC1 and BFNC2 respectively. While as many as 73 mutations of KCNQ2 have been described up to date, only 4 mutations in KCNQ3, 3 of them appearing in exon 5, have been identified. Mutation in exon 6 was found for the first time in a Chinese family, and here we report the same missense mutation of KCNQ3 within exon 6 in a Caucasian family, whose history and clinical picture were in accordance with BFNC. Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  18. Abnormal Methylation Status of the GNAS Exon 1A Region in Pseudohypohyperparathyroidism Combined With Turner Syndrome.

    Science.gov (United States)

    Zhu, Jie; Wang, Dong; Ren, An; Xing, Yan; Zhang, Dongliang; Wei, Jun; Yu, Ning; Xing, Xuenong; Ye, Shandong

    2015-12-01

    Pseudohypohyperparathyroidism (PHHP) is a rare type of pseudohypoparathyroidism (PHP), which seems to have a normal skeletal response to parathyroid hormone but shows renal resistance. Almost all patients with PHHP have PHP Ib, a subtype of PHP that is usually caused by GNAS methylation defects, often in exon 1A. Some features of Albright hereditary osteodystrophy can occasionally be found in patients with PHHP, but these features are also common in Turner syndrome. The authors report on an extremely rare case of a patient with PHHP and Turner syndrome, a 47-year-old woman who sought medical attention for hypocalcemia and elevated parathyroid hormone. She had no family history of hypocalcemia and no STX16 gene deletions. She had a mosaic karyotype of 46, X, del(X)(p11.4)/45, XO. Pyrosequencing was performed to determine the GNAS exon 1A methylation. The degree of methylation found in exon 1A of the patient was lower than her unaffected relatives.

  19. Role of the intracellular receptor domain of gp130 (exon 17) in human inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Christoph J. Auernhammer; Thomas Ochsenkühn; Kathrin Zitzmann; Fabian Schnitzler; Julia Seiderer; Peter Lohse; George Vlotides; Dieter Engelhardt; Michael Sackmann; Burkhard G(o)ke

    2005-01-01

    AIM: To study the role of the intracellular receptor domain of gp130 in human inflammatory bowel disease (IBD).METHODS: We amplified and sequenced the complete exon 17 of the human gp130 gene in 146 patients with IBD. According to clinical and histopathological signs,the 146 patients with IBD were classified as having Crohn's disease (n = 73) or ulcerative colitis (n = 63),or as indeterminate status (n = 10).RESULTS: No mutations in exon 17 of the gp130 gene could be detected in any of the 146 patients with IBD examined.CONCLUSION: There is no evidence that mutations in exon 17 of the gp130 gene are involved in the pathogenesis of human IBD.

  20. Computational analysis and prediction for exons of PAC579 genomic sequence

    Institute of Scientific and Technical Information of China (English)

    黄弋; 覃文新; 万大方; 赵新泰; 顾健人

    2001-01-01

    To isolate the novel genes related to human hepatocellular carcinoma (HCC), we sequenced P1-derived artificial chromosome PAC579 (D17S926 locus) mapped in the minimum LOH (loss of heterozygosity) deletion region of chromosome 17p13.3 in HCC, Four novel genes mapped in this genomic sequence area were isolated and cloned by wet-lab experiments, and the exons of these genes were located. 0-60 kb of this genomic sequence including the genes of interest was scanned with five different computational exon prediction programs as well as four splice site recognition programs. After analyzing and comparing the computationally predicted results with the wet-lab experiment results, some potential exons were predicted in the genomic sequence by using these programs.

  1. Histone modifications involved in cassette exon inclusions: a quantitative and interpretable analysis.

    Science.gov (United States)

    Liu, Hui; Jin, Ting; Guan, Jihong; Zhou, Shuigeng

    2014-12-19

    Chromatin structure and epigenetic modifications have been shown to involve in the co-transcriptional splicing of RNA precursors. In particular, some studies have suggested that some types of histone modifications (HMs) may participate in the alternative splicing and function as exon marks. However, most existing studies pay attention to the qualitative relationship between epigenetic modifications and exon inclusion. The quantitative analysis that reveals to what extent each type of epigenetic modification is responsible for exon inclusion is very helpful for us to understand the splicing process. In this paper, we focus on the quantitative analysis of HMs' influence on the inclusion of cassette exons (CEs) into mature RNAs. With the high-throughput ChIP-seq and RNA-seq data obtained from ENCODE website, we modeled the association of HMs with CE inclusions by logistic regression whose coefficients are meaningful and interpretable for us to reveal the effect of each type of HM. Three type of HMs, H3K36me3, H3K9me3 and H4K20me1, were found to play major role in CE inclusions. HMs' effect on CE inclusions is conservative across cell types, and does not depend on the expression levels of the genes hosting CEs. HMs located in the flanking regions of CEs were also taken into account in our analysis, and HMs within bounded flanking regions were shown to affect moderately CE inclusions. Moreover, we also found that HMs on CEs whose length is approximately close to nucleosomal-DNA length affect greatly on CE inclusion. We suggested that a few types of HMs correlate closely to alternative splicing and perhaps function jointly with splicing machinery to regulate the inclusion level of exons. Our findings are helpful to understand HMs' effect on exon definition, as well as the mechanism of co-transcriptional splicing.

  2. 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.

  3. A Fast Hybrid Algorithm Approach for the Exact String Matching Problem Via Berry Ravindran and Alpha Skip Search Algorithms

    Directory of Open Access Journals (Sweden)

    A. A. Almazroi

    2011-01-01

    Full Text Available Problem statement: String matching algorithm had been an essential means for searching biological sequence database. With the constant expansion in scientific data such as DNA and Protein; the development of enhanced algorithms have even become more critical as the major concern had always been how to raise the performances of these search algorithms to meet challenges of scientific information. Approach: Therefore a new hybrid algorithm comprising Berry Ravindran (BR and Alpha Skip Search (ASS is presented. The concept is based on BR shift function and combines with ASS to ensure improved performance. Results: The results obtained in percentages from the proposed hybrid algorithm displayed superior results in terms of number of attempts and number of character comparisons than the original algorithms when various types of data namely DNA, Protein and English text are applied to appraise the hybrid performances. The enhancement of the proposed hybrid algorithm performs better at 71%, 60% and 63% when compared to Berry-Ravindran in DNA, Protein and English text correspondingly. Moreover the rate of enhancement over Alpha Skip Search algorithm in DNA, Protein and English text are 48%, 28% and 36% respectively. Conclusion: The new proposed hybrid algorithm is relevant for searching biological science sequence database and also other string search systems.

  4. Impact of Breakfast Skipping and Breakfast Choice on the Nutrient Intake and Body Mass Index of Australian Children

    Directory of Open Access Journals (Sweden)

    Flavia Fayet-Moore

    2016-08-01

    Full Text Available Recent data on breakfast consumption among Australian children are limited. This study examined the impact of breakfast skipping and breakfast type (cereal or non-cereal on nutrient intakes, likelihood of meeting nutrient targets and anthropometric measures. A secondary analysis of two 24-h recall data from the 2007 Australian National Children’s Nutrition and Physical Activity Survey was conducted (2–16 years; n = 4487 to identify (a breakfast skippers and (b breakfast consumers, with breakfast consumers further sub-divided into (i non-cereal and (ii cereal consumers. Only 4% skipped breakfast and 59% of skippers were 14–16 years. Breakfast consumers had significantly higher intakes of calcium and folate, and significantly lower intakes of total fat than breakfast skippers. Cereal consumers were more likely to meet targets and consume significantly higher fibre, calcium, iron, had significantly higher intakes of folate, total sugars and carbohydrate, and significantly lower intakes of total fat and sodium than non-cereal consumers. The prevalence of overweight was lower among breakfast consumers compared to skippers, and among cereal consumers compared to-cereal consumers (p < 0.001, while no significant differences were observed for mean body mass index (BMI, BMI z-score, waist circumference and physical activity level across the categories. Breakfast and particularly breakfast cereal consumption contributes important nutrients to children’s diets.

  5. Impact of Breakfast Skipping and Breakfast Choice on the Nutrient Intake and Body Mass Index of Australian Children.

    Science.gov (United States)

    Fayet-Moore, Flavia; Kim, Jean; Sritharan, Nilani; Petocz, Peter

    2016-08-10

    Recent data on breakfast consumption among Australian children are limited. This study examined the impact of breakfast skipping and breakfast type (cereal or non-cereal) on nutrient intakes, likelihood of meeting nutrient targets and anthropometric measures. A secondary analysis of two 24-h recall data from the 2007 Australian National Children's Nutrition and Physical Activity Survey was conducted (2-16 years; n = 4487) to identify (a) breakfast skippers and (b) breakfast consumers, with breakfast consumers further sub-divided into (i) non-cereal and (ii) cereal consumers. Only 4% skipped breakfast and 59% of skippers were 14-16 years. Breakfast consumers had significantly higher intakes of calcium and folate, and significantly lower intakes of total fat than breakfast skippers. Cereal consumers were more likely to meet targets and consume significantly higher fibre, calcium, iron, had significantly higher intakes of folate, total sugars and carbohydrate, and significantly lower intakes of total fat and sodium than non-cereal consumers. The prevalence of overweight was lower among breakfast consumers compared to skippers, and among cereal consumers compared to-cereal consumers (p Breakfast and particularly breakfast cereal consumption contributes important nutrients to children's diets.

  6. 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.

  7. Identification of conserved splicing motifs in mutually exclusive exons of 15 insect species.

    Science.gov (United States)

    Buendia, Patricia; Tyree, John; Loredo, Robert; Hsu, Shu-Ning

    2012-04-12

    During alternative splicing, the inclusion of an exon in the final mRNA molecule is determined by nuclear proteins that bind cis-regulatory sequences in a target pre-mRNA molecule. A recent study suggested that the regulatory codes of individual RNA-binding proteins may be nearly immutable between very diverse species such as mammals and insects. The model system Drosophila melanogaster therefore presents an excellent opportunity for the study of alternative splicing due to the availability of quality EST annotations in FlyBase. In this paper, we describe an in silico analysis pipeline to extract putative exonic splicing regulatory sequences from a multiple alignment of 15 species of insects. Our method, ESTs-to-ESRs (E2E), uses graph analysis of EST splicing graphs to identify mutually exclusive (ME) exons and combines phylogenetic measures, a sliding window approach along the multiple alignment and the Welch's t statistic to extract conserved ESR motifs. The most frequent 100% conserved word of length 5 bp in different insect exons was "ATGGA". We identified 799 statistically significant "spike" hexamers, 218 motifs with either a left or right FDR corrected spike magnitude p-value < 0.05 and 83 with both left and right uncorrected p < 0.01. 11 genes were identified with highly significant motifs in one ME exon but not in the other, suggesting regulation of ME exon splicing through these highly conserved hexamers. The majority of these genes have been shown to have regulated spatiotemporal expression. 10 elements were found to match three mammalian splicing regulator databases. A putative ESR motif, GATGCAG, was identified in the ME-13b but not in the ME-13a of Drosophila N-Cadherin, a gene that has been shown to have a distinct spatiotemporal expression pattern of spliced isoforms in a recent study. Analysis of phylogenetic relationships and variability of sequence conservation as implemented in the E2E spikes method may lead to improved identification of ESRs

  8. MX1 exon 13 polymorphisms in broiler breeder chickens and associations with commercial traits.

    Science.gov (United States)

    Livant, E J; Avendano, S; McLeod, S; Ye, X; Lamont, S J; Dekkers, J C M; Ewald, S J

    2007-04-01

    The Mx1 gene in mice is induced by type I interferons and is the major determinant of resistance to influenza virus and related orthomyxoviruses. It has been previously shown that a SNP in exon 13 of the chicken MX1 gene determines differential antiviral activity of the protein. We evaluated this SNP and two additional SNPs in elite broiler lines by PCR amplification and sequence analysis. Associations between MX1 exon 13 SNPs and several traits of economic interest were evaluated. Significant associations were found between the SNP determining antiviral activity and mortality in one line and leg defects in another line.

  9. A modified group I intron can function as both a ribozyme and a 5' exon in a trans-exon ligation reaction.

    Science.gov (United States)

    Tasiouka, K I; Burke, J M

    1994-06-24

    Here, we show that a single RNA molecule derived from a group-I intron can provide the catalytic activity, the substrate recognition domain and the attacking nucleophile in a reaction that mimics the exon ligation step of splicing. To accomplish this reaction, we have linked a 5' exon sequence to the 3' end of an attenuated form of the self-splicing Tetrahymena rRNA intron. The ribozyme (I-E1) attacks an oligoribonucleotide analog of the 3' splice site (I'-E2) to generate a product containing ligated exons (I-E1-E2) and a small intron fragment (I'). Two modified introns were constructed and tested for activity. A construct designed to interact with the 3' splice site through intermolecular P9.0 and P10 helices was found to be inactive due to failure to form a stable ribozyme-substrate complex. A second modified intron and substrate combination was engineered, in which the complex was further stabilized by an intermolecular P9.2 helix. In this case, stable complexes and reaction products were identified. The reaction efficiency was low compared to splicing of the unmodified intron-containing precursor, and will be optimized in future experiments. Following optimization, we believe that this system may be exploited to examine the functional consequences of a wide variety of 3' splice-site modifications, and may provide the basis for development of highly selective trans-acting ribozymes.

  10. Exon definition complexes contain the tri-snRNP and can be directly converted into B-like precatalytic splicing complexes.

    OpenAIRE

    Schneider, M.; Will, C.; Anokhina, M.; Tazi, J; Urlaub, H; Lührmann, R

    2010-01-01

    The first step in splicing of pre-mRNAs with long introns is exon definition, where U1 and U2 snRNPs bind at opposite ends of an exon. After exon definition, these snRNPs must form a complex across the upstream intron to allow splicing catalysis. Exon definition and conversion of cross-exon to cross-intron spliceosomal complexes are poorly understood. Here we demonstrate that, in addition to U1 and U2 snRNPs, cross-exon complexes contain U4, U5, and U6 (which form the tri-snRNP). Tri-snRNP do...

  11. Skipping breakfast, alcohol consumption and physical inactivity as risk factors for overweight and obesity in adolescents: results of the E-MOVO project

    NARCIS (Netherlands)

    Croezen, S.; Visscher, T.L.S.; Bogt, ter N.C.W.; Veling, M.L.; Haveman-Nies, A.

    2009-01-01

    Objective/Background: To investigate the association between skipping breakfast, alcohol consumption and physical inactivity with overweight and obesity in adolescents. The design comprises cross-sectional electronic health survey (E-MOVO). Subjects/Methods: Over 35 000 Dutch adolescents in grade 2

  12. Skipping breakfast, alcohol consumption and physical inactivity as risk factors for overweight and obesity in adolescents : results of the E-MOVO project

    NARCIS (Netherlands)

    Croezen, S.; Visscher, T. L. S.; ter Bogt, N. C. W.; Veling, M. L.; Haveman-Nies, A.

    Objective/Background: To investigate the association between skipping breakfast, alcohol consumption and physical inactivity with overweight and obesity in adolescents. The design comprises cross-sectional electronic health survey (E-MOVO). Subjects/Methods: Over 35 000 Dutch adolescents in grade 2

  13. The addition of a protein-rich breakfast and its effects on acute appetite control and food intake in 'breakfast-skipping' adolescents.

    Science.gov (United States)

    Leidy, H J; Racki, E M

    2010-07-01

    Breakfast skipping (BS) is closely associated with overeating (in the evening), weight gain and obesity. It is unclear whether the addition of breakfast, with emphasis on dietary protein, leads to better appetite and energy intake regulation in adolescents. The purpose of the study was to examine the impact of addition of a normal-protein (PN) breakfast vs protein-rich (PR) breakfast on appetite and food intake in 'breakfast-skipping' adolescents. A total of 13 adolescents (age 14.3+/-0.3 years; body mass index percentile 79+/-4 percentile; skipped breakfast 5+/-1 x per week) randomly completed 3 testing days that included a PN (18+/-1 g protein), PR (48+/-2 g protein) or BS. Breakfast was 24% of estimated daily energy needs. Appetite, satiety and hormonal responses were collected over 5 h followed by an ad libitum lunch and 24-h food intake assessments. Perceived appetite was not different following PN vs BS; PR led to greater reductions vs BS (Pintake was not different following PN vs BS; PR led to fewer kcal consumed vs BS (Pfood intake was not different among treatments. Breakfast led to increased satiety through increased fullness and PYY concentrations in 'breakfast skipping' adolescents. A breakfast rich in dietary protein provides additional benefits through reductions in appetite and energy intake. These findings suggest that the addition of a protein-rich breakfast might be an effective strategy to improve appetite control in young people.

  14. Do breakfast skipping and breakfast type affect energy intake, nutrient intake, nutrient adequacy, and diet quality in young adults? NHANES 1999-2002

    Science.gov (United States)

    The objective of this study was to assess the impact of breakfast skipping and type of breakfast consumed on energy/nutrient intake, nutrient adequacy, and diet quality using a cross-sectional design. The setting was The National Health and Nutrition Examination Survey (NHANES), 1999-2002. The sub...

  15. Skipping breakfast, alcohol consumption and physical inactivity as risk factors for overweight and obesity in adolescents : results of the E-MOVO project

    NARCIS (Netherlands)

    Croezen, S.; Visscher, T. L. S.; ter Bogt, N. C. W.; Veling, M. L.; Haveman-Nies, A.

    2009-01-01

    Objective/Background: To investigate the association between skipping breakfast, alcohol consumption and physical inactivity with overweight and obesity in adolescents. The design comprises cross-sectional electronic health survey (E-MOVO). Subjects/Methods: Over 35 000 Dutch adolescents in grade 2

  16. Skipping breakfast, alcohol consumption and physical inactivity as risk factors for overweight and obesity in adolescents: results of the E-MOVO project

    NARCIS (Netherlands)

    Croezen, S.; Visscher, T.L.S.; Bogt, ter N.C.W.; Veling, M.L.; Haveman-Nies, A.

    2009-01-01

    Objective/Background: To investigate the association between skipping breakfast, alcohol consumption and physical inactivity with overweight and obesity in adolescents. The design comprises cross-sectional electronic health survey (E-MOVO). Subjects/Methods: Over 35 000 Dutch adolescents in grade 2

  17. Cryptic exon incorporation occurs in Alzheimer's brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43.

    Science.gov (United States)

    Sun, Mingkuan; Bell, William; LaClair, Katherine D; Ling, Jonathan P; Han, Heather; Kageyama, Yusuke; Pletnikova, Olga; Troncoso, Juan C; Wong, Philip C; Chen, Liam L

    2017-06-01

    Abnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying nuclear clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), has also been found in Alzheimer' disease (AD). TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients, suggesting that nuclear clearance of TDP-43 underlies its inability to repress cryptic exons. However, whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons is not known. Here, we assessed hippocampal tissues from 34 human postmortem brains including cases with confirmed diagnosis of AD neuropathologic changes along with age-matched controls. We found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Importantly, cryptic exon incorporation could be detected in AD brains lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. These data supports the notion that the functional consequence of nuclear depletion of TDP-43 as determined by cryptic exon incorporation likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. Early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.

  18. Integrated exon level expression analysis of driver genes explain their role in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Mohammad Azhar Aziz

    Full Text Available Integrated analysis of genomic and transcriptomic level changes holds promise for a better understanding of colorectal cancer (CRC biology. There is a pertinent need to explain the functional effect of genome level changes by integrating the information at the transcript level. Using high resolution cytogenetics array, we had earlier identified driver genes by 'Genomic Identification of Significant Targets In Cancer (GISTIC' analysis of paired tumour-normal samples from colorectal cancer patients. In this study, we analyze these driver genes at three levels using exon array data--gene, exon and network. Gene level analysis revealed a small subset to experience differential expression. These results were reinforced by carrying out separate differential expression analyses (SAM and LIMMA. ATP8B1 was found to be the novel gene associated with CRC that shows changes at cytogenetic, gene and exon levels. Splice index of 29 exons corresponding to 13 genes was found to be significantly altered in tumour samples. Driver genes were used to construct regulatory networks for tumour and normal groups. There were rearrangements in transcription factor genes suggesting the presence of regulatory switching. The regulatory pattern of AHR gene was found to have the most significant alteration. Our results integrate data with focus on driver genes resulting in highly enriched novel molecules that need further studies to establish their role in CRC.

  19. A novel first exon directs hormone-sensitive transcription of the pig prolactin receptor

    Science.gov (United States)

    Endocrine, paracrine, and autocrine prolactin (PRL) acts through its receptor (PRLR) to confer a wide range of biological functions, including its established role during lactation.We have identified a novel first exon of the porcine PRLR that gives rise to three different mRNA transcripts. Transcri...

  20. Detection EGFR exon 19 status of lung cancer patients by DNA electrochemical biosensor.

    Science.gov (United States)

    Xu, Xiong-Wei; Weng, Xiu-Hua; Wang, Chang-Lian; Lin, Wei-Wei; Liu, Ai-Lin; Chen, Wei; Lin, Xin-Hua

    2016-06-15

    Epidermal growth factor receptor (EGFR) exon 19 mutation status is a very important prediction index for tyrosine kinase inhibitors (TKIs) therapy. In this paper, we constructed a superior selective sandwich-type electrochemical biosensor to detect in-frame deletions in exon 19 of EGFR in real samples of patients with non-small cell lung carcinoma. Based on the characteristics of different hybridization efficiency in different hybridization phase conditions, different region around EGFR exon 19 deletion hotspots was selected to design DNA probes to improve biosensor performance. The results confirm that alteration of deletion location in target deliberately according to different hybridization phase is able to improve selectivity of sandwich-type DNA biosensor. Satisfactory discrimination ability can be achieved when the deletions are located in the capture probe interaction region. In order to improve efficiency of ssDNA generation from dsDNA, we introduce Lambda exonuclease (λ-exo) to sandwich-type biosensor system. EGFR exon 19 statuses of clinical real samples from lung cancer patients can be discriminated successfully by the proposed method. Our research would make the electrochemical biosensor be an excellent candidate for EGFR detection for lung cancer patients.

  1. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.

    NARCIS (Netherlands)

    Tarpey, P.S.; Smith, R.; Pleasance, E.; Whibley, A.; Edkins, S.; Hardy, C.; O'Meara, S.; Latimer, C.; Dicks, E.; Menzies, A.; Stephens, P.; Blow, M.; Greenman, C.; Xue, Y.; Tyler-Smith, C.; Thompson, D.; Gray, K.; Andrews, J.; Barthorpe, S.; Buck, G.; Cole, J.; Dunmore, R.; Jones, D.; Maddison, M.; Mironenko, T.; Turner, R.; Turrell, K.; Varian, J.; West, S.; Widaa, S.; Wray, P.; Teague, J.; Butler, A.; Jenkinson, A.; Jia, M.; Richardson, D.; Shepherd, R.; Wooster, R.; Tejada, M.I.; Martinez, F.; Carvill, G.; Goliath, R.; Brouwer, A.P.M. de; Bokhoven, H. van; Esch, H. van; Chelly, J.; Raynaud, M.; Ropers, H.H.; Abidi, F.E.; Srivastava, A.K.; Cox, J.; Luo, Y.; Mallya, U.; Moon, J.; Parnau, J.; Mohammed, S.; Tolmie, J.L.; Shoubridge, C.; Corbett, M.; Gardner, A.; Haan, E.; Rujirabanjerd, S.; Shaw, M.A.; Vandeleur, L.; Fullston, T.; Easton, D.F.; Boyle, J.; Partington, M.; Hackett, A.; Field, M.; Skinner, C.; Stevenson, R.E.; Bobrow, M.; Turner, G.; Schwartz, C.E.; Gecz, J.; Raymond, F.L.; Futreal, P.A.; Stratton, M.R.

    2009-01-01

    Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR),

  2. Improvements to previous algorithms to predict gene structure and isoform concentrations using Affymetrix Exon arrays

    Directory of Open Access Journals (Sweden)

    Aramburu Ander

    2010-11-01

    Full Text Available Abstract Background Exon arrays provide a way to measure the expression of different isoforms of genes in an organism. Most of the procedures to deal with these arrays are focused on gene expression or on exon expression. Although the only biological analytes that can be properly assigned a concentration are transcripts, there are very few algorithms that focus on them. The reason is that previously developed summarization methods do not work well if applied to transcripts. In addition, gene structure prediction, i.e., the correspondence between probes and novel isoforms, is a field which is still unexplored. Results We have modified and adapted a previous algorithm to take advantage of the special characteristics of the Affymetrix exon arrays. The structure and concentration of transcripts -some of them possibly unknown- in microarray experiments were predicted using this algorithm. Simulations showed that the suggested modifications improved both specificity (SP and sensitivity (ST of the predictions. The algorithm was also applied to different real datasets showing its effectiveness and the concordance with PCR validated results. Conclusions The proposed algorithm shows a substantial improvement in the performance over the previous version. This improvement is mainly due to the exploitation of the redundancy of the Affymetrix exon arrays. An R-Package of SPACE with the updated algorithms have been developed and is freely available.

  3. 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

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

    Science.gov (United States)

    Palmirotta, Raffaele; Savonarola, Annalisa; Ludovici, Giorgia; De Marchis, Maria Laura; Covello, Renato; Ettorre, Giuseppe Maria; Ialongo, Cristiano; Guadagni, Fiorella

    2011-01-01

    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.

  5. Intron 1 and exon 1 alpha estrogen receptor gene polymorphisms in women with endometriosis.

    Science.gov (United States)

    Sato, Hélio; Nogueira-de-Souza, Naiara C; D'Amora, Paulo; Silva, Ismael D C G; Girão, Manoel J B C; Schor, Eduardo

    2008-12-01

    To evaluate the association of intron 1 and exon 1 polymorphisms in the estrogen receptor alpha gene (ER-alpha) with endometriosis in women. Association study. Endometriosis Unit, Federal University of São Paulo. The control group consisted of volunteers older than 45 years who had no evidence of endometriosis antecedents. Two groups with the disease were evaluated: the first group had stage I or II endometriosis and the second group stage III or IV. Polymerase chain reaction (PCR) followed by digestion with HaeIII and MspI endonucleases (RFLP) were applied to detect intron 1 and exon 1 polymorphisms, respectively, in a total of 125 controls and 105 affected women. Frequency and distribution of HaeIII and MspI polymorphisms in ER-alpha. No significant differences in the frequency of polymorphisms either in intron 1 or exon 1 of ER-alpha were found when endometriosis patients were compared with control subjects. Furthermore, the frequency of ER-alpha polymorphisms within the two different groups of patients with disease was statistically similar. The odds ratio between presence of intron 1 single-nucleotide polymorphisms (SNP) and endometriosis was 0.904, and the odds ratio between exon 1 SNP and endometriosis was 0.976. The evaluated polymorphisms were not associated with endometriosis.

  6. Defining the ends of Parkin exon 4 deletions in two different families with Parkinson's disease.

    Science.gov (United States)

    Clarimon, Jordi; Johnson, Janel; Dogu, Okan; Horta, Wagner; Khan, Naheed; Lees, Andrew J; Hardy, John; Singleton, Andrew

    2005-02-05

    Autosomal recessive juvenile parkinsonism (AR-JP, PARK2) is characterized by an early onset parkinsonism, often presenting with dystonia as an early feature. Mutations in Parkin are a relatively common cause of AR-JP and are estimated to be present in approximately 30% of familial young onset Parkinson disease (PD) [Abbas et al. (1999); Hum Mol Genet 8:567-574]. These mutations include exon rearrangements (deletions and duplications), point mutations, and small deletions. Similar genomic mutations have been described in unrelated patients, thereby indicating independent mutational events or ancient founder effects. We have identified homozygous deletion mutations of exon 4 in Parkin in two unrelated families, one from Brazil and the other from Turkey [Dogu et al. (2004); Mov Dis 9:812-816; Khan et al., Mov Dis, in press]. We have performed molecular analysis of the deletion breakpoints and this data indicates these mutations originated independently. We present here data demonstrating that the mutation responsible for disease in the Brazilian kindred consists of two separate deletions (1,069 and 1,750 bp) surrounding and including exon 4. The deletion removing parkin exon 4 identified in the Turkish family extended 156,203 bp. In addition to demonstrating that disease in these families is not caused by a single founder mutation, these data show that there is no common fragile site between these mutational events.

  7. MOLECULAR ANALYSIS OF RADIATION-INDUCED MUTATION IN EXON 7/8 OF RAT HPRT GENE

    Institute of Scientific and Technical Information of China (English)

    任晓庆; 黄定九; 黄钢; 王利民

    2003-01-01

    Objective To investigate the relationship between the radiation dose and the HPRT gene locus mutation in rat smooth muscle cells, and provide the molecular basis for prevention of restenosis after percutaneous transluminal coronary angioplasty (PTCA).MethodsThe smooth muscle cells cultured in vitro were irradiated by radionuclide 188Re in different doses. HPRT gene mutation colonies were selected and isolated by 6 thioguanine. Analysis of mutation in exon 7/8 of HPRT gene were accomplished by polymerase chain reaction and single strand conformation polymorphism.ResultsThe HPRT gene mutation frequency of rat smooth muscle cells that were irradiated by radionuclide 188Re ranged from 5.5×10-6 to 13×10-6. Of 91 HPRT gene mutation colonies, 13(14.3%) contained exon 7/8 deletion and 15(16.5%) had point mutation. The exon 7/8 mutation frequency was 30.8%. There were significant relationships between radiation dose and mutation frequency of HPRT gene and exon 7/8.ConclusionThe DNA damage and gene mutation induced by radiation has positive relationship with radiation dose, and is a basis of proliferation inhibition and apoptosis of smooth muscle cells.

  8. 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.

  9. Epidermal growth factor receptor exon 20 p.S768I mutation in non-small cell lung carcinoma

    DEFF Research Database (Denmark)

    Improta, Giuseppina; Pettinato, Angela; Gieri, Stefania;

    2016-01-01

    mutations may be used to identify tumors sensitive to the effects of small-molecule EGFR-TKIs (gefitinib and erlotinib), and alternative, less frequently observed mutations, including the majority of mutations identified within exon 20, may be associated with a lack of response to TKIs. However, due...... to the comparative rarity of EGFR exon 20 mutations, clinical information concerning the association between EGFR exon 20 mutations and responsiveness to TKIs has been limited within the relevant literature, particularly for certain rare mutations, including p.S768I. The current study reports the case of a patient...... with NSCLC harboring a p.S768I mutation in the EGFR gene [a substitution at codon 768 of exon 20 (c.2303G>T, p.S768I)], as well as a mutation at codon 719, exon 18 (p.G719A). The relevant literature concerning this rare EGFR somatic mutation is also reviewed....

  10. 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

  11. Short Tandem Repeats in Human Exons: A Target for Disease Mutations

    Directory of Open Access Journals (Sweden)

    Villesen Palle

    2008-09-01

    Full Text Available Abstract Background In recent years it has been demonstrated that structural variations, such as indels (insertions and deletions, are common throughout the genome, but the implications of structural variations are still not clearly understood. Long tandem repeats (e.g. microsatellites or simple repeats are known to be hypermutable (indel-rich, but are rare in exons and only occasionally associated with diseases. Here we focus on short (imperfect tandem repeats (STRs which fall below the radar of conventional tandem repeat detection, and investigate whether STRs are targets for disease-related mutations in human exons. In particular, we test whether they share the hypermutability of the longer tandem repeats and whether disease-related genes have a higher STR content than non-disease-related genes. Results We show that validated human indels are extremely common in STR regions compared to non-STR regions. In contrast to longer tandem repeats, our definition of STRs found them to be present in exons of most known human genes (92%, 99% of all STR sequences in exons are shorter than 33 base pairs and 62% of all STR sequences are imperfect repeats. We also demonstrate that STRs are significantly overrepresented in disease-related genes in both human and mouse. These results are preserved when we limit the analysis to STRs outside known longer tandem repeats. Conclusion Based on our findings we conclude that STRs represent hypermutable regions in the human genome that are linked to human disease. In addition, STRs constitute an obvious target when screening for rare mutations, because of the relatively low amount of STRs in exons (1,973,844 bp and the limited length of STR regions.

  12. Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

    Science.gov (United States)

    Hoop, Cody L.; Lin, Hsiang-Kai; Kar, Karunakar; Magyarfalvi, Gábor; Lamley, Jonathan M.; Boatz, Jennifer C.; Mandal, Abhishek; Lewandowski, Józef R.; Wetzel, Ronald

    2016-01-01

    Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington’s disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid-state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intramolecular and intermolecular contacts, backbone and side-chain torsion angles, relaxation measurements, and calculations of chemical shifts. These experiments reveal the presence of β-hairpin–containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand–based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are coassembled from differently structured monomers, which we describe as a type of “intrinsic” polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. We show that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms. PMID:26831073

  13. Alternatively Spliced Homologous Exons Have Ancient Origins and Are Highly Expressed at the Protein Level

    Science.gov (United States)

    Abascal, Federico; Ezkurdia, Iakes; Rodriguez-Rivas, Juan; Rodriguez, Jose Manuel; del Pozo, Angela; Vázquez, Jesús; Valencia, Alfonso; Tress, Michael L.

    2015-01-01

    Alternative splicing of messenger RNA can generate a wide variety of mature RNA transcripts, and these transcripts may produce protein isoforms with diverse cellular functions. While there is much supporting evidence for the expression of alternative transcripts, the same is not true for the alternatively spliced protein products. Large-scale mass spectroscopy experiments have identified evidence of alternative splicing at the protein level, but with conflicting results. Here we carried out a rigorous analysis of the peptide evidence from eight large-scale proteomics experiments to assess the scale of alternative splicing that is detectable by high-resolution mass spectroscopy. We find fewer splice events than would be expected: we identified peptides for almost 64% of human protein coding genes, but detected just 282 splice events. This data suggests that most genes have a single dominant isoform at the protein level. Many of the alternative isoforms that we could identify were only subtly different from the main splice isoform. Very few of the splice events identified at the protein level disrupted functional domains, in stark contrast to the two thirds of splice events annotated in the human genome that would lead to the loss or damage of functional domains. The most striking result was that more than 20% of the splice isoforms we identified were generated by substituting one homologous exon for another. This is significantly more than would be expected from the frequency of these events in the genome. These homologous exon substitution events were remarkably conserved—all the homologous exons we identified evolved over 460 million years ago—and eight of the fourteen tissue-specific splice isoforms we identified were generated from homologous exons. The combination of proteomics evidence, ancient origin and tissue-specific splicing indicates that isoforms generated from homologous exons may have important cellular roles. PMID:26061177

  14. Alternatively Spliced Homologous Exons Have Ancient Origins and Are Highly Expressed at the Protein Level.

    Directory of Open Access Journals (Sweden)

    Federico Abascal

    2015-06-01

    Full Text Available Alternative splicing of messenger RNA can generate a wide variety of mature RNA transcripts, and these transcripts may produce protein isoforms with diverse cellular functions. While there is much supporting evidence for the expression of alternative transcripts, the same is not true for the alternatively spliced protein products. Large-scale mass spectroscopy experiments have identified evidence of alternative splicing at the protein level, but with conflicting results. Here we carried out a rigorous analysis of the peptide evidence from eight large-scale proteomics experiments to assess the scale of alternative splicing that is detectable by high-resolution mass spectroscopy. We find fewer splice events than would be expected: we identified peptides for almost 64% of human protein coding genes, but detected just 282 splice events. This data suggests that most genes have a single dominant isoform at the protein level. Many of the alternative isoforms that we could identify were only subtly different from the main splice isoform. Very few of the splice events identified at the protein level disrupted functional domains, in stark contrast to the two thirds of splice events annotated in the human genome that would lead to the loss or damage of functional domains. The most striking result was that more than 20% of the splice isoforms we identified were generated by substituting one homologous exon for another. This is significantly more than would be expected from the frequency of these events in the genome. These homologous exon substitution events were remarkably conserved--all the homologous exons we identified evolved over 460 million years ago--and eight of the fourteen tissue-specific splice isoforms we identified were generated from homologous exons. The combination of proteomics evidence, ancient origin and tissue-specific splicing indicates that isoforms generated from homologous exons may have important cellular roles.

  15. Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity-Oriented Synthesis.

    Science.gov (United States)

    Tejedor, David; López-Tosco, Sara; Méndez-Abt, Gabriela; Cotos, Leandro; García-Tellado, Fernando

    2016-04-19

    During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4-O-C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB' three-component reaction for PVEs; A2BB' four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile

  16. Inhibition of allergic airway inflammation by antisense-induced blockade of STAT6 expression

    Institute of Scientific and Technical Information of China (English)

    TIAN Xin-rui; TIAN Xin-li; BO Jian-ping; LI Shao-gang; LIU Zhuo-la; NIU Bo

    2011-01-01

    Background The signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a pivotal role in asthma pathogenesis. Activation of STAT6 expression results in T helper cell type 2 (Th2) cell differentiation leading to Th2-mediated IgE production, development of allergic airway inflammation and hyperreactivity. Therefore,antagonizing the expression and/or the function of STAT6 could be used as a mode of therapy for allergic airway inflammation.Methods In this study, we synthesized a 20-mer phosphorothioate antisense oligonucleotide (ASODN) overlapping the translation starting site of STAT6 and constructed STAT6 antisense RNA (pANTI-STAT6), then transfected them into murine spleen lymphocytes and analyzed the effects of antagonizing STAT6 function in vitro and in a murine model of asthma.Results In vitro, we showed suppression of STAT6 expression and interleukin (IL)-4 production of lymphocytes by STAT6 ASODN. This effect was more prominent when cells were cultured with pANTI-STAT6. In a murine model of asthma associated with allergic pulmonary inflammation in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate (FITC)-labeled STAT6 ASODN to DNA uptake in lung cells was accompanied by a reduction of intracellular STAT6 expression. Such intrapulmonary blockade of STAT6 expression abrogated signs of lung inflammation, infiltration of eosinophils and Th2 cytokine production.Conclusion These data suggest a critical role of STAT6 in the pathogenesis of asthma and the use of local delivery of STAT6 ASODN as a novel approach for the treatment of allergic airway inflammation such as in asthma.

  17. Even-Skipped(+) Interneurons Are Core Components of a Sensorimotor Circuit that Maintains Left-Right Symmetric Muscle Contraction Amplitude.

    Science.gov (United States)

    Heckscher, Ellie S; Zarin, Aref Arzan; Faumont, Serge; Clark, Matthew Q; Manning, Laurina; Fushiki, Akira; Schneider-Mizell, Casey M; Fetter, Richard D; Truman, James W; Zwart, Maarten F; Landgraf, Matthias; Cardona, Albert; Lockery, Shawn R; Doe, Chris Q

    2015-10-21

    Bilaterally symmetric motor patterns--those in which left-right pairs of muscles contract synchronously and with equal amplitude (such as breathing, smiling, whisking, and locomotion)--are widespread throughout the animal kingdom. Yet, surprisingly little is known about the underlying neural circuits. We performed a thermogenetic screen to identify neurons required for bilaterally symmetric locomotion in Drosophila larvae and identified the evolutionarily conserved Even-skipped(+) interneurons (Eve/Evx). Activation or ablation of Eve(+) interneurons disrupted bilaterally symmetric muscle contraction amplitude, without affecting the timing of motor output. Eve(+) interneurons are not rhythmically active and thus function independently of the locomotor CPG. GCaMP6 calcium imaging of Eve(+) interneurons in freely moving larvae showed left-right asymmetric activation that correlated with larval behavior. TEM reconstruction of Eve(+) interneuron inputs and outputs showed that the Eve(+) interneurons are at the core of a sensorimotor circuit capable of detecting and modifying body wall muscle contraction.

  18. Efficient Design of Ripple Carry Adder and Carry Skip Adder with Low Quantum Cost and Low Power Consumption

    Directory of Open Access Journals (Sweden)

    Nidhi

    2014-07-01

    Full Text Available The addition of two binary numbers is the important and most frequently used arithmetic process on microprocessors, digital signal processors (DSP, and data-processing application-specific integrated circuits (ASIC. Therefore, binary adders are critical structure blocks in very large-scale integrated (VLSI circuits. Their effective application is not trivial because a costly carry spread operation involving all operand bits has to be achieved. Many different circuit constructions for binary addition have been planned over the last decades, covering a wide range of presentation characteristics. In today era, reversibility has become essential part of digital world to make digital circuits more efficient. In this paper, we have proposed a new method to reduce quantum cost for ripple carry adder and carry skip adder. The results are simulated in Xilinx by using VHDL language.

  19. Skip spawning as a reproductive strategy in Antarctic fish species: the Antarctic silverfish (Pleuragramma antarctica case study

    Directory of Open Access Journals (Sweden)

    Eva Pisano

    2015-11-01

    Full Text Available The Antarctic silverfish Pleuragramma antarctica (Notothenioidei, Nototheniidae is the most abundant pelagic fish inhabiting the frigid Antarctic coastal waters. It plays relevant roles in the local ecosystems, where it is often considered a keystone species connecting lower and upper trophic levels within the coastal marine food web. Despite its ecological relevance, and although many aspects of the Antarctic silverfish biology have already been elucidated, knowledge on important components of its life cycle, including the reproductive features, is still poor. The available data on the reproduction of the Antarctic silverfish remains fragmentary and, in particular, information on the silverfish from the Ross Sea is lacking, in spite of the intensive ecological studies on this unique region and the fact that the only known nursery ground for this species is located in Terra Nova Bay (Ross Sea where hatching occurs under the sea-ice. We present the here first description of the reproductive features of Antarctic silverfish from fish sampled in late Summer (mid February 2008 in the Ross Sea. The gross reproductive traits are consistent with those reported from other Antarctic sectors but, interestingly, widespread follicular atresia has been detected in the fish examined. The intensity and prevalence of such a follicular degenerative process suggest that skip spawning (not all adults spawn every year could be a reproductive strategy of this Antarctic species. Such an hypothesis is discussed both on the short-term and on the evolutionary time-scale. Overall, the data presented also contribute to support the acknowledgment that skip-spawning is a diffuse phenomenon in fishes.

  20. Skipping breakfast reduces energy intake and physical activity in healthy women who are habitual breakfast eaters: A randomized crossover trial.

    Science.gov (United States)

    Yoshimura, Eiichi; Hatamoto, Yoichi; Yonekura, Satomi; Tanaka, Hiroaki

    2017-03-09

    Many epidemiological studies indicate a positive relationship between skipping breakfast (SB) and obesity. However, it is unclear whether SB affects energy intake and physical activity during the day. The objective of the present study was to evaluate the acute effects of SB on energy intake and physical activity under free-living conditions. The present study used a randomized, crossover trial design comparing eating breakfast (EB) and SB days. Twenty lean, healthy women 21-25years old who were habitual breakfast eaters (≥5daysperweek) took part in this study. On EB days, participants were provided a standard breakfast (542kcal). The meals and physical activity after breakfast were under free-living conditions. The meals consisted of foods available at supermarkets, restaurants, and convenience stores. Dietary intake was evaluated by adding values from food labels. Physical activity was assessed using a tri-axial accelerometer. Energy intake at lunch was significantly increased after SB compared with EB (+131±188kcal; p=0.0057). Total energy intake per day was significantly lower after SB compared with EB (-262±428kcal, p=0.013). Physical activity energy expenditure was slightly lower after SB compared with EB (-41±75kcal in the morning, p=0.024; -56±129kcalperday, p=0.064). Step counts and time spent physically active over the whole day were not significantly different between conditions. Skipping breakfast reduced energy intake during the day and morning physical activity in healthy women who were habitual breakfast eaters. The decreased energy expenditure related to physical activity after SB did not exceed the decreased energy intake.