Sample records for noncoding repeat expansions

  1. Expansion of protein domain repeats.

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    Asa K Björklund


    Full Text Available Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e.g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  2. DNA triplet repeat expansion and mismatch repair. (United States)

    Iyer, Ravi R; Pluciennik, Anna; Napierala, Marek; Wells, Robert D


    DNA mismatch repair is a conserved antimutagenic pathway that maintains genomic stability through rectification of DNA replication errors and attenuation of chromosomal rearrangements. Paradoxically, mutagenic action of mismatch repair has been implicated as a cause of triplet repeat expansions that cause neurological diseases such as Huntington disease and myotonic dystrophy. This mutagenic process requires the mismatch recognition factor MutSβ and the MutLα (and/or possibly MutLγ) endonuclease, and is thought to be triggered by the transient formation of unusual DNA structures within the expanded triplet repeat element. This review summarizes the current knowledge of DNA mismatch repair involvement in triplet repeat expansion, which encompasses in vitro biochemical findings, cellular studies, and various in vivo transgenic animal model experiments. We present current mechanistic hypotheses regarding mismatch repair protein function in mediating triplet repeat expansions and discuss potential therapeutic approaches targeting the mismatch repair pathway.

  3. Electrochemical detection of DNA triplet repeat expansion

    Czech Academy of Sciences Publication Activity Database

    Fojta, Miroslav; Havran, Luděk; Vojtíšková, Marie; Paleček, Emil


    Roč. 126, č. 21 (2004), s. 6532-6533 ISSN 0002-7863 R&D Projects: GA AV ČR IAA4004402; GA AV ČR IBS5004355; GA AV ČR KJB4004302; GA AV ČR KSK4055109 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA triplet repeat expansion * PCR amplification * neurodegenerative diseases Subject RIV: BO - Biophysics Impact factor: 6.903, year: 2004

  4. Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures (United States)

    McFarland, Karen N.; Liu, Jilin; Landrian, Ivette; Zeng, Desmond; Raskin, Salmo; Moscovich, Mariana; Gatto, Emilia M.; Ochoa, Adriana; Teive, Hélio A. G.; Rasmussen, Astrid; Ashizawa, Tetsuo


    Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed “ATCCT interruptions,” experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confers a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling. PMID:24318420

  5. CTG trinucleotide repeat "big jumps": large expansions, small mice.

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    Mário Gomes-Pereira


    Full Text Available Trinucleotide repeat expansions are the genetic cause of numerous human diseases, including fragile X mental retardation, Huntington disease, and myotonic dystrophy type 1. Disease severity and age of onset are critically linked to expansion size. Previous mouse models of repeat instability have not recreated large intergenerational expansions ("big jumps", observed when the repeat is transmitted from one generation to the next, and have never attained the very large tract lengths possible in humans. Here, we describe dramatic intergenerational CTG*CAG repeat expansions of several hundred repeats in a transgenic mouse model of myotonic dystrophy type 1, resulting in increasingly severe phenotypic and molecular abnormalities. Homozygous mice carrying over 700 trinucleotide repeats on both alleles display severely reduced body size and splicing abnormalities, notably in the central nervous system. Our findings demonstrate that large intergenerational trinucleotide repeat expansions can be recreated in mice, and endorse the use of transgenic mouse models to refine our understanding of triplet repeat expansion and the resulting pathogenesis.

  6. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats.

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    Zhenming Yu

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating, rapidly progressive disease leading to paralysis and death. Recently, intermediate length polyglutamine (polyQ repeats of 27-33 in ATAXIN-2 (ATXN2, encoding the ATXN2 protein, were found to increase risk for ALS. In ATXN2, polyQ expansions of ≥ 34, which are pure CAG repeat expansions, cause spinocerebellar ataxia type 2. However, similar length expansions that are interrupted with other codons, can present atypically with parkinsonism, suggesting that configuration of the repeat sequence plays an important role in disease manifestation in ATXN2 polyQ expansion diseases. Here we determined whether the expansions in ATXN2 associated with ALS were pure or interrupted CAG repeats, and defined single nucleotide polymorphisms (SNPs rs695871 and rs695872 in exon 1 of the gene, to assess haplotype association. We found that the expanded repeat alleles of 40 ALS patients and 9 long-repeat length controls were all interrupted, bearing 1-3 CAA codons within the CAG repeat. 21/21 expanded ALS chromosomes with 3CAA interruptions arose from one haplotype (GT, while 18/19 expanded ALS chromosomes with <3CAA interruptions arose from a different haplotype (CC. Moreover, age of disease onset was significantly earlier in patients bearing 3 interruptions vs fewer, and was distinct between haplotypes. These results indicate that CAG repeat expansions in ATXN2 associated with ALS are uniformly interrupted repeats and that the nature of the repeat sequence and haplotype, as well as length of polyQ repeat, may play a role in the neurological effect conferred by expansions in ATXN2.

  7. Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity. (United States)

    Maag, Jesper L V; Panja, Debabrata; Sporild, Ida; Patil, Sudarshan; Kaczorowski, Dominik C; Bramham, Clive R; Dinger, Marcel E; Wibrand, Karin


    Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.

  8. A dynamic trinucleotide repeat (TNR) expansion in the DMD gene. (United States)

    Kekou, Kyriaki; Sofocleous, Christalena; Papadimas, George; Petichakis, Dimitris; Svingou, Maria; Pons, Roser-Maria; Vorgia, Pelagia; Gika, Artemis; Kitsiou-Tzeli, Sophia; Kanavakis, Emmanuel


    Dystrophinopathies are allelic X-linked myopathies caused by large deletions/duplications or small lesions along the DMD gene. An unexpected dynamic trinucleotide (GAA) expansion, ranging from ∼59 to 82 pure GAA repeats, within the DMD intron 62, was revealed to segregate through three family generations. From the pedigree, two female patients were referred for DMD investigation due to chronic myopathy and a muscle biopsy compatible with dystrophinopathy. As the size of the GAA repeat is limited to 11-33 within the general population our findings may provide a novel insight towards a Trinucleotide Repeat Expansion. Whether this TNR has an impact on the reported phenotype remains to be resolved. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity. (United States)

    Cusanelli, Emilio; Chartrand, Pascal


    Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer.

  10. Idiopathic Parkinson's disease phenotype related to C9ORF72 repeat expansions: contribution of the neuropsychological assessment. (United States)

    Annan, Mariam; Beaufils, Émilie; Viola, Ursule-Catherine; Vourc'h, Patrick; Hommet, Caroline; Mondon, Karl


    Expanded GGGGCC hexanucleotide repeats in the non-coding region of the C9ORF72 gene was recently identified as being responsible for over 40% of the cases of amyotrophic lateral sclerosis associated with frontotemporal lobar degeneration, in various extrapyramidal syndromes including supranuclear gaze palsy and corticobasal degeneration, and in addition, has been found to be a rare genetic cause of isolated Parkinsonism. To our knowledge, there is no published data concerning the neuropsychological evaluation of patients diagnosed with idiopathic Parkinson's disease related with C9ORF72 repeat expansions. We report the results of the comprehensive neuropsychological evaluation in a newly described case in the literature (the sixth) of a patient presenting isolated idiopathic Parkinson's disease associated with C9ORF72 repeat expansions.The decrease in the patient's prefrontal functions resulted in a slight decrease in global efficiency. These abnormalities did not appear to be different, with respect to the deficit observed and the intensity of the cognitive impairment, from those classically observed in cases of sporadic idiopathic Parkinson's disease. Our patient also exhibited a significant impairment in visual gnosis. If confirmed in other patients, visuoperceptive deficits in idiopathic Parkinson's disease could represent a red flag that should prompt the clinician to perform addition diagnostic procedures. A thorough neuropsychological assessment may prove to be useful for detecting idiopathic Parkinson's disease in patients who are suspected of having repeat abnormalities of C9ORF72 expansions.

  11. The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion


    Guo, Pei; Lam, Sik Lok


    CCTG repeat expansions in intron 1 of the cellular nucleic acid-binding protein gene are associated with myotonic dystrophy type 2. Recently, we have reported a novel mini-dumbbell (MDB) structure formed by two CCTG or TTTA repeats, which potentially has a critical role in repeat expansions. Here we present a mechanism, called the competing MDB mechanism, to explain how the formation of MDB can lead to efficient mismatch repair (MMR) escape and thus CCTG repeat expansions during DNA replicati...

  12. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

    DEFF Research Database (Denmark)

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten


    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective...

  13. C9ORF72 Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients


    Dobson-Stone, Carol; Hallupp, Marianne; Loy, Clement T.; Thompson, Elizabeth M.; Haan, Eric; Sue, Carolyn M.; Panegyres, Peter K.; Razquin, Cristina; Seijo-Mart?nez, Manuel; Rene, Ramon; Gascon, Jordi; Campdelacreu, Jaume; Schmoll, Birgit; Volk, Alexander E.; Brooks, William S.


    A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in 'non-expansion...

  14. Expansion of the Spinocerebellar ataxia type 10 (SCA10 repeat in a patient with Sioux Native American ancestry.

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    Khalaf Bushara

    Full Text Available Spinocerebellar ataxia type 10 (SCA10, an autosomal dominant cerebellar ataxia, is caused by the expansion of the non-coding ATTCT pentanucleotide repeat in the ATAXIN 10 gene. To date, all cases of SCA10 are restricted to patients with ancestral ties to Latin American countries. Here, we report on a SCA10 patient with Sioux Native American ancestry and no reported Hispanic or Latino heritage. Neurological exam findings revealed impaired gait with mild, age-consistent cerebellar atrophy and no evidence of epileptic seizures. The age at onset for this patient, at 83 years of age, is the latest documented for SCA10 patients and is suggestive of a reduced penetrance allele in his family. Southern blot analysis showed an SCA10 expanded allele of 1400 repeats. Established SNPs surrounding the SCA10 locus showed a disease haplotype consistent with the previously described "SCA10 haplotype". This case suggests that the SCA10 expansion represents an early mutation event that possibly occurred during the initial peopling of the Americas.

  15. The competing mini-dumbbell mechanism: new insights into CCTG repeat expansion. (United States)

    Guo, Pei; Lam, Sik Lok


    CCTG repeat expansions in intron 1 of the cellular nucleic acid-binding protein gene are associated with myotonic dystrophy type 2. Recently, we have reported a novel mini-dumbbell (MDB) structure formed by two CCTG or TTTA repeats, which potentially has a critical role in repeat expansions. Here we present a mechanism, called the competing MDB mechanism, to explain how the formation of MDB can lead to efficient mismatch repair (MMR) escape and thus CCTG repeat expansions during DNA replication. In a long tract of CCTG repeats, two competing MDBs can be formed in any segment of three repeats. Fast exchange between these MDBs will make the commonly occupied repeat behave like a mini-loop. Further participations of the 5'- or 3'-flanking repeat in forming competing MDBs will make the mini-loop shift in the 5'- or 3'-direction, thereby providing a pathway for the mini-loop to escape from MMR. To avoid the complications due to the formation of hairpin conformers in longer CCTG repeats, we made use of TTTA repeats as model sequences to demonstrate the formation of competing MDBs and shifting of mini-loop in a long tract of repeating sequence.

  16. Nucleotide excision repair and the 26S proteasome function together to promote trinucleotide repeat expansions. (United States)

    Concannon, Claire; Lahue, Robert S


    Trinucleotide repeat (TNR) expansion underpins a number of inheritable neurological human disorders. Multiple mechanisms are thought to contribute to the expansion process. The incorrect processing of the repeat tract by DNA repair proteins can drive this mutation process forward, as expansions are suppressed following ablation of certain repair factors in mouse models and cell models of disease. Nucleotide excision repair (NER) is one repair pathway implicated in TNR instability, although most previous work focussed on TNR contractions, not expansions. Here we investigated the role of NER in modulating expansions of threshold-length (CTG·CAG) repeats in yeast. We show that both the global genome and transcription-coupled repair subpathways promote expansions of threshold-length TNRs. Furthermore, NER works with the 26S proteasome to drive expansions, based on analysis of double mutants defective in both pathways, and of Rad23, a protein involved in both NER and the shuttling of ubiquitinated proteins to the proteasome. This work provides the first evidence that both subpathways of NER can promote threshold-length TNR expansions and that NER interacts with the proteasome to drive expansions. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis. (United States)

    Farg, Manal A; Konopka, Anna; Soo, Kai Ying; Ito, Daisuke; Atkin, Julie D


    Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease affecting motor neurons. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide. The C9orf72 repeat expansion undergoes repeat-associated non-ATG (RAN) translation to produce five dipeptide repeat proteins (DRPs), including poly(GR) and poly(PR). Whilst it remains unclear how mutations in C9orf72 lead to neurodegeneration in ALS/FTD, dysfunction to the nucleolus and R loop formation are implicated as pathogenic mechanisms. These events can damage DNA and hence genome integrity. Cells activate the DNA damage response (DDR) with the aim of repairing this damage. However, if the damage cannot be repaired, apoptosis is triggered. In lumbar motor neurons from C9orf72-positive ALS patients, we demonstrate significant up-regulation of markers of the DDR compared to controls: phosphorylated histone 2AX (γ-H2AX), phosphorylated ataxia telangiectasia mutated (p-ATM), cleaved poly (ADP-Ribose) polymerase 1 (PARP-1) and tumour suppressor p53-binding protein (53BP1). Similarly, significant up-regulation of γ-H2AX and p-ATM was detected in neuronal cells expressing poly(GR)100 and poly(PR)100 compared to controls, revealing that DNA damage is triggered by the DRPs. Nucleophosmin (NPM1) is a histone chaperone induced during the DDR, which interacts with APE1 to enhance DNA repair. We also demonstrate that more NPM1 precipitates with APE1 in C9orf72 patients compared to controls. Furthermore, overexpression of NPM1 inhibits apoptosis in cells expressing poly(GR)100 and poly(PR)100. This study therefore demonstrates that DNA damage is activated by the C9orf72 repeat expansion in ALS. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email:

  18. Maternal intermediate repeat expansion into the affected range in Huntington's disease

    NARCIS (Netherlands)

    Van Belzen, M.J.; Belfroid, R.D.M.; Losekoot, M.; Walstra, G.J.M.; Van Langen, I.M.


    Background: Intermediate repeat alleles are usually stable when transmitted to the next generation. However, in a small percentage of transmissions these repeats expand into the affected range, leading to a new mutation and a sporadic patient. Until now, expansions of intermediate alleles into the

  19. Expansion and Function of Repeat Domain Proteins During Stress and Development in Plants

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    Manisha eSharma


    Full Text Available The recurrent repeats having conserved stretches of amino acids exists across all domains of life. Subsequent repetition of single sequence motif and the number and length of the minimal repeating motifs are essential characteristics innate to these proteins. The proteins with tandem peptide repeats are essential for providing surface to mediate protein-protein interactions for fundamental biological functions. Plants are enriched in tandem repeat containing proteins typically distributed into various families. This has been assumed that the occurrence of multigene repeats families in plants enable them to cope up with adverse environmental conditions and allow them to rapidly acclimatize to these conditions. The evolution, structure and function of repeat proteins have been studied in all kingdoms of life. The presence of repeat proteins is particularly profuse in multicellular organisms in comparison to prokaryotes. The precipitous expansion of repeat proteins in plants is presumed to be through internal tandem duplications. Several repeat protein gene families have been identified in plants. Such as Armadillo (ARM, Ankyrin (ANK, HEAT, Kelch-like repeats, Tetratricopeptide (TPR, Leucine rich repeats (LRR, WD40, and Pentatricopeptide repeats (PPR. The structure and functions of these repeat proteins have been extensively studied in plants suggesting a critical role of these repeating peptides in plant cell physiology, stress and development. In this review, we illustrate the structural, functional and evolutionary prospects of prolific repeat proteins in plants.

  20. Selection pressure on human STR loci and its relevance in repeat expansion disease

    KAUST Repository

    Shimada, Makoto K.


    Short Tandem Repeats (STRs) comprise repeats of one to several base pairs. Because of the high mutability due to strand slippage during DNA synthesis, rapid evolutionary change in the number of repeating units directly shapes the range of repeat-number variation according to selection pressure. However, the remaining questions include: Why are STRs causing repeat expansion diseases maintained in the human population; and why are these limited to neurodegenerative diseases? By evaluating the genome-wide selection pressure on STRs using the database we constructed, we identified two different patterns of relationship in repeat-number polymorphisms between DNA and amino-acid sequences, although both patterns are evolutionary consequences of avoiding the formation of harmful long STRs. First, a mixture of degenerate codons is represented in poly-proline (poly-P) repeats. Second, long poly-glutamine (poly-Q) repeats are favored at the protein level; however, at the DNA level, STRs encoding long poly-Qs are frequently divided by synonymous SNPs. Furthermore, significant enrichments of apoptosis and neurodevelopment were biological processes found specifically in genes encoding poly-Qs with repeat polymorphism. This suggests the existence of a specific molecular function for polymorphic and/or long poly-Q stretches. Given that the poly-Qs causing expansion diseases were longer than other poly-Qs, even in healthy subjects, our results indicate that the evolutionary benefits of long and/or polymorphic poly-Q stretches outweigh the risks of long CAG repeats predisposing to pathological hyper-expansions. Molecular pathways in neurodevelopment requiring long and polymorphic poly-Q stretches may provide a clue to understanding why poly-Q expansion diseases are limited to neurodegenerative diseases. © 2016, Springer-Verlag Berlin Heidelberg.

  1. Screening for the C9ORF72 repeat expansion in a greek frontotemporal dementia cohort. (United States)

    Kartanou, Chrisoula; Karadima, Georgia; Koutsis, Georgios; Breza, Marianthi; Papageorgiou, Sokratis G; Paraskevas, George P; Kapaki, Elisabeth; Panas, Marios


    The C9orf72 repeat expansion is a common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in European populations. A previous study has reported a high frequency of the expansion in Greek ALS. However, no data have been reported on the frequency of the expansion in Greek FTD. Currently, we investigated the frequency of the C9orfF72 expansion in a well-characterized cohort of 64 Greek FTD patients. We detected the C9orf72 repeat expansion in 9.3% of cases. Overall, 27.7% of familial and 2.2% of sporadic cases were expansion-positive. Five out of 6 cases had a diagnosis of behavioral variant FTD. All expansion-positive cases had fairly typical FTD presentations. Clinical features included motor neuron disease, Parkinsonism and hallucinations. We conclude that the overall frequency of C9orf72-positive cases in Greek FTD is high, comparable to Greek ALS, similar to some Western European, but significantly higher than some Mediterranean FTD populations.

  2. FRA2A is a CGG repeat expansion associated with silencing of AFF3.

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    Sofie Metsu


    Full Text Available Folate-sensitive fragile sites (FSFS are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID. Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship.

  3. Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion. (United States)

    Pliner, Hannah A; Mann, David M; Traynor, Bryan J


    Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects ~6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent.

  4. In vitro expansion of mammalian telomere repeats by DNA polymerase α-primase (United States)

    Nozawa, Katsura; Suzuki, Motoshi; Takemura, Masaharu; Yoshida, Shonen


    Among the polymerases, DNA polymerase α-primase is involved in lagging strand DNA synthesis. A previous report indicated that DNA polymerase α-primase initiates primer RNA synthesis with purine bases on a single-stranded G-rich telomere repeat. In this study, we found that DNA polymerase α-primase precisely initiated with adenosine opposite the 3′-side thymidine in the G-rich telomere repeat 5′-(TTAGGG)n-3′ under rATP-rich conditions. Then, DNA polymerase α-primase synthesized the nascent DNA fragments by extending the primer. It was remarkable that DNA polymerase α-primase further expanded the product DNA far beyond the length of the template DNA, as ladders of multiple hexanucleotides on polyacrylamide gel electrophoresis. Using an oligomer duplex 5′-A(GGGTTA)5-3′/5′-(TAACCC)5T-3′ as a template–primer, we show that both the Klenow fragment of Escherichia coli DNA polymerase I and HIV reverse transcriptase could expand telomere DNA sequences as well, giving products greater than the size of the template DNA. The maximum product lengths with these polymerases were ∼40–90 nt longer than the template length. Our data imply that DNA polymerases have an intrinsic activity to expand the hexanucleotide repeats of the telomere sequence by a slippage mechanism and that DNA polymerase α uses both the repeat DNA primers and the de novo RNA primers for expansion. On the other hand, a plasmid harboring a eukaryotic telomere repeat showed remarkable genetic instability in E.coli. The telomere repeats exhibited either expansions or deletions by multiple hexanucleotide repeats during culture for a number of generations, suggesting involvement of the slippage mechanism in the instability of telomeric DNA in vivo. PMID:10931927

  5. Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1. (United States)

    Chen, Jonathan L; VanEtten, Damian M; Fountain, Matthew A; Yildirim, Ilyas; Disney, Matthew D


    RNA repeat expansions cause a host of incurable, genetically defined diseases. The most common class of RNA repeats consists of trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3×CAG)] or r(CUG) [r(3×CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics. The 1 × 1 internal loops of r(3×CAG) are stabilized by one-hydrogen bond (cis Watson-Crick/Watson-Crick) AA pairs, while those of r(3×CUG) prefer one- or two-hydrogen bond (cis Watson-Crick/Watson-Crick) UU pairs. Assigned chemical shifts for the residues depended on the identity of neighbors or next nearest neighbors. Additional insights into the dynamics of these RNA constructs were gained by molecular dynamics simulations and a discrete path sampling method. Results indicate that the global structures of the RNA are A-form and that the loop regions are dynamic. The results will be useful for understanding the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics.

  6. Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7. (United States)

    Trang, Heather; Stanley, Sabrina Y; Thorner, Paul; Faghfoury, Hannaneh; Schulze, Andreas; Hawkins, Cynthia; Pearson, Christopher E; Yoon, Grace


    We report the first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of (CAG)45 expands to lengths as large as (CAG)92-250. A 38-year-old woman with classic SCA7 (and a son, who died at age 3 years) had pronounced cerebellar atrophy and a renal biopsy specimen that showed focal segmental glomerulosclerosis with abnormal podocytes containing cytoplasmic inclusions. Polymerase chain reaction amplification across the SCA7 repeat tract assessed expansion levels in tissues of the affected son. High levels of somatic CAG instability were observed in blood, kidney, and skeletal muscle. This transmitted expansion is considerably larger than previously reported maternal transmission expansions of 5 to 10 gained repeats. We document the first intertissue CAG instability reported to date in patients with SCA7, similar to SCA7 mouse models. Infantile SCA7, which is often paternally transmitted, can rarely arise by maternal transmission, which has implications for diagnosis and counseling among families of patients with SCA7.

  7. Trinucleotide repeat expansion of TATA-binding protein gene associated with Parkinson's disease: A Thai multicenter study. (United States)

    Choubtum, Lulin; Witoonpanich, Pirada; Kulkantrakorn, Kongkiat; Hanchaiphiboolkul, Suchat; Pongpakdee, Sunsanee; Tiamkao, Somsak; Pulkes, Teeratorn


    Spinocerebellar ataxia type 17 (SCA17) is an inherited cerebellar degeneration associated with trinucleotide repeat expansions in the TATA-binding protein gene (TBP). Low-range expansions of TBP have recently been described in association with Parkinson's disease (PD). However, these low-range expansion alleles were also observed in healthy individuals. Prior distinct findings may result from reduced penetrance or age-dependent susceptibility, which may influence phenotypic expression. A case-control study of 456 PD patients and 374 control subjects was conducted. Data and blood samples were collected during 2008-2013. Control subjects were individuals over 65 years old without parkinsonism. Sizes of TBP trinucleotide repeats were analyzed. All available carriers of the TBP repeat of ≥40 repeats were re-examined. A high prevalence of carriers of TBP repeat expansion ≥41 developed PD, mainly at an advanced age. Half of these carriers had onset after 70 years of age (range 34-84). Seven participants carried expansion alleles of ≥42, and all had PD. Fourteen participants (six patients and eight controls) carried a heterozygous 41-repeat allele. At the current mean age of 79 years and mean follow-up period of 4 years, three out of the eight control carriers of the 41-repeat allele developed PD, while none of the thirteen asymptomatic carriers of the 40-repeat allele did. A high prevalence of PD was observed in carriers of low-range expansions of TBP (41-45 repeats), especially in elderly. This finding suggests that cut-off value for pathological TBP repeat expansion appear to be 41. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Facial emotion recognition in myotonic dystrophy type 1 correlates with CTG repeat expansion

    Directory of Open Access Journals (Sweden)

    Stefan Winblad


    Full Text Available We investigated the ability of patients with myotonic dystrophy type 1 to recognise basic facial emotions. We also explored the relationship between facial emotion recognition, neuropsychological data, personality, and CTG repeat expansion data in the DM-1 group. In total, 50 patients with DM-1 (28 women and 22 men participated, with 41 healthy controls. Recognition of facial emotional expressions was assessed using photographs of basic emotions. A set of tests measured cognition and personality dimensions, and CTG repeat size was quantified in blood lymphocytes. Patients with DM-1 showed impaired recognition of facial emotions compared with controls. A significant negative correlation was found between total score of emotion recognition in a forced choice task and CTG repeat size. Furthermore, specific cognitive functions (vocabulary, visuospatial construction ability, and speed and personality dimensions (reward dependence and cooperativeness correlated with scores on the forced choice emotion recognition task.These findings revealed a CTG repeat dependent facial emotion recognition deficit in the DM-1 group, which was associated with specific neuropsychological functions. Furthermore, a correlation was found between facial emotional recognition ability and personality dimensions associated with sociability. This adds a new clinically relevant dimension in the cognitive deficits associated with DM-1.

  9. Mimosoid legume plastome evolution: IR expansion, tandem repeat expansions, and accelerated rate of evolution in clpP. (United States)

    Dugas, Diana V; Hernandez, David; Koenen, Erik J M; Schwarz, Erika; Straub, Shannon; Hughes, Colin E; Jansen, Robert K; Nageswara-Rao, Madhugiri; Staats, Martijn; Trujillo, Joshua T; Hajrah, Nahid H; Alharbi, Njud S; Al-Malki, Abdulrahman L; Sabir, Jamal S M; Bailey, C Donovan


    The Leguminosae has emerged as a model for studying angiosperm plastome evolution because of its striking diversity of structural rearrangements and sequence variation. However, most of what is known about legume plastomes comes from few genera representing a subset of lineages in subfamily Papilionoideae. We investigate plastome evolution in subfamily Mimosoideae based on two newly sequenced plastomes (Inga and Leucaena) and two recently published plastomes (Acacia and Prosopis), and discuss the results in the context of other legume and rosid plastid genomes. Mimosoid plastomes have a typical angiosperm gene content and general organization as well as a generally slow rate of protein coding gene evolution, but they are the largest known among legumes. The increased length results from tandem repeat expansions and an unusual 13 kb IR-SSC boundary shift in Acacia and Inga. Mimosoid plastomes harbor additional interesting features, including loss of clpP intron1 in Inga, accelerated rates of evolution in clpP for Acacia and Inga, and dN/dS ratios consistent with neutral and positive selection for several genes. These new plastomes and results provide important resources for legume comparative genomics, plant breeding, and plastid genetic engineering, while shedding further light on the complexity of plastome evolution in legumes and angiosperms.

  10. Positive selection of a pre-expansion CAG repeat of the human SCA2 gene.

    Directory of Open Access Journals (Sweden)

    Fuli Yu


    Full Text Available A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2. Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG8CAA(CAG4CAA(CAG8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (-2.20, p < 0.01 on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.

  11. Positive Selection of a Pre-Expansion CAG Repeat of the Human SCA2 Gene.

    Directory of Open Access Journals (Sweden)


    Full Text Available A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2. Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG(8CAA(CAG(4CAA(CAG(8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (-2.20, p < 0.01 on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.

  12. NRF2/Long Noncoding RNA ROR Signaling Regulates Mammary Stem Cell Expansion and Protects against Estrogen Genotoxicity* (United States)

    Zhang, Yongshu; Xia, Jixiang; Li, Qinglin; Yao, Yuan; Eades, Gabriel; Gernapudi, Ramkishore; Duru, Nadire; Kensler, Thomas W.; Zhou, Qun


    Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression in embryonic stem cell (ESC) self-renewal and differentiation. In ESCs, lncRNAs are regulated at the genetic level via transcription factor binding to lncRNA gene promoters. Here we demonstrate that the key cytoprotective transcription factor NRF2 controls lncRNA expression in mammary stem cells. By profiling lncRNAs in wild-type and NRF2 knockdown mammary stem cells, we demonstrate that the lncRNA ROR, a regulator of embryonic stem cell pluripotency, is overexpressed upon NRF2 knockdown. We performed promoter analyses and examined predicted NRF2 binding elements in the ROR promoter using luciferase reporter constructs of a ROR promoter deletion series. Our studies revealed that NRF2 binds to two specific NRF2 response elements flanking the ROR promoter and that these two NRF2 response elements are equally important to suppress ROR transcription. In addition, we identified associated H3K27me3 chromatin modification and EZH2 binding at the ROR promoter that was dependent on NRF2 binding. We observed that NRF2 knockdown or ROR overexpression leads to increased stem cell self-renewal in mammary stem cells. Furthermore, we demonstrate Nrf2 regulation of the mammary stem cell population in vivo. These observations provide further evidence for the critical role of NRF2 in maintaining normal stem cell subpopulations in mammary epithelium. PMID:25231996

  13. NRF2/long noncoding RNA ROR signaling regulates mammary stem cell expansion and protects against estrogen genotoxicity. (United States)

    Zhang, Yongshu; Xia, Jixiang; Li, Qinglin; Yao, Yuan; Eades, Gabriel; Gernapudi, Ramkishore; Duru, Nadire; Kensler, Thomas W; Zhou, Qun


    Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression in embryonic stem cell (ESC) self-renewal and differentiation. In ESCs, lncRNAs are regulated at the genetic level via transcription factor binding to lncRNA gene promoters. Here we demonstrate that the key cytoprotective transcription factor NRF2 controls lncRNA expression in mammary stem cells. By profiling lncRNAs in wild-type and NRF2 knockdown mammary stem cells, we demonstrate that the lncRNA ROR, a regulator of embryonic stem cell pluripotency, is overexpressed upon NRF2 knockdown. We performed promoter analyses and examined predicted NRF2 binding elements in the ROR promoter using luciferase reporter constructs of a ROR promoter deletion series. Our studies revealed that NRF2 binds to two specific NRF2 response elements flanking the ROR promoter and that these two NRF2 response elements are equally important to suppress ROR transcription. In addition, we identified associated H3K27me3 chromatin modification and EZH2 binding at the ROR promoter that was dependent on NRF2 binding. We observed that NRF2 knockdown or ROR overexpression leads to increased stem cell self-renewal in mammary stem cells. Furthermore, we demonstrate Nrf2 regulation of the mammary stem cell population in vivo. These observations provide further evidence for the critical role of NRF2 in maintaining normal stem cell subpopulations in mammary epithelium. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Molecular genetic and clinical characterization of myotonic dystrophy type 1 patients carrying variant repeats within DMPK expansions. (United States)

    Pešović, Jovan; Perić, S; Brkušanin, M; Brajušković, G; Rakočević-Stojanović, V; Savić-Pavićević, Dušanka


    Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the DMPK gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the DMPK expansions have emerged as potential disease modifiers. The frequency of variant expanded alleles was estimated in 242 DM1 patients from 174 Serbian families using repeat-primed PCR (RP-PCR). The patterns of variant repeats were determined by direct sequencing of RP-PCR or PCR products. PCR-based southern blot was performed to get insight into the intergenerational mutational dynamics of variant expanded alleles. All patients carrying variant repeats were clinically re-examined. Variant repeats were observed in eight patients from five families (2.9%). They were detected only at the 3' end of DMPK expansions. CCG variant repeats were present in seven patients, either as a part of regular runs of CCGCTG hexamer, individual repeats, or CCG blocks. Analyses of three intergenerational transmissions revealed a considerable stability or likely a contraction of variant expanded alleles. Intriguingly, a decrease in age at onset accompanied these transmissions. Overall, patients were characterized by a milder phenotype and/or some atypical symptoms that could be rather clinically suggestive of myotonic dystrophy type 2. In addition, the first case of de novo CTC variant repeat was observed. Variant repeats might explain a part of the phenotypic variability in a small percent of DM1 patients and likely display a stabilizing effect on the meiotic instability of DMPK expanded alleles.

  15. A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAAn Repeats Associated with Friedreich’s Ataxia

    Directory of Open Access Journals (Sweden)

    Ryan J. McGinty


    Full Text Available Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich’s ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1 of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAAn repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach.

  16. C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population. (United States)

    Koutsis, Georgios; Karadima, Georgia; Kartanou, Chrisoula; Kladi, Athina; Panas, Marios


    An expanded hexanucleotide repeat in C9ORF72 has been identified as the most common genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia in many populations, including the Greek. Recently, C9ORF72 expansions were reported as the most common genetic cause of Huntington disease (HD) phenocopies in a UK population. In the present study, we screened a selected cohort of 40 Greek patients with HD phenocopies for C9ORF72 hexanucleotide repeat expansions using repeat-primed polymerase chain reaction. We identified 2 patients (5%) with pathologic expansions. The first patient had chorea, behavioral-psychiatric disturbance, cognitive impairment, and a positive family history, fulfilling the strictest criteria for HD phenocopy. The second patient was sporadic and had parkinsonism, behavioral-psychiatric disturbance, and cognitive impairment, corresponding to a broader definition of HD phenocopy. These findings identify C9ORF72 expansions as a frequent cause of HD phenocopies in the Greek population, confirming recent findings in other populations and supporting proposed diagnostic testing for C9ORF72 expansions in patients with HD-like syndromes. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

    NARCIS (Netherlands)

    Gallagher, M.D.; Suh, E.R.; Grossman, M.; Elman, L.; McCluskey, L.; van Swieten, J.C.; Al-Sarraj, S.; Neumann, M.; Gelpi, E.; Ghetti, B.; Rohrer, J.D.; Halliday, G.; Van Broeckhoven, C.; Seilhean, D.; Shaw, P.J.; Frosch, M.P.; Alafuzoff, I.; Antonell, A.; Bogdanovic, N.; Brooks, W.; Cairns, N.J.; Cooper-Knock, J.; Cotman, C.; Cras, P.; Cruts, M.; de Deyn, P.P.; deCarli, C.; Dobson-Stone, C.; Engelborghs, S.; Fox, N.; Galasko, D.; Gearing, M.; Gijselinck, I.; Grafman, J.; Hartikainen, P.; Hatanpaa, K.J.; Highley, J.R.; Hodges, J.; Hulette, C.; Ince, P.G.; Jin, L.W.; Kirby, J.; Kofler, J.; Kril, J.; Kwok, J.B.J.; Levey, A.; Lieberman, A.; Llado, A.; Martin, J.J.; Masliah, E.; McDermott, C.J.; McKee, A.; McLean, C.; Mead, S.; Miller, C.A.; Miller, J.; Munoz, D.G.; Murrell, J.; Paulson, H.; Piguet, O.; Rossor, M.; Sanchez-Valle, R.; Sano, M.; Schneider, J.; Silbert, L.C.; Spina, S.; van der Zee, J.; Van Langenhove, T.; Warren, J.; Wharton, S.B.; White, C.L.; Woltjer, R.L.; Trojanowski, J.Q.; Lee, V.M.Y.; Van Deerlin, V.; Chen-Plotkin, A.S.


    Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B

  18. TGC repeat expansion in the TCF4 gene increases the risk of Fuchs' endothelial corneal dystrophy in Australian cases.

    Directory of Open Access Journals (Sweden)

    Abraham Kuot

    Full Text Available Fuchs' endothelial corneal dystrophy (FECD is a progressive, vision impairing disease. Common single nucleotide polymorphisms (SNPs and a trinucleotide repeat polymorphism, thymine-guanine-cytosine (TGC, in the TCF4 gene have been associated with the risk of FECD in some populations. We previously reported association of SNPs in TCF4 with FECD risk in the Australian population. The aim of this study was to determine whether TGC repeat polymorphism in TCF4 is associated with FECD in the Australian population. In 189 unrelated Australian cases with advanced late-onset FECD and 183 matched controls, the TGC repeat polymorphism located in intron 3 of TCF4 was genotyped using a short tandem repeat (STR assay. The repeat length was verified by direct sequencing in selected homozygous carriers. We found significant association between the expanded TGC repeat (≥ 40 repeats in TCF4 and advanced FECD (P = 2.58 × 10-22; OR = 15.66 (95% CI: 7.79-31.49. Genotypic analysis showed that 51% of cases (97 compared to 5% of controls (9 were heterozygous or homozygous for the expanded repeat allele. Furthermore, the repeat expansion showed stronger association than the most significantly associated SNP, rs613872, in TCF4, with the disease in the Australian cohort. This and haplotype analysis of both the polymorphisms suggest that considering both the polymorphisms together rather than either of the two alone would better predict susceptibility to FECD in the Australian population. This is the first study to report association of the TGC trinucleotide repeat expansion in TCF4 with advanced FECD in the Australian population.

  19. Expansion of the CGG repeat in fragile X in the FRM1 gene depends on the sex of the offspring

    Energy Technology Data Exchange (ETDEWEB)

    Loesch, D.Z.; Huggins, R. [La Trobe Univ., Bundoora, Victoria (Australia); Petrovic, V. [Royal Children`s Hospital, Melbourne (Australia)] [and others


    Analysis of 139 mother-to-offspring transmissions of fragile X CGG triplet repeats revealed that the repeat expansion is enhanced in mother-to-son transmissions compared with mother-to-daughter transmissions. Evidence has been based on analysis of mother-offspring differences in the size of repeat (in kb), as well as on comparisons between proportions of male and female offspring with premutations, and full mutations, inherited from mothers carrying a premutation. Mean difference in the repeat size from mother-son transmissions was 1.45 kb, compared with mother-daughter transmissions of 0.76 kb. The difference is due primarily to a greater proportion of male than female offspring with full mutation from the premutation mothers and also to a higher frequency of reduction in repeat size from mothers to daughters than from mothers to sons. Our findings suggest the possibility of an interaction of the normal X homologue in a female zygote with the FMR1 sequence on the fragile X during replication to account for the lower level of expansion in mother-to-daughter transmissions relative to mother-to-son transmissions. 27 refs., 3 figs., 2 tabs.

  20. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

    DEFF Research Database (Denmark)

    Lee, J-M; Ramos, E M; Lee, J-H


    Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound...... implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs....

  1. Expansion during PCR of short single-stranded DNA fragments carrying nonselfcomplementary dinucleotide or trinucleotide repeats

    Czech Academy of Sciences Publication Activity Database

    Reichová, Naďa; Kypr, Jaroslav


    Roč. 30, č. 3 (2003), s. 155-163 ISSN 0301-4851 R&D Projects: GA ČR GA301/01/0590 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA * PCR * expansion Subject RIV: BO - Biophysics Impact factor: 0.565, year: 2003

  2. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. (United States)

    Lee, J-M; Ramos, E M; Lee, J-H; Gillis, T; Mysore, J S; Hayden, M R; Warby, S C; Morrison, P; Nance, M; Ross, C A; Margolis, R L; Squitieri, F; Orobello, S; Di Donato, S; Gomez-Tortosa, E; Ayuso, C; Suchowersky, O; Trent, R J A; McCusker, E; Novelletto, A; Frontali, M; Jones, R; Ashizawa, T; Frank, S; Saint-Hilaire, M H; Hersch, S M; Rosas, H D; Lucente, D; Harrison, M B; Zanko, A; Abramson, R K; Marder, K; Sequeiros, J; Paulsen, J S; Landwehrmeyer, G B; Myers, R H; MacDonald, M E; Gusella, J F


    Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

  3. Accumulation of Laforin and Other Related Proteins in Canine Lafora Disease With EPM2B Repeat Expansion. (United States)

    Chambers, James K; Thongtharb, Atigan; Shiga, Takanori; Azakami, Daigo; Saito, Miyoko; Sato, Masumi; Morozumi, Motoji; Nakayama, Hiroyuki; Uchida, Kazuyuki


    Canine Lafora disease (LD) is an autosomal recessive genetic disorder causing nonfatal structural epilepsy, mainly affecting miniature wirehaired dachshunds. Repeat expansion in the EPM2B gene causes a functional impairment of the ubiquitin ligase malin which regulates glycogen metabolism. Abnormally structured glycogen accumulates and develop polyglucosan bodies predominantly in the central nervous system. The authors performed a comprehensive clinical, genetic, and pathological study of 4 LD cases affecting miniature wirehaired dachshund dogs with EPM2B repeat expansions, with systemic distribution of polyglucosan bodies and accumulation of laforin and other functionally associated proteins in the polyglucosan bodies. Myoclonic seizures first appeared at 7-9 years of age, and the dogs died at 14-16 years of age. Immunohistochemistry for calbindin revealed that the polyglucosan bodies were located in the cell bodies and dendritic processes of Purkinje cells. Polyglucosan bodies were also positive for laforin, hsp70, α/β-synuclein, ubiquitin, LC3, and p62. Laforin-positive polyglucosan bodies were located in neurofilament-positive neurons but not in GFAP-positive astrocytes. In nonneural tissues, periodic acid-Schiff (PAS)-positive polyglucosan bodies were observed in the heart, skeletal muscle, liver, apocrine sweat gland, and smooth muscle layer of the urinary bladder. In the skeletal muscle, polyglucosan bodies were observed only in type 1 fibers and not in type 2 fibers. The results indicate that although the repeat expansion of the EPM2B gene is specific to dogs, the immunohistochemical properties of polyglucosan body in canine LD are comparable to human LD. However, important phenotypic variations exist between the 2 species including the affected skeletal muscle fiber type.

  4. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion (United States)

    Lee, J.-M.; Ramos, E.M.; Lee, J.-H.; Gillis, T.; Mysore, J.S.; Hayden, M.R.; Warby, S.C.; Morrison, P.; Nance, M.; Ross, C.A.; Margolis, R.L.; Squitieri, F.; Orobello, S.; Di Donato, S.; Gomez-Tortosa, E.; Ayuso, C.; Suchowersky, O.; Trent, R.J.A.; McCusker, E.; Novelletto, A.; Frontali, M.; Jones, R.; Ashizawa, T.; Frank, S.; Saint-Hilaire, M.H.; Hersch, S.M.; Rosas, H.D.; Lucente, D.; Harrison, M.B.; Zanko, A.; Abramson, R.K.; Marder, K.; Sequeiros, J.; Paulsen, J.S.; Landwehrmeyer, G.B.; Myers, R.H.; MacDonald, M.E.; Durr, Alexandra; Rosenblatt, Adam; Frati, Luigi; Perlman, Susan; Conneally, Patrick M.; Klimek, Mary Lou; Diggin, Melissa; Hadzi, Tiffany; Duckett, Ayana; Ahmed, Anwar; Allen, Paul; Ames, David; Anderson, Christine; Anderson, Karla; Anderson, Karen; Andrews, Thomasin; Ashburner, John; Axelson, Eric; Aylward, Elizabeth; Barker, Roger A.; Barth, Katrin; Barton, Stacey; Baynes, Kathleen; Bea, Alexandra; Beall, Erik; Beg, Mirza Faisal; Beglinger, Leigh J.; Biglan, Kevin; Bjork, Kristine; Blanchard, Steve; Bockholt, Jeremy; Bommu, Sudharshan Reddy; Brossman, Bradley; Burrows, Maggie; Calhoun, Vince; Carlozzi, Noelle; Chesire, Amy; Chiu, Edmond; Chua, Phyllis; Connell, R.J.; Connor, Carmela; Corey-Bloom, Jody; Craufurd, David; Cross, Stephen; Cysique, Lucette; Santos, Rachelle Dar; Davis, Jennifer; Decolongon, Joji; DiPietro, Anna; Doucette, Nicholas; Downing, Nancy; Dudler, Ann; Dunn, Steve; Ecker, Daniel; Epping, Eric A.; Erickson, Diane; Erwin, Cheryl; Evans, Ken; Factor, Stewart A.; Farias, Sarah; Fatas, Marta; Fiedorowicz, Jess; Fullam, Ruth; Furtado, Sarah; Garde, Monica Bascunana; Gehl, Carissa; Geschwind, Michael D.; Goh, Anita; Gooblar, Jon; Goodman, Anna; Griffith, Jane; Groves, Mark; Guttman, Mark; Hamilton, Joanne; Harrington, Deborah; Harris, Greg; Heaton, Robert K.; Helmer, Karl; Henneberry, Machelle; Hershey, Tamara; Herwig, Kelly; Howard, Elizabeth; Hunter, Christine; Jankovic, Joseph; Johnson, Hans; Johnson, Arik; Jones, Kathy; Juhl, Andrew; Kim, Eun Young; Kimble, Mycah; King, Pamela; Klimek, Mary Lou; Klöppel, Stefan; Koenig, Katherine; Komiti, Angela; Kumar, Rajeev; Langbehn, Douglas; Leavitt, Blair; Leserman, Anne; Lim, Kelvin; Lipe, Hillary; Lowe, Mark; Magnotta, Vincent A.; Mallonee, William M.; Mans, Nicole; Marietta, Jacquie; Marshall, Frederick; Martin, Wayne; Mason, Sarah; Matheson, Kirsty; Matson, Wayne; Mazzoni, Pietro; McDowell, William; Miedzybrodzka, Zosia; Miller, Michael; Mills, James; Miracle, Dawn; Montross, Kelsey; Moore, David; Mori, Sasumu; Moser, David J.; Moskowitz, Carol; Newman, Emily; Nopoulos, Peg; Novak, Marianne; O'Rourke, Justin; Oakes, David; Ondo, William; Orth, Michael; Panegyres, Peter; Pease, Karen; Perlman, Susan; Perlmutter, Joel; Peterson, Asa; Phillips, Michael; Pierson, Ron; Potkin, Steve; Preston, Joy; Quaid, Kimberly; Radtke, Dawn; Rae, Daniela; Rao, Stephen; Raymond, Lynn; Reading, Sarah; Ready, Rebecca; Reece, Christine; Reilmann, Ralf; Reynolds, Norm; Richardson, Kylie; Rickards, Hugh; Ro, Eunyoe; Robinson, Robert; Rodnitzky, Robert; Rogers, Ben; Rosenblatt, Adam; Rosser, Elisabeth; Rosser, Anne; Price, Kathy; Price, Kathy; Ryan, Pat; Salmon, David; Samii, Ali; Schumacher, Jamy; Schumacher, Jessica; Sendon, Jose Luis Lópenz; Shear, Paula; Sheinberg, Alanna; Shpritz, Barnett; Siedlecki, Karen; Simpson, Sheila A.; Singer, Adam; Smith, Jim; Smith, Megan; Smith, Glenn; Snyder, Pete; Song, Allen; Sran, Satwinder; Stephan, Klaas; Stober, Janice; Sü?muth, Sigurd; Suter, Greg; Tabrizi, Sarah; Tempkin, Terry; Testa, Claudia; Thompson, Sean; Thomsen, Teri; Thumma, Kelli; Toga, Arthur; Trautmann, Sonja; Tremont, Geoff; Turner, Jessica; Uc, Ergun; Vaccarino, Anthony; van Duijn, Eric; Van Walsem, Marleen; Vik, Stacie; Vonsattel, Jean Paul; Vuletich, Elizabeth; Warner, Tom; Wasserman, Paula; Wassink, Thomas; Waterman, Elijah; Weaver, Kurt; Weir, David; Welsh, Claire; Werling-Witkoske, Chris; Wesson, Melissa; Westervelt, Holly; Weydt, Patrick; Wheelock, Vicki; Williams, Kent; Williams, Janet; Wodarski, Mary; Wojcieszek, Joanne; Wood, Jessica; Wood-Siverio, Cathy; Wu, Shuhua; Yastrubetskaya, Olga; de Yebenes, Justo Garcia; Zhao, Yong Qiang; Zimbelman, Janice; Zschiegner, Roland; Aaserud, Olaf; Abbruzzese, Giovanni; Andrews, Thomasin; Andrich, Jurgin; Antczak, Jakub; Arran, Natalie; Artiga, Maria J. Saiz; Bachoud-Lévi, Anne-Catherine; Banaszkiewicz, Krysztof; di Poggio, Monica Bandettini; Bandmann, Oliver; Barbera, Miguel A.; Barker, Roger A.; Barrero, Francisco; Barth, Katrin; Bas, Jordi; Beister, Antoine; Bentivoglio, Anna Rita; Bertini, Elisabetta; Biunno, Ida; Bjørgo, Kathrine; Bjørnevoll, Inga; Bohlen, Stefan; Bonelli, Raphael M.; Bos, Reineke; Bourne, Colin; Bradbury, Alyson; Brockie, Peter; Brown, Felicity; Bruno, Stefania; Bryl, Anna; Buck, Andrea; Burg, Sabrina; Burgunder, Jean-Marc; Burns, Peter; Burrows, Liz; Busquets, Nuria; Busse, Monica; Calopa, Matilde; Carruesco, Gemma T.; Casado, Ana Gonzalez; Catena, Judit López; Chu, Carol; Ciesielska, Anna; Clapton, Jackie; Clayton, Carole; Clenaghan, Catherine; Coelho, Miguel; Connemann, Julia; Craufurd, David; Crooks, Jenny; Cubillo, Patricia Trigo; Cubo, Esther; Curtis, Adrienne; De Michele, Giuseppe; De Nicola, A.; de Souza, Jenny; de Weert, A. Marit; de Yébenes, Justo Garcia; Dekker, M.; Descals, A. Martínez; Di Maio, Luigi; Di Pietro, Anna; Dipple, Heather; Dose, Matthias; Dumas, Eve M.; Dunnett, Stephen; Ecker, Daniel; Elifani, F.; Ellison-Rose, Lynda; Elorza, Marina D.; Eschenbach, Carolin; Evans, Carole; Fairtlough, Helen; Fannemel, Madelein; Fasano, Alfonso; Fenollar, Maria; Ferrandes, Giovanna; Ferreira, Jaoquim J.; Fillingham, Kay; Finisterra, Ana Maria; Fisher, K.; Fletcher, Amy; Foster, Jillian; Foustanos, Isabella; Frech, Fernando A.; Fullam, Robert; Fullham, Ruth; Gago, Miguel; García, RocioGarcía-Ramos; García, Socorro S.; Garrett, Carolina; Gellera, Cinzia; Gill, Paul; Ginestroni, Andrea; Golding, Charlotte; Goodman, Anna; Gørvell, Per; Grant, Janet; Griguoli, A.; Gross, Diana; Guedes, Leonor; BascuñanaGuerra, Monica; Guerra, Maria Rosalia; Guerrero, Rosa; Guia, Dolores B.; Guidubaldi, Arianna; Hallam, Caroline; Hamer, Stephanie; Hammer, Kathrin; Handley, Olivia J.; Harding, Alison; Hasholt, Lis; Hedge, Reikha; Heiberg, Arvid; Heinicke, Walburgis; Held, Christine; Hernanz, Laura Casas; Herranhof, Briggitte; Herrera, Carmen Durán; Hidding, Ute; Hiivola, Heli; Hill, Susan; Hjermind, Lena. E.; Hobson, Emma; Hoffmann, Rainer; Holl, Anna Hödl; Howard, Liz; Hunt, Sarah; Huson, Susan; Ialongo, Tamara; Idiago, Jesus Miguel R.; Illmann, Torsten; Jachinska, Katarzyna; Jacopini, Gioia; Jakobsen, Oda; Jamieson, Stuart; Jamrozik, Zygmunt; Janik, Piotr; Johns, Nicola; Jones, Lesley; Jones, Una; Jurgens, Caroline K.; Kaelin, Alain; Kalbarczyk, Anna; Kershaw, Ann; Khalil, Hanan; Kieni, Janina; Klimberg, Aneta; Koivisto, Susana P.; Koppers, Kerstin; Kosinski, Christoph Michael; Krawczyk, Malgorzata; Kremer, Berry; Krysa, Wioletta; Kwiecinski, Hubert; Lahiri, Nayana; Lambeck, Johann; Lange, Herwig; Laver, Fiona; Leenders, K.L.; Levey, Jamie; Leythaeuser, Gabriele; Lezius, Franziska; Llesoy, Joan Roig; Löhle, Matthias; López, Cristobal Diez-Aja; Lorenza, Fortuna; Loria, Giovanna; Magnet, Markus; Mandich, Paola; Marchese, Roberta; Marcinkowski, Jerzy; Mariotti, Caterina; Mariscal, Natividad; Markova, Ivana; Marquard, Ralf; Martikainen, Kirsti; Martínez, Isabel Haro; Martínez-Descals, Asuncion; Martino, T.; Mason, Sarah; McKenzie, Sue; Mechi, Claudia; Mendes, Tiago; Mestre, Tiago; Middleton, Julia; Milkereit, Eva; Miller, Joanne; Miller, Julie; Minster, Sara; Möller, Jens Carsten; Monza, Daniela; Morales, Blas; Moreau, Laura V.; Moreno, Jose L. López-Sendón; Münchau, Alexander; Murch, Ann; Nielsen, Jørgen E.; Niess, Anke; Nørremølle, Anne; Novak, Marianne; O'Donovan, Kristy; Orth, Michael; Otti, Daniela; Owen, Michael; Padieu, Helene; Paganini, Marco; Painold, Annamaria; Päivärinta, Markku; Partington-Jones, Lucy; Paterski, Laurent; Paterson, Nicole; Patino, Dawn; Patton, Michael; Peinemann, Alexander; Peppa, Nadia; Perea, Maria Fuensanta Noguera; Peterson, Maria; Piacentini, Silvia; Piano, Carla; Càrdenas, Regina Pons i; Prehn, Christian; Price, Kathleen; Probst, Daniela; Quarrell, Oliver; Quiroga, Purificacion Pin; Raab, Tina; Rakowicz, Maryla; Raman, Ashok; Raymond, Lucy; Reilmann, Ralf; Reinante, Gema; Reisinger, Karin; Retterstol, Lars; Ribaï, Pascale; Riballo, Antonio V.; Ribas, Guillermo G.; Richter, Sven; Rickards, Hugh; Rinaldi, Carlo; Rissling, Ida; Ritchie, Stuart; Rivera, Susana Vázquez; Robert, Misericordia Floriach; Roca, Elvira; Romano, Silvia; Romoli, Anna Maria; Roos, Raymond A.C.; Røren, Niini; Rose, Sarah; Rosser, Elisabeth; Rosser, Anne; Rossi, Fabiana; Rothery, Jean; Rudzinska, Monika; Ruíz, Pedro J. García; Ruíz, Belan Garzon; Russo, Cinzia Valeria; Ryglewicz, Danuta; Saft, Carston; Salvatore, Elena; Sánchez, Vicenta; Sando, Sigrid Botne; Šašinková, Pavla; Sass, Christian; Scheibl, Monika; Schiefer, Johannes; Schlangen, Christiane; Schmidt, Simone; Schöggl, Helmut; Schrenk, Caroline; Schüpbach, Michael; Schuierer, Michele; Sebastián, Ana Rojo; Selimbegovic-Turkovic, Amina; Sempolowicz, Justyna; Silva, Mark; Sitek, Emilia; Slawek, Jaroslaw; Snowden, Julie; Soleti, Francesco; Soliveri, Paola; Sollom, Andrea; Soltan, Witold; Sorbi, Sandro; Sorensen, Sven Asger; Spadaro, Maria; Städtler, Michael; Stamm, Christiane; Steiner, Tanja; Stokholm, Jette; Stokke, Bodil; Stopford, Cheryl; Storch, Alexander; Straßburger, Katrin; Stubbe, Lars; Sulek, Anna; Szczudlik, Andrzej; Tabrizi, Sarah; Taylor, Rachel; Terol, Santiago Duran-Sindreu; Thomas, Gareth; Thompson, Jennifer; Thomson, Aileen; Tidswell, Katherine; Torres, Maria M. Antequera; Toscano, Jean; Townhill, Jenny; Trautmann, Sonja; Tucci, Tecla; Tuuha, Katri; Uhrova, Tereza; Valadas, Anabela; van Hout, Monique S.E.; van Oostrom, J.C.H.; van Vugt, Jeroen P.P.; vanm, Walsem Marleen R.; Vandenberghe, Wim; Verellen-Dumoulin, Christine; Vergara, Mar Ruiz; Verstappen, C.C.P.; Verstraelen, Nichola; Viladrich, Celia Mareca; Villanueva, Clara; Wahlström, Jan; Warner, Thomas; Wehus, Raghild; Weindl, Adolf; Werner, Cornelius J.; Westmoreland, Leann; Weydt, Patrick; Wiedemann, Alexandra; Wild, Edward; Wild, Sue; Witjes-Ané, Marie-Noelle; Witkowski, Grzegorz; Wójcik, Magdalena; Wolz, Martin; Wolz, Annett; Wright, Jan; Yardumian, Pam; Yates, Shona; Yudina, Elizaveta; Zaremba, Jacek; Zaugg, Sabine W.; Zdzienicka, Elzbieta; Zielonka, Daniel; Zielonka, Euginiusz; Zinzi, Paola; Zittel, Simone; Zucker, Birgrit; Adams, John; Agarwal, Pinky; Antonijevic, Irina; Beck, Christopher; Chiu, Edmond; Churchyard, Andrew; Colcher, Amy; Corey-Bloom, Jody; Dorsey, Ray; Drazinic, Carolyn; Dubinsky, Richard; Duff, Kevin; Factor, Stewart; Foroud, Tatiana; Furtado, Sarah; Giuliano, Joe; Greenamyre, Timothy; Higgins, Don; Jankovic, Joseph; Jennings, Dana; Kang, Un Jung; Kostyk, Sandra; Kumar, Rajeev; Leavitt, Blair; LeDoux, Mark; Mallonee, William; Marshall, Frederick; Mohlo, Eric; Morgan, John; Oakes, David; Panegyres, Peter; Panisset, Michel; Perlman, Susan; Perlmutter, Joel; Quaid, Kimberly; Raymond, Lynn; Revilla, Fredy; Robertson, Suzanne; Robottom, Bradley; Sanchez-Ramos, Juan; Scott, Burton; Shannon, Kathleen; Shoulson, Ira; Singer, Carlos; Tabbal, Samer; Testa, Claudia; van, Kammen Dan; Vetter, Louise; Walker, Francis; Warner, John; Weiner, illiam; Wheelock, Vicki; Yastrubetskaya, Olga; Barton, Stacey; Broyles, Janice; Clouse, Ronda; Coleman, Allison; Davis, Robert; Decolongon, Joji; DeLaRosa, Jeanene; Deuel, Lisa; Dietrich, Susan; Dubinsky, Hilary; Eaton, Ken; Erickson, Diane; Fitzpatrick, Mary Jane; Frucht, Steven; Gartner, Maureen; Goldstein, Jody; Griffith, Jane; Hickey, Charlyne; Hunt, Victoria; Jaglin, Jeana; Klimek, Mary Lou; Lindsay, Pat; Louis, Elan; Loy, Clemet; Lucarelli, Nancy; Malarick, Keith; Martin, Amanda; McInnis, Robert; Moskowitz, Carol; Muratori, Lisa; Nucifora, Frederick; O'Neill, Christine; Palao, Alicia; Peavy, Guerry; Quesada, Monica; Schmidt, Amy; Segro, Vicki; Sperin, Elaine; Suter, Greg; Tanev, Kalo; Tempkin, Teresa; Thiede, Curtis; Wasserman, Paula; Welsh, Claire; Wesson, Melissa; Zauber, Elizabeth


    Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695 PMID:22323755

  5. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.

    LENUS (Irish Health Repository)

    Byrne, Susan


    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion.

  6. Oligonucleotide-Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion: A Perspective

    Directory of Open Access Journals (Sweden)

    Stephanie A. Fernandes


    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5–10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.

  7. Expansion of tandem repeats in sea anemone Nematostella vectensis proteome: A source for gene novelty?

    Directory of Open Access Journals (Sweden)

    Linial Michal


    Full Text Available Abstract Background The complete proteome of the starlet sea anemone, Nematostella vectensis, provides insights into gene invention dating back to the Cnidarian-Bilaterian ancestor. With the addition of the complete proteomes of Hydra magnipapillata and Monosiga brevicollis, the investigation of proteins having unique features in early metazoan life has become practical. We focused on the properties and the evolutionary trends of tandem repeat (TR sequences in Cnidaria proteomes. Results We found that 11-16% of N. vectensis proteins contain tandem repeats. Most TRs cover 150 amino acid segments that are comprised of basic units of 5-20 amino acids. In total, the N. Vectensis proteome has about 3300 unique TR-units, but only a small fraction of them are shared with H. magnipapillata, M. brevicollis, or mammalian proteomes. The overall abundance of these TRs stands out relative to that of 14 proteomes representing the diversity among eukaryotes and within the metazoan world. TR-units are characterized by a unique composition of amino acids, with cysteine and histidine being over-represented. Structurally, most TR-segments are associated with coiled and disordered regions. Interestingly, 80% of the TR-segments can be read in more than one open reading frame. For over 100 of them, translation of the alternative frames would result in long proteins. Most domain families that are characterized as repeats in eukaryotes are found in the TR-proteomes from Nematostella and Hydra. Conclusions While most TR-proteins have originated from prediction tools and are still awaiting experimental validations, supportive evidence exists for hundreds of TR-units in Nematostella. The existence of TR-proteins in early metazoan life may have served as a robust mode for novel genes with previously overlooked structural and functional characteristics.

  8. Strong population bottleneck and repeated demographic expansions of Populus adenopoda (Salicaceae) in subtropical China. (United States)

    Fan, Liqiang; Zheng, Honglei; Milne, Richard I; Zhang, Lei; Mao, Kangshan


    Glacial refugia and inter-/postglacial recolonization routes during the Quaternary of tree species in Europe and North America are well understood, but far less is known about those of tree species in subtropical eastern Asia. Thus, we have examined the phylogeographic history of Populus adenopoda (Salicaceae), one of the few poplars that naturally occur in this subtropical area. Genetic variations across the range of the species in subtropical China were surveyed using ten nuclear microsatellite loci and four chloroplast fragments (matK, trnG-psbK, psbK-psbI and ndhC-trnV). Coalescent-based analyses were used to test demographic and migration hypotheses. In addition, species distribution models (SDMs) were constructed to infer past, present and future potential distributions of the species. Thirteen chloroplast haplotypes were detected, and haplotype-rich populations were found in central and southern parts of the species' range. STRUCTURE analyses of nuclear microsatellite loci suggest obvious lineage admixture, especially in peripheral and northern populations. DIYABC analysis suggests that the species might have experienced two independent rounds of demographic expansions and a strong bottleneck in the late Quaternary. SDMs indicate that the species' range contracted during the Last Glacial Maximum (LGM), and contracted northward but expanded eastward during the Last Interglacial (LIG). Chloroplast data and SDMs suggest that P. adenopoda might have survived in multiple glacial refugia in central and southern parts of its range during the LGM. Populations of the Yunnan-Guizhou Plateau in the southern part have high chloroplast DNA diversity, but may have contributed little to the postglacial recolonization of northern and eastern parts. The three major demographic events inferred by DIYABC coincide with the initiation of the LIG, start of the LGM and end of the LGM, respectively. The species may have experienced multiple rounds of range contraction during

  9. Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.

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    Jong-Min Lee

    Full Text Available Age at onset of Huntington's disease (HD is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month, maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process.

  10. Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases. (United States)

    Koon, Alex C; Chan, Ho Yin Edwin


    For nearly a century, the fruit fly, Drosophila melanogaster , has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development.

  11. Revisiting genotype-phenotype overlap in neurogenetics: triplet-repeat expansions mimicking spastic paraplegias. (United States)

    Bettencourt, Conceição; Quintáns, Beatriz; Ros, Raquel; Ampuero, Israel; Yáñez, Zuleima; Pascual, Samuel Ignacio; de Yébenes, Justo García; Sobrido, María-Jesús


    Hereditary spastic paraplegias (HSPs) constitute a heterogeneous group of neurological disorders, characterized primarily by progressive spasticity and weakness of the lower limbs. HSPs are caused by mutations in multiple genes (at least 48 loci and 28 causative genes). The clinical spectrum of HSPs is wide and important differences have been reported between patients with distinct mutations in the same gene, or even between different family members bearing the same mutation. Many patients with HSP present clinical deficits related to the involvement of neuronal systems other than corticospinal tracts, namely, peripheral nerves, sensory, or cerebellar pathways. These cases may be difficult to differentiate from other neurological diseases (e.g., hereditary ataxias), also genetically and clinically heterogeneous. As an illustration of how overlapping this genotype-phenotype relationship is, and the difficulties that it brings upon the development of neurogenetic algorithms and databases, we review the main clinical and genetic features of HSPs, and summarize reports on cases of triplet-repeat spinocerebellar ataxias that can mimic HSP phenotypes. This complex scenario makes the necessity of high-quality, curated mutation databases even more urgent, in order to develop adequate diagnostic guidelines, correct interpretation of genetic testing, and appropriate genetic counseling. © 2012 Wiley Periodicals, Inc.

  12. Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases. (United States)

    Varela, Miguel A; Curtis, Helen J; Douglas, Andrew G L; Hammond, Suzan M; O'Loughlin, Aisling J; Sobrido, Maria J; Scholefield, Janine; Wood, Matthew J A


    Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.

  13. Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution

    Directory of Open Access Journals (Sweden)

    Wang Tian-Tian


    Full Text Available Abstract Background Nuclear receptors are hormone-regulated transcription factors whose signaling controls numerous aspects of development and physiology. Many receptors recognize DNA hormone response elements formed by direct repeats of RGKTCA motifs separated by 1 to 5 bp (DR1-DR5. Although many known such response elements are conserved in the mouse and human genomes, it is unclear to which extent transcriptional regulation by nuclear receptors has evolved specifically in primates. Results We have mapped the positions of all consensus DR-type hormone response elements in the human genome, and found that DR2 motifs, recognized by retinoic acid receptors (RARs, are heavily overrepresented (108,582 elements. 90% of these are present in Alu repeats, which also contain lesser numbers of other consensus DRs, including 50% of consensus DR4 motifs. Few DR2s are in potentially mobile AluY elements and the vast majority are also present in chimp and macaque. 95.5% of Alu-DR2s are distributed throughout subclasses of AluS repeats, and arose largely through deamination of a methylated CpG dinucleotide in a non-consensus motif present in AluS sequences. We find that Alu-DR2 motifs are located adjacent to numerous known retinoic acid target genes, and show by chromatin immunoprecipitation assays in squamous carcinoma cells that several of these elements recruit RARs in vivo. These findings are supported by ChIP-on-chip data from retinoic acid-treated HL60 cells revealing RAR binding to several Alu-DR2 motifs. Conclusion These data provide strong support for the notion that Alu-mediated expansion of DR elements contributed to the evolution of gene regulation by RARs and other nuclear receptors in primates and humans.

  14. A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families. (United States)

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


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

  15. Low-pass shotgun sequencing of the barley genome facilitates rapid identification of genes, conserved non-coding sequences and novel repeats

    Directory of Open Access Journals (Sweden)

    Graner Andreas


    Full Text Available Abstract Background Barley has one of the largest and most complex genomes of all economically important food crops. The rise of new short read sequencing technologies such as Illumina/Solexa permits such large genomes to be effectively sampled at relatively low cost. Based on the corresponding sequence reads a Mathematically Defined Repeat (MDR index can be generated to map repetitive regions in genomic sequences. Results We have generated 574 Mbp of Illumina/Solexa sequences from barley total genomic DNA, representing about 10% of a genome equivalent. From these sequences we generated an MDR index which was then used to identify and mark repetitive regions in the barley genome. Comparison of the MDR plots with expert repeat annotation drawing on the information already available for known repetitive elements revealed a significant correspondence between the two methods. MDR-based annotation allowed for the identification of dozens of novel repeat sequences, though, which were not recognised by hand-annotation. The MDR data was also used to identify gene-containing regions by masking of repetitive sequences in eight de-novo sequenced bacterial artificial chromosome (BAC clones. For half of the identified candidate gene islands indeed gene sequences could be identified. MDR data were only of limited use, when mapped on genomic sequences from the closely related species Triticum monococcum as only a fraction of the repetitive sequences was recognised. Conclusion An MDR index for barley, which was obtained by whole-genome Illumina/Solexa sequencing, proved as efficient in repeat identification as manual expert annotation. Circumventing the labour-intensive step of producing a specific repeat library for expert annotation, an MDR index provides an elegant and efficient resource for the identification of repetitive and low-copy (i.e. potentially gene-containing sequences regions in uncharacterised genomic sequences. The restriction that a particular

  16. Long noncoding RNAs are dynamically regulated during β-cell mass expansion in mouse pregnancy and control β-cell proliferation in vitro. (United States)

    Sisino, Giorgia; Zhou, Alex-Xianghua; Dahr, Niklas; Sabirsh, Alan; Soundarapandian, Mangala M; Perera, Ranjan; Larsson-Lekholm, Erik; Magnone, Maria Chiara; Althage, Magnus; Tyrberg, Björn


    Pregnancy is associated with increased β-cell proliferation driven by prolactin. Long noncoding RNAs (lncRNA) are the most abundant RNA species in the mammalian genome, yet, their functional importance is mainly elusive. This study tests the hypothesis that lncRNAs regulate β-cell proliferation in response to prolactin in the context of β-cell mass compensation in pregnancy. The expression profile of lncRNAs in mouse islets at day 14.5 of pregnancy was explored by a bioinformatics approach, further confirmed by quantitative PCR at different days of pregnancy, and islet specificity was evaluated by comparing expression in islets versus other tissues. In order to establish the role of the candidate lncRNAs we studied cell proliferation in mouse islets and the MIN6 β-cell line by EdU incorporation and cell count. We found that a group of lncRNAs is differentially regulated in mouse islets at 14.5 days of pregnancy. At different stages of pregnancy, these lncRNAs are dynamically expressed, and expression is prolactin dependent in mouse islets and MIN6 cells. One of those lncRNAs, Gm16308 (Lnc03), is dynamically regulated during pregnancy, prolactin-dependent and islet-enriched. Silencing Lnc03 in primary β-cells and MIN6 cells inhibits, whereas over-expression stimulates, proliferation even in the absence of prolactin, demonstrating that Lnc03 regulates β-cell growth. During pregnancy mouse islet proliferation is correlated with dynamic changes of lncRNA expression. In particular, Lnc03 regulates mouse β-cell proliferation and may be a crucial component of β-cell proliferation in β-cell mass adaptation in both health and disease.

  17. SCA8 Repeat Expansion: Large CTA/CTG Repeat Alleles Are More Common in Ataxic Patients, Including Those with SCA6


    Izumi, Yuishin; Maruyama, Hirofumi; Oda, Masaya; Morino, Hiroyuki; Okada, Takayuki; Ito, Hidefumi; Sasaki, Iwao; Tanaka, Hiroyasu; Komure, Osamu; Udaka, Fukashi; Nakamura, Shigenobu; Kawakami, Hideshi


    We analyzed the SCA8 CTA/CTG repeat in a large group of Japanese subjects. The frequency of large alleles (85–399 CTA/CTG repeats) was 1.9% in spinocerebellar ataxia (SCA), 0.4% in Parkinson disease, 0.3% in Alzheimer disease, and 0% in a healthy control group; the frequency was significantly higher in the group with SCA than in the control group. Homozygotes for large alleles were observed only in the group with SCA. In five patients with SCA from two families, a large SCA8 CTA/CTG repeat an...

  18. Chloroplast DNA Phylogeography Reveals Repeated Range Expansion in a Widespread Aquatic Herb Hippuris vulgaris in the Qinghai-Tibetan Plateau and Adjacent Areas (United States)

    Sun, Shan-Shan; Gituru, Robert Wahiti; Wang, Qing-Feng


    Background The Qinghai-Tibetan Plateau (QTP) is one of the most extensive habitats for alpine plants in the world. Climatic oscillations during the Quaternary ice age had a dramatic effect on species ranges on the QTP and the adjacent areas. However, how the distribution ranges of aquatic plant species shifted on the QTP in response to Quaternary climatic changes remains almost unknown. Methodology and Principal Findings We studied the phylogeography and demographic history of the widespread aquatic herb Hippuris vulgaris from the QTP and adjacent areas. Our sampling included 385 individuals from 47 natural populations of H. vulgaris. Using sequences from four chloroplast DNA (cpDNA) non-coding regions, we distinguished eight different cpDNA haplotypes. From the cpDNA variation in H. vulgaris, we found a very high level of population differentiation (GST = 0.819) but the phylogeographical structure remained obscure (NST = 0.853>GST = 0.819, P>0.05). Phylogenetic analyses revealed two main cpDNA haplotype lineages. The split between these two haplotype groups can be dated back to the mid-to-late Pleistocene (ca. 0.480 Myr). Mismatch distribution analyses showed that each of these had experienced a recent range expansion. These two expansions (ca. 0.12 and 0.17 Myr) might have begun from the different refugees before the Last Glacial Maximum (LGM). Conclusions/Significance This study initiates a research on the phylogeography of aquatic herbs in the QTP and for the first time sheds light on the response of an alpine aquatic seed plant species in the QTP to Quaternary climate oscillations. PMID:23565290

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

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


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

  20. The expansion of heterochromatin blocks in rye reflects the co-amplification of tandem repeats and adjacent transposable elements

    Czech Academy of Sciences Publication Activity Database

    Evtushenko, E.V.; Levitsky, V.G.; Elisafenko, E.A.; Gunbin, K.V.; Belousov, A.I.; Šafář, Jan; Doležel, Jaroslav; Vershinin, A.V.


    Roč. 17, MAY 4 (2016), s. 337 ISSN 1471-2164 R&D Projects: GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : Tandem repeats * Transposable elements * Subtelomeric heterochromatin Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.729, year: 2016

  1. Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation.

    Directory of Open Access Journals (Sweden)

    Guray Kuzu


    Full Text Available Dosage compensation is an essential process that equalizes transcript levels of X-linked genes between sexes by forming a domain of coordinated gene expression. Throughout the evolution of Diptera, many different X-chromosomes acquired the ability to be dosage compensated. Once each newly evolved X-chromosome is targeted for dosage compensation in XY males, its active genes are upregulated two-fold to equalize gene expression with XX females. In Drosophila melanogaster, the CLAMP zinc finger protein links the dosage compensation complex to the X-chromosome. However, the mechanism for X-chromosome identification has remained unknown. Here, we combine biochemical, genomic and evolutionary approaches to reveal that expansion of GA-dinucleotide repeats likely accumulated on the X-chromosome over evolutionary time to increase the density of CLAMP binding sites, thereby driving the evolution of dosage compensation. Overall, we present new insight into how subtle changes in genomic architecture, such as expansions of a simple sequence repeat, promote the evolution of coordinated gene expression.

  2. Expansion of GA Dinucleotide Repeats Increases the Density of CLAMP Binding Sites on the X-Chromosome to Promote Drosophila Dosage Compensation (United States)

    Chery, Jessica; Siggers, Trevor; Boor, Sonia; Bliss, Jacob; Liu, Wei; Jogl, Gerwald; Rohs, Remo; Singh, Nadia D.; Bulyk, Martha L.; Tolstorukov, Michael Y.; Larschan, Erica


    Dosage compensation is an essential process that equalizes transcript levels of X-linked genes between sexes by forming a domain of coordinated gene expression. Throughout the evolution of Diptera, many different X-chromosomes acquired the ability to be dosage compensated. Once each newly evolved X-chromosome is targeted for dosage compensation in XY males, its active genes are upregulated two-fold to equalize gene expression with XX females. In Drosophila melanogaster, the CLAMP zinc finger protein links the dosage compensation complex to the X-chromosome. However, the mechanism for X-chromosome identification has remained unknown. Here, we combine biochemical, genomic and evolutionary approaches to reveal that expansion of GA-dinucleotide repeats likely accumulated on the X-chromosome over evolutionary time to increase the density of CLAMP binding sites, thereby driving the evolution of dosage compensation. Overall, we present new insight into how subtle changes in genomic architecture, such as expansions of a simple sequence repeat, promote the evolution of coordinated gene expression. PMID:27414415

  3. Exploration of noncoding sequences in metagenomes.

    Directory of Open Access Journals (Sweden)

    Fabián Tobar-Tosse

    Full Text Available Environment-dependent genomic features have been defined for different metagenomes, whose genes and their associated processes are related to specific environments. Identification of ORFs and their functional categories are the most common methods for association between functional and environmental features. However, this analysis based on finding ORFs misses noncoding sequences and, therefore, some metagenome regulatory or structural information could be discarded. In this work we analyzed 23 whole metagenomes, including coding and noncoding sequences using the following sequence patterns: (G+C content, Codon Usage (Cd, Trinucleotide Usage (Tn, and functional assignments for ORF prediction. Herein, we present evidence of a high proportion of noncoding sequences discarded in common similarity-based methods in metagenomics, and the kind of relevant information present in those. We found a high density of trinucleotide repeat sequences (TRS in noncoding sequences, with a regulatory and adaptive function for metagenome communities. We present associations between trinucleotide values and gene function, where metagenome clustering correlate with microorganism adaptations and kinds of metagenomes. We propose here that noncoding sequences have relevant information to describe metagenomes that could be considered in a whole metagenome analysis in order to improve their organization, classification protocols, and their relation with the environment.

  4. Noncoding Elements: Evolution and Epigenetic Regulation

    KAUST Repository

    Seridi, Loqmane


    When the human genome project was completed, it revealed a surprising result. 98% of the genome did not code for protein of which more than 50% are repeats— later known as ”Junk DNA”. However, comparative genomics unveiled that many noncoding elements are evolutionarily constrained; thus luckily to have a role in genome stability and regulation. Though, their exact functions remained largely unknown. Several large international consortia such as the Functional Annotation of Mammalian Genomes (FANTOM) and the Encyclopedia of DNA Elements (ENCODE) were set to understand the structure and the regulation of the genome. Specifically, these endeavors aim to measure and reveal the transcribed components and functional elements of the genome. One of the most the striking findings of these efforts is that most of the genome is transcribed, including non-conserved noncoding elements and repeat elements. Specifically, we investigated the evolution and epigenetic properties of noncoding elements. 1. We compared genomes of evolutionarily distant species and showed the ubiquity of constrained noncoding elements in metazoa. 2. By integrating multi-omic data (such as transcriptome, nucleosome profiling, histone modifications), I conducted a comprehensive analysis of epigenetic properties (chromatin states) of conserved noncoding elements in insects. We showed that those elements have distinct and protective sequence features, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. 3. I focused on the relationship between enhancers and repetitive elements. Using Cap Analysis of Gene Expression (CAGE) and RNASeq, I compiled a full catalog of active enhancers (a class of noncoding elements) during myogenesis of human primary cells of healthy donors and donors affected by Duchenne muscular dystrophy (DMD). Comparing the two time-courses, a significant change in the epigenetic

  5. JPH3 Repeat Expansions Cause a Progressive Akinetic-Rigid Syndrome with Severe Dementia and Putaminal Rim in a Five-Generation African-American Family (United States)

    Schneider, Susanne A.; Marshall, Kate E.; Xiao, Jianfeng; LeDoux, Mark S.


    We report the clinical, neuropsychological, genetic and radiological features of a large five-generation African-American kindred from the southern United States presenting with a progressive akinetic-rigid syndrome and severe dementia, but clinically insignificant chorea, due to mutations in JPH3. Overt disease onset was in the mid-twenties to late thirties with cognitive decline, REM sleep disturbance or psychiatric features, followed by development of a levodopa-unresponsive akinetic-rigid motor syndrome. Dystonia and myoclonus were present in some subjects. A bedridden, non-verbal severely akinetic-rigid state developed within 10 to 15 years after onset. CTG repeat expansions ranged from 47 to 53. Imaging revealed generalized cerebral atrophy with severe striatal involvement and putaminal rim hyperintensity. Analysis of our kindred indicates that JPH3 mutations should be considered in the differential diagnosis of early-onset dementia and hypokinetic-rigid syndromes in individuals of African descent. Moreover, chorea may not be overtly manifest at presentation or during significant parts of the disease course. PMID:22447335

  6. Approaching TERRA Firma: Genomic Functions of Telomeric Noncoding RNA. (United States)

    Roake, Caitlin M; Artandi, Steven E


    Functions of the telomeric repeat-containing RNA (TERRA), the long noncoding RNA (lncRNA) transcribed from telomeres, have eluded researchers. In this issue of Cell, Graf el al. and Chu et al. uncover new regulatory roles for TERRA at the telomere and at distant genomic sites. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Lack of expansion of triplet repeats in the FMR1, FRAXE, and FRAXF loci in male multiplex families with autism and pervasive developmental disorders

    Energy Technology Data Exchange (ETDEWEB)

    Holden, J.J.A.; Julien-Inalsingh, C. [Queen`s Univ., Kingston (Canada); Wing, M. [Ongwanada Resource Centre, Kingston (Canada)] [and others


    Sib, twin, and family studies have shown that a genetic cause exists in many cases of autism, with a portion of cases associated with a fragile X chromosome. Three folate-sensitive fragile sites in the Xq27{r_arrow}Xq28 region have been cloned and found to have polymorphic trinucleotide repeats at the respective sites; these repeats are amplified and methylated in individuals who are positive for the different fragile sites. We have tested affected boys and their mothers from 19 families with two autistic/PDD boys for amplification and/or instability of the triplet repeats at these loci and concordance of inheritance of alleles by affected brothers. In all cases, the triplet repeat numbers were within the normal range, with no individuals having expanded or premutation-size alleles. For each locus, there was no evidence for an increased frequency of concordance, indicating that mutations within these genes are unlikely to be responsible for the autistic/PDD phenotypes in the affected boys. Thus, we think it is important to retest those autistic individuals who were cytogenetically positive for a fragile X chromosome, particularly cases where there is no family history of the fragile X syndrome, using the more accurate DNA-based testing procedures. 29 refs., 1 fig., 1 tab.

  8. Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Karen Kelley


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

  9. Maxillary Expansion


    Agarwal, Anirudh; Mathur, Rinku


    ABSTRACT Maxillary transverse discrepancy usually requires expansion of the palate by a combination of orthopedic and orthodontic tooth movements. Three expansion treatment modalities are used today: rapid maxillary expansion, slow maxillary expansion and surgically assisted maxillary expansion.This article aims to review the maxillary expansion by all the three modalities and a brief on commonly used appliances.

  10. Impact of Noncoding Satellite Repeats on Pancreatic Cancer Metastasis (United States)


    SW620 cells before xenograft implants , which was set at 1 (T2, T6, T10 = 1 wk of culture after the second, sixth, and 10th serial transplants...evident in five of 13 (38%) kidney cancers (SI Appendix, Fig. S6B). To extend our study of HSATII gene copy changes at specific loci, we performed a...Leukine Sanofi Oncology) and 300 U/ml IL-4 (RandD) in RPMI plus 5% human AB serum (Gemini Bio Products). Differentiation media was renewed on day 2 and

  11. Impact of Noncoding Satellite Repeats on Pancreatic Cancer Metastasis (United States)


    Ramaswamy S, Getz G, Iafrate AJ, Benes C, Toner M, Maheswaran S, and Haber DA, Cancer therapy. Ex vivo culture of circulating breast tumor cells for...Lawrence DP, Flaherty KT, Sequist LV, McMahon M, Bosenberg MW, Stott SL, Ting DT, Ramaswamy S, Toner M, Fisher DE, Maheswaran S, Haber DA. Isolation and

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

    Directory of Open Access Journals (Sweden)

    Veronica Julia Peschansky


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

  13. Panning for Long Noncoding RNAs

    Directory of Open Access Journals (Sweden)

    Li Yang


    Full Text Available The recent advent of high-throughput approaches has revealed widespread transcription of the human genome, leading to a new appreciation of transcription regulation, especially from noncoding regions. Distinct from most coding and small noncoding RNAs, long noncoding RNAs (lncRNAs are generally expressed at low levels, are less conserved and lack protein-coding capacity. These intrinsic features of lncRNAs have not only hampered their full annotation in the past several years, but have also generated controversy concerning whether many or most of these lncRNAs are simply the result of transcriptional noise. Here, we assess these intrinsic features that have challenged lncRNA discovery and further summarize recent progress in lncRNA discovery with integrated methodologies, from which new lessons and insights can be derived to achieve better characterization of lncRNA expression regulation. Full annotation of lncRNA repertoires and the implications of such annotation will provide a fundamental basis for comprehensive understanding of pervasive functions of lncRNAs in biological regulation.

  14. A Triplet Repeat Expansion Genetic Mouse Model of Infantile Spasms Syndrome, Arx(GCG)10+7, with Interneuronopathy, Spasms in Infancy, Persistent Seizures, and Adult Cognitive and Behavioral Impairment (United States)

    Price, Maureen G.; Yoo, Jong W.; Burgess, Daniel L.; Deng, Fang; Hrachovy, Richard A.; Frost, James D.; Noebels, Jeffrey L.


    Infantile spasms syndrome (ISS) is a catastrophic pediatric epilepsy with motor spasms, persistent seizures, mental retardation, and in some cases, autism. One of its monogenic causes is an insertion mutation (c.304ins (GCG)7) on the X chromosome, expanding the first polyalanine tract of the interneuron-specific transcription factor ARX from 16 to 23 alanine codons. Null mutation of the Arx gene impairs GABA- and cholinergic interneuronal migration but results in a neonatal lethal phenotype. We developed the first viable genetic mouse model of ISS that spontaneously recapitulates salient phenotypic features of the human triplet-repeat expansion mutation. Arx (GCG)10+7 (“Arx Plus7”) pups display abnormal spasm-like myoclonus and other key EEG features, including multifocal spikes, electrodecremental episodes, and spontaneous seizures persisting into maturity. The neurobehavioral profile of Arx mutants was remarkable for lowered anxiety, impaired associative learning, and abnormal social interaction. Laminar decreases of Arx+ cortical interneurons and a selective reduction of calbindin-, but not parvalbumin- or calretinin-expressing interneurons in neocortical layers and hippocampus indicate that specific classes of synaptic inhibition are missing from the adult forebrain, providing a basis for the seizures and cognitive disorder. A significant reduction of calbindin, NPY-expressing and cholinergic interneurons in the mutant striatum suggest that dysinhibition within this network may contribute to the dyskinetic motor spasms. This mouse model narrows the range of critical pathogenic elements within brain inhibitory networks essential to recreate this complex neurodevelopmental syndrome. PMID:19587282

  15. The Long Non-coding RNA HOTTIP Enhances Pancreatic Cancer Cell Proliferation, Survival and Migration (United States)

    ABSTRACTHOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expres...

  16. Long noncoding RNAs and atherosclerosis. (United States)

    Zhou, Tian; Ding, Jia-wang; Wang, Xin-an; Zheng, Xia-xia


    Atherosclerosis is universally recognized as a chronic lipid-induced inflammation of the vessel wall in response to dyslipidemia and haemodynamic stress involving dysfunction and activation of resident vascular cells as well as infiltration of leukocytes. As members of nonprotein-coding RNAs, the long noncoding RNAs (lncRNAs) are implicated in various biological processes. Accumulating evidences suggest that lncRNAs regulate the function of vascular wall, activation of macrophages, lipid metabolism and immune response. Here, we review the effects of lncRNAs on the progress of atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. The Intertwining of Transposable Elements and Non-Coding RNAs

    Directory of Open Access Journals (Sweden)

    Nicholas Delihas


    Full Text Available Growing evidence shows a close association of transposable elements (TE with non-coding RNAs (ncRNA, and a significant number of small ncRNAs originate from TEs. Further, ncRNAs linked with TE sequences participate in a wide-range of regulatory functions. Alu elements in particular are critical players in gene regulation and molecular pathways. Alu sequences embedded in both long non-coding RNAs (lncRNA and mRNAs form the basis of targeted mRNA decay via short imperfect base-pairing. Imperfect pairing is prominent in most ncRNA/target RNA interactions and found throughout all biological kingdoms. The piRNA-Piwi complex is multifunctional, but plays a major role in protection against invasion by transposons. This is an RNA-based genetic immune system similar to the one found in prokaryotes, the CRISPR system. Thousands of long intergenic non-coding RNAs (lincRNAs are associated with endogenous retrovirus LTR transposable elements in human cells. These TEs can provide regulatory signals for lincRNA genes. A surprisingly large number of long circular ncRNAs have been discovered in human fibroblasts. These serve as “sponges” for miRNAs. Alu sequences, encoded in introns that flank exons are proposed to participate in RNA circularization via Alu/Alu base-pairing. Diseases are increasingly found to have a TE/ncRNA etiology. A single point mutation in a SINE/Alu sequence in a human long non-coding RNA leads to brainstem atrophy and death. On the other hand, genomic clusters of repeat sequences as well as lncRNAs function in epigenetic regulation. Some clusters are unstable, which can lead to formation of diseases such as facioscapulohumeral muscular dystrophy. The future may hold more surprises regarding diseases associated with ncRNAs andTEs.

  18. Battles and hijacks: Noncoding transcription in plants

    KAUST Repository

    Ariel, Federico


    Noncoding RNAs have emerged as major components of the eukaryotic transcriptome. Genome-wide analyses revealed the existence of thousands of long noncoding RNAs (lncRNAs) in several plant species. Plant lncRNAs are transcribed by the plant-specific RNA polymerases Pol IV and Pol V, leading to transcriptional gene silencing, as well as by Pol II. They are involved in a wide range of regulatory mechanisms impacting on gene expression, including chromatin remodeling, modulation of alternative splicing, fine-tuning of miRNA activity, and the control of mRNA translation or accumulation. Recently, dual noncoding transcription by alternative RNA polymerases was implicated in epigenetic and chromatin conformation dynamics. This review integrates the current knowledge on the regulatory mechanisms acting through plant noncoding transcription. © 2015 Elsevier Ltd.

  19. Repeated Miscarriage (United States)

    ... treated? • What treatment is available if I have antiphospholipid syndrome? • What are my chances of having a successful ... may have an increased risk of repeated miscarriages. Antiphospholipid syndrome (APS) is an autoimmune disorder in which a ...

  20. Systematic analysis of coding and noncoding DNA sequences using methods of statistical linguistics (United States)

    Mantegna, R. N.; Buldyrev, S. V.; Goldberger, A. L.; Havlin, S.; Peng, C. K.; Simons, M.; Stanley, H. E.


    We compare the statistical properties of coding and noncoding regions in eukaryotic and viral DNA sequences by adapting two tests developed for the analysis of natural languages and symbolic sequences. The data set comprises all 30 sequences of length above 50 000 base pairs in GenBank Release No. 81.0, as well as the recently published sequences of C. elegans chromosome III (2.2 Mbp) and yeast chromosome XI (661 Kbp). We find that for the three chromosomes we studied the statistical properties of noncoding regions appear to be closer to those observed in natural languages than those of coding regions. In particular, (i) a n-tuple Zipf analysis of noncoding regions reveals a regime close to power-law behavior while the coding regions show logarithmic behavior over a wide interval, while (ii) an n-gram entropy measurement shows that the noncoding regions have a lower n-gram entropy (and hence a larger "n-gram redundancy") than the coding regions. In contrast to the three chromosomes, we find that for vertebrates such as primates and rodents and for viral DNA, the difference between the statistical properties of coding and noncoding regions is not pronounced and therefore the results of the analyses of the investigated sequences are less conclusive. After noting the intrinsic limitations of the n-gram redundancy analysis, we also briefly discuss the failure of the zeroth- and first-order Markovian models or simple nucleotide repeats to account fully for these "linguistic" features of DNA. Finally, we emphasize that our results by no means prove the existence of a "language" in noncoding DNA.

  1. Polymorphism of the simple sequence repeat (AAC)5 in the ...

    Indian Academy of Sciences (India)


    Dec 4, 2013 ... Simple sequence repeats (SSRs) or microsatellites have been widely used as cytogenetic markers in cereals. SSRs could be present in coding and noncoding regions, contributing to genome dynamics and evolution. Previous studies by our research group detected molecular and cytogenetic riboso-.

  2. Coding repeats and evolutionary "agility". (United States)

    Caburet, Sandrine; Cocquet, Julie; Vaiman, Daniel; Veitia, Reiner A


    The rapid generation of new shapes observed in the living world is the result of genetic variation, especially in "morphological" developmental genes. Many of these genes contain coding tandem repeats. Fondon and Garner have shown that expansions and contractions of these repeats are associated with the great diversity of morphologies observed in the domestic dog, Canis familiaris. In particular, they found that the repeat variations in two genes were significantly associated with changes in limb and skull morphology. These results open the possibility that such a mechanism contributes to the diversity of life.

  3. Visualization of enhancer-derived noncoding RNA

    CSIR Research Space (South Africa)

    Shibayama, Y


    Full Text Available Enhancers are principal regulators that allow spatiotemporal tissue-specifi c control of gene expression. While mounting evidence suggests that enhancer-derived long noncoding RNAs (long ncRNAs), including enhancer RNAs (eRNAs), are an important...

  4. Bleomycin Can Cleave an Oncogenic Noncoding RNA. (United States)

    Angelbello, Alicia J; Disney, Matthew D


    Noncoding RNAs are pervasive in cells and contribute to diseases such as cancer. A question in biomedical research is whether noncoding RNAs are targets of medicines. Bleomycin is a natural product that cleaves DNA; however, it is known to cleave RNA in vitro. Herein, an in-depth analysis of the RNA cleavage preferences of bleomycin A5 is presented. Bleomycin A5 prefers to cleave RNAs with stretches of AU base pairs. Based on these preferences and bioinformatic analysis, the microRNA-10b hairpin precursor was identified as a potential substrate for bleomycin A5. Both in vitro and cellular experiments demonstrated cleavage. Importantly, chemical cleavage by bleomycin A5 in the microRNA-10b hairpin precursors occurred near the Drosha and Dicer enzymatic processing sites and led to destruction of the microRNA. Evidently, oncogenic noncoding RNAs can be considered targets of cancer medicines and might elicit their pharmacological effects by targeting noncoding RNA. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Familial transmission of the FMR1 CGG repeat.


    Nolin, S. L.; Lewis, F. A.; Ye, L. L.; Houck, G. E.; Glicksman, A. E.; Limprasert, P.; Li, S. Y.; Zhong, N.; Ashley, A. E.; Feingold, E.; Sherman, S. L.; Brown, W. T.


    To better define the nature of FMR1 CGG-repeat expansions, changes in allele sizes for 191 families with fragile X and for 33 families with gray-zone repeats (40-60) were analyzed. Expansion of the fragile X chromosome to the full mutation was seen in 13.4% of offspring from premutation mothers with 56-59 repeats, 20.6% of those with 60-69 repeats, 57.8% of those with 70-79 repeats, 72.9% of those with 80-89 repeats, and 97.3% of those with 90-199 repeats. For premutation fathers, the majorit...

  6. Deployment Repeatability (United States)


    Deployment repeatability Olive Stohlman (NASA Langley), Mark Silver (Lincoln Labs), and Dave Waller (Ball Aerospace) Abstract Every time a...of motors or deployment drivers  Loss or redistribution of lubrication Hysteresis errors  Material creep due to time in storage and time in the...controlled or where friction changes unreliably in vacuum or thermal conditions (where these affect the deployment, and not only postdeployment stability

  7. Non-coding RNAs Functioning in Colorectal Cancer Stem Cells. (United States)

    Fanale, Daniele; Barraco, Nadia; Listì, Angela; Bazan, Viviana; Russo, Antonio

    In recent years, the hypothesis of the presence of tumor-initiating cancer stem cells (CSCs) has received a considerable support. This model suggested the existence of CSCs which, thanks to their self-renewal properties, are able to drive the expansion and the maintenance of malignant cell populations with invasive and metastatic potential in cancer. Increasing evidence showed the ability of such cells to acquire self-renewal, multipotency, angiogenic potential, immune evasion, symmetrical and asymmetrical divisions which, along with the presence of several DNA repair mechanisms, further enhance their oncogenic potential making them highly resistant to common anticancer treatments. The main signaling pathways involved in the homeostasis of colorectal (CRC) stem cells are the Wnt, Notch, Sonic Hedgehog, and Bone Morfogenic Protein (BMP) pathways, which are mostly responsible for all the features that have been widely referred to stem cells. The same pathways have been identified in colorectal cancer stem cells (CRCSCs), conferring a more aggressive phenotype compared to non-stem CRC cells. Recently, several evidences suggested that non-coding RNAs (ncRNAs) may play a crucial role in the regulation of different biological mechanisms in CRC, by modulating the expression of critical stem cell transcription factors that have been found active in CSCs. In this chapter, we will discuss the involvement of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in stemness acquisition and maintenance by CRCSCs, through the regulation of pathways modulating the CSC phenotype and growth, carcinogenesis, differentiation, and epithelial to mesenchymal transition (EMT).

  8. Noncoding sequence classification based on wavelet transform analysis: part I (United States)

    Paredes, O.; Strojnik, M.; Romo-Vázquez, R.; Vélez Pérez, H.; Ranta, R.; Garcia-Torales, G.; Scholl, M. K.; Morales, J. A.


    DNA sequences in human genome can be divided into the coding and noncoding ones. Coding sequences are those that are read during the transcription. The identification of coding sequences has been widely reported in literature due to its much-studied periodicity. Noncoding sequences represent the majority of the human genome. They play an important role in gene regulation and differentiation among the cells. However, noncoding sequences do not exhibit periodicities that correlate to their functions. The ENCODE (Encyclopedia of DNA elements) and Epigenomic Roadmap Project projects have cataloged the human noncoding sequences into specific functions. We study characteristics of noncoding sequences with wavelet analysis of genomic signals.

  9. Expansion dynamics

    International Nuclear Information System (INIS)

    Knoll, J.


    A quantum dynamical model is suggested which describes the expansion and disassembly phase of highly excited compounds formed in energetic heavy-ion collisions. First applications in two space and one time dimensional model world are discussed and qualitatively compared to standard freeze-out concepts. (orig.)

  10. expansion method

    Indian Academy of Sciences (India)

    ... (G /G)-expansion method, here in the present work, we investigate five nonlinear equations of physical importance, namely the (2+1)-dimensional Maccari system, the Pochhammer–Chree equation, the Newell–. Whitehead equation, the Fitzhugh–Nagumo equation and the Burger–Fisher equation. The organization of the ...

  11. A Role for Noncoding Variation in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Panos Roussos


    Full Text Available A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL. The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell–derived neurons for the L-type calcium channel (CACNA1C risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.

  12. Long noncoding RNAs in diseases of aging. (United States)

    Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon; Yoon, Je-Hyun; Abdelmohsen, Kotb; Gorospe, Myriam


    Aging is a process during which progressive deteriorating of cells, tissues, and organs over time lead to loss of function, disease, and death. Towards the goal of extending human health span, there is escalating interest in understanding the mechanisms that govern aging-associated pathologies. Adequate regulation of expression of coding and noncoding genes is critical for maintaining organism homeostasis and preventing disease processes. Long noncoding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression at all levels--transcriptional, post-transcriptional and post-translational. In this review, we discuss our emerging understanding of lncRNAs implicated in aging illnesses. We focus on diseases arising from age-driven impairment in energy metabolism (obesity, diabetes), the declining capacity to respond homeostatically to proliferative and damaging stimuli (cancer, immune dysfunction), and neurodegeneration. We identify the lncRNAs involved in these ailments and discuss the rising interest in lncRNAs as diagnostic and therapeutic targets to ameliorate age-associated pathologies and prolong health. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. Published by Elsevier B.V.

  13. Long Noncoding RNA Identification: Comparing Machine Learning Based Tools for Long Noncoding Transcripts Discrimination

    Directory of Open Access Journals (Sweden)

    Siyu Han


    Full Text Available Long noncoding RNA (lncRNA is a kind of noncoding RNA with length more than 200 nucleotides, which aroused interest of people in recent years. Lots of studies have confirmed that human genome contains many thousands of lncRNAs which exert great influence over some critical regulators of cellular process. With the advent of high-throughput sequencing technologies, a great quantity of sequences is waiting for exploitation. Thus, many programs are developed to distinguish differences between coding and long noncoding transcripts. Different programs are generally designed to be utilised under different circumstances and it is sensible and practical to select an appropriate method according to a certain situation. In this review, several popular methods and their advantages, disadvantages, and application scopes are summarised to assist people in employing a suitable method and obtaining a more reliable result.

  14. Universal Alternative Splicing of Noncoding Exons

    DEFF Research Database (Denmark)

    Deveson, Ira W; Brunck, Marion E; Blackburn, James


    The human transcriptome is so large, diverse, and dynamic that, even after a decade of investigation by RNA sequencing (RNA-seq), we have yet to resolve its true dimensions. RNA-seq suffers from an expression-dependent bias that impedes characterization of low-abundance transcripts. We performed......, indicative of regulation by a deeply conserved splicing code. We propose that noncoding exons are functionally modular, with alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for gene evolution....

  15. Evolution and functions of long noncoding RNAs. (United States)

    Ponting, Chris P; Oliver, Peter L; Reik, Wolf


    RNA is not only a messenger operating between DNA and protein. Transcription of essentially the entire eukaryotic genome generates a myriad of non-protein-coding RNA species that show complex overlapping patterns of expression and regulation. Although long noncoding RNAs (lncRNAs) are among the least well-understood of these transcript species, they cannot all be dismissed as merely transcriptional "noise." Here, we review the evolution of lncRNAs and their roles in transcriptional regulation, epigenetic gene regulation, and disease.

  16. Long noncoding RNAs in Diseases of Aging (United States)

    Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon; Yoon, Je-Hyun; Abdelmohsen, Kotb; Gorospe, Myriam


    Aging is a process during which progressive deteriorating of cells, tissues, and organs over time lead to loss of function, disease, and death. Towards the goal of extending human health span, there is escalating interest in understanding the mechanisms that govern aging-associated pathologies. Adequate regulation of expression of coding and noncoding genes is critical for maintaining organism homeostasis and preventing disease processes. Long noncoding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression at all levels – transcriptional, post-transcriptional and post-translational. In this review, we discuss our emerging understanding of lncRNAs implicated in aging illnesses. We focus on diseases arising from age-driven impairment in energy metabolism (obesity, diabetes), the declining capacity to respond homeostatically to proliferative and damaging stimuli (cancer, immune dysfunction), and neurodegeneration. We identify the lncRNAs involved in these ailments and discuss the rising interest in lncRNAs as diagnostic and therapeutic targets to ameliorate age-associated pathologies and prolong health. PMID:26141605

  17. Non-coding RNAs and gastric cancer (United States)

    Li, Pei-Fei; Chen, Sheng-Can; Xia, Tian; Jiang, Xiao-Ming; Shao, Yong-Fu; Xiao, Bing-Xiu; Guo, Jun-Ming


    Non-coding RNAs (ncRNAs) play key roles in development, proliferation, differentiation and apoptosis. Altered ncRNA expression is associated with gastric cancer occurrence, invasion, and metastasis. Moreover, aberrant expression of microRNAs (miRNAs) is significantly related to gastric cancer tumor stage, size, differentiation and metastasis. MiRNAs interrupt cellular signaling pathways, inhibit the activity of tumor suppressor genes, and affect the cell cycle in gastric cancer cells. Some miRNAs, including miR-21, miR-106a and miR-421, could be potential markers for the diagnosis of gastric cancer. Long non-coding RNAs (lncRNAs), a new research hotspot among cancer-associated ncRNAs, play important roles in epigenetic, transcriptional and post-transcriptional regulation. Several gastric cancer-associated lncRNAs, such as CCAT1, GACAT1, H19, and SUMO1P3, have been explored. In addition, Piwi-interacting RNAs, another type of small ncRNA that is recognized by gastroenterologists, are involved in gastric carcinogenesis, and piR-651/823 represents an efficient diagnostic biomarker of gastric cancer that can be detected in the blood and gastric juice. Small interfering RNAs also function in post-transcriptional regulation in gastric cancer and might be useful in gastric cancer treatment. PMID:24833871

  18. Non-coding RNA in Deinococcus radiodurans

    International Nuclear Information System (INIS)

    Chen Zhongzhong; Wang Liangyan; Lin Jun; Tian Bing; Hua Yuejin


    Researches on DNA damage and repair pathways of Deinococcus radiodurans show its extreme resistance to ionizing radiation, ultraviolet radiation and reactive oxygen species. Non-coding (ncRNA) RNAs are involved in a variety of processes such as transcriptional regulations, RNA processing and modification, mRNA translation, protein transportation and stability. The conserved secondary structures of intergenic regions of Deinococcus radiodurans R1 were predicted using Stochastic Context Free Grammar (SCFG) scan strategy. Results showed that 28 ncRNA families were present in the non-coding regions of the genome of Deinococcus radiodurans R1. Among these families, IRE is the largest family, followed by Histone3, tRNA, SECIS. DicF, ctRNA-pGA1 and tmRNA are one discovered in bacteria. Results from the comparison with other organisms showed that these ncRNA can be applied to the study of biological function of Deinococcus radiodurans and supply reference for the further study of DNA damage and repair mechanisms of this bacterium. (authors)

  19. Visualization of Enhancer-Derived Noncoding RNA. (United States)

    Shibayama, Youtaro; Fanucchi, Stephanie; Mhlanga, Musa M


    Enhancers are principal regulators that allow spatiotemporal tissue-specific control of gene expression. While mounting evidence suggests that enhancer-derived long noncoding RNAs (long ncRNAs), including enhancer RNAs (eRNAs), are an important component of enhancer function, their expression has not been broadly analyzed at a single cell level via imaging techniques. This protocol describes a method to image eRNA in single cells by in situ hybridization followed by tyramide signal amplification (TSA). The procedure can be multiplexed to simultaneously visualize both eRNA and protein-coding transcript at the site of transcriptional elongation, thereby permitting analysis of dynamics between the two transcript species in single cells. Our approach is not limited to eRNAs, but can be implemented on other transcripts.

  20. Non-Radioactive Detection of Trinucleotide Repeat Size Variability


    Tomé, Stéphanie; Nicole, Annie; Gomes-Pereira, Mario; Gourdon, Genevieve


    Many human diseases are associated with the abnormal expansion of unstable trinucleotide repeat sequences. The mechanisms of trinucleotide repeat size mutation have not been fully dissected, and their understanding must be grounded on the detailed analysis of repeat size distributions in human tissues and animal models. Small-pool PCR (SP-PCR) is a robust, highly sensitive and efficient PCR-based approach to assess the levels of repeat size variation, providing both quantitative and qualitati...

  1. Short tandem repeats in CdLS-causing genes: distribution and ...

    Indian Academy of Sciences (India)

    are more abundant in noncoding region as compared to cod- ing region. The genomewide study of STR has shown that. ∗For correspondence. E-mail: trinucleotide and hexanucleotide STR types are dominant in coding regions of the genome whereas other STR repeat types, such as mono, ...

  2. Global Identification of Noncoding RNAs in S. cerevisiae (United States)

    National Aeronautics and Space Administration — Genome-wide detection of novel non-coding RNAs in S. cerevisiae by modulating an RNase P pathway through the depletion of a component RPP1. Nearly 400,000 36-mer...

  3. Hypoxic regulation of the noncoding genome and NEAT1 (United States)

    Choudhry, Hani


    Activation of hypoxia pathways is both associated with and contributes to an aggressive phenotype across multiple types of solid cancers. The regulation of gene transcription by hypoxia-inducible factor (HIF) is a key element in this response. HIF directly upregulates the expression of many hundreds of protein-coding genes, which act to both improve oxygen delivery and to reduce oxygen demand. However, it is now becoming apparent that many classes of noncoding RNAs are also regulated by hypoxia, with several (e.g. micro RNAs, long noncoding RNAs and antisense RNAs) under direct transcriptional regulation by HIF. These hypoxia-regulated, noncoding RNAs may act as effectors of the indirect response to HIF by acting on specific coding transcripts or by affecting generic RNA-processing pathways. In addition, noncoding RNAs may also act as modulators of the HIF pathway, either by integrating other physiological responses or, in the case of HIF-regulated, noncoding RNAs, by providing negative or positive feedback and feedforward loops that affect upstream or downstream components of the HIF cascade. These hypoxia-regulated, noncoding transcripts play important roles in the aggressive hypoxic phenotype observed in cancer. PMID:26590207

  4. Non-Coding RNAs in Pediatric Airway Diseases

    Directory of Open Access Journals (Sweden)

    Beata Narożna


    Full Text Available Non-coding RNAs (ncRNAs are involved in the regulation of numerous biological processes and pathways and therefore have been extensively studied in human diseases. Previous reports have shown that non-coding RNAs play a crucial role in the pathogenesis and aberrant regulation of respiratory diseases. The altered expression of microRNAs (miRNAs and long non-coding RNAs in blood and also locally in sputum or exhaled breath condensate influences lung function, immune response, and disease phenotype and may be used for the development of biomarkers specific for airway disease. In this review, we provide an overview of the recent works studying the non-coding RNAs in airway diseases, with a particular focus on chronic respiratory diseases of childhood. We have chosen the most common chronic respiratory condition—asthma—and the most severe, chronic disease of the airways—cystic fibrosis. Study of the altered expression of non-coding RNAs in these diseases may be key to better understanding their pathogenesis and improving diagnosis, while also holding promise for the development of therapeutic strategies using the regulatory potential of non-coding RNAs.

  5. Annotating pathogenic non-coding variants in genic regions. (United States)

    Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi; Ren, Zhong; La Carpia, Francesca; Halvorsen, Matt; Schoch, Kelly; Ratzon, Fanni; Heinzen, Erin L; Boland, Michael J; Petrovski, Slavé; Goldstein, David B


    Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

  6. Short stories on zebrafish long noncoding RNAs. (United States)

    Haque, Shadabul; Kaushik, Kriti; Leonard, Vincent Elvin; Kapoor, Shruti; Sivadas, Ambily; Joshi, Adita; Scaria, Vinod; Sivasubbu, Sridhar


    The recent re-annotation of the transcriptome of human and other model organisms, using next-generation sequencing approaches, has unravelled a hitherto unknown repertoire of transcripts that do not have a potential to code for proteins. These transcripts have been largely classified into an amorphous class popularly known as long noncoding RNAs (lncRNA). This discovery of lncRNAs in human and other model systems have added a new layer to the understanding of gene regulation at the transcriptional and post-transcriptional levels. In recent years, three independent studies have discovered a number of lncRNAs expressed in different stages of zebrafish development and adult tissues using a high-throughput RNA sequencing approach, significantly adding to the repertoire of genes known in zebrafish. A subset of these transcripts also shows distinct and specific spatiotemporal patterns of gene expression, pointing to a tight regulatory control and potential functional roles in development, organogenesis, and/ or homeostasis. This review provides an overview of the lncRNAs in zebrafish and discusses how their discovery could provide new insights into understanding biology, explaining mutant phenotypes, and helping in potentially modeling disease processes.

  7. Triplet repeat DNA structures and human genetic disease: dynamic ...

    Indian Academy of Sciences (India)


    formed at the loop-outs. [Sinden R R, Potaman V N, Oussatcheva E A, Pearson C E, Lyubchenko Y L and Shlyakhtenko L S 2002 Triplet repeat DNA structures .... 36–39. 40–121 Huntingtin/polyglutamine expansion. Spinocerebellar ataxia 1. SCA1. 6p23. (CAG)n. 6–44. –. 39–82 (pure) Ataxin-1/polyglutamine expansion.

  8. A Repeat Look at Repeating Patterns (United States)

    Markworth, Kimberly A.


    A "repeating pattern" is a cyclical repetition of an identifiable core. Children in the primary grades usually begin pattern work with fairly simple patterns, such as AB, ABC, or ABB patterns. The unique letters represent unique elements, whereas the sequence of letters represents the core that is repeated. Based on color, shape,…

  9. Disease-associated repeat instability and mismatch repair. (United States)

    Schmidt, Monika H M; Pearson, Christopher E


    Expanded tandem repeat sequences in DNA are associated with at least 40 human genetic neurological, neurodegenerative, and neuromuscular diseases. Repeat expansion can occur during parent-to-offspring transmission, and arise at variable rates in specific tissues throughout the life of an affected individual. Since the ongoing somatic repeat expansions can affect disease age-of-onset, severity, and progression, targeting somatic expansion holds potential as a therapeutic target. Thus, understanding the factors that regulate this mutation is crucial. DNA repair, in particular mismatch repair (MMR), is the major driving force of disease-associated repeat expansions. In contrast to its anti-mutagenic roles, mammalian MMR curiously drives the expansion mutations of disease-associated (CAG)·(CTG) repeats. Recent advances have broadened our knowledge of both the MMR proteins involved in disease repeat expansions, including: MSH2, MSH3, MSH6, MLH1, PMS2, and MLH3, as well as the types of repeats affected by MMR, now including: (CAG)·(CTG), (CGG)·(CCG), and (GAA)·(TTC) repeats. Mutagenic slipped-DNA structures have been detected in patient tissues, and the size of the slip-out and their junction conformation can determine the involvement of MMR. Furthermore, the formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis (United States)

    El Khodiry, Aya; Afify, Menna; El Tayebi, Hend M


    Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren’t as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future. PMID:29434445

  11. CRISPR/Cas9-mediated noncoding RNA editing in human cancers. (United States)

    Yang, Jie; Meng, Xiaodan; Pan, Jinchang; Jiang, Nan; Zhou, Chengwei; Wu, Zhenhua; Gong, Zhaohui


    Cancer is characterized by multiple genetic and epigenetic alterations, including a higher prevalence of mutations of oncogenes and/or tumor suppressors. Mounting evidences have shown that noncoding RNAs (ncRNAs) are involved in the epigenetic regulation of cancer genes and their associated pathways. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease 9 (CRISPR/Cas9) system, a revolutionary genome-editing technology, has shed light on ncRNA-based cancer therapy. Here, we briefly introduce the classifications and mechanisms of CRISPR/Cas9 system. Importantly, we mainly focused on the applications of CRISPR/Cas9 system as a molecular tool for ncRNA (microRNA, long noncoding RNA and circular RNA, etc.) editing in human cancers, and the novel techniques that are based on CRISPR/Cas9 system. Additionally, the off-target effects and the corresponding solutions as well as the challenges toward CRISPR/Cas9 were also evaluated and discussed. Long- and short-ncRNAs have been employed as targets in precision oncology, and CRISPR/Cas9-mediated ncRNA editing may provide an excellent way to cure cancer.

  12. Structure of noncoding RNA is a determinant of function of RNA binding proteins in transcriptional regulation

    Directory of Open Access Journals (Sweden)

    Oyoshi Takanori


    Full Text Available Abstract The majority of the noncoding regions of mammalian genomes have been found to be transcribed to generate noncoding RNAs (ncRNAs, resulting in intense interest in their biological roles. During the past decade, numerous ncRNAs and aptamers have been identified as regulators of transcription. 6S RNA, first described as a ncRNA in E. coli, mimics an open promoter structure, which has a large bulge with two hairpin/stalk structures that regulate transcription through interactions with RNA polymerase. B2 RNA, which has stem-loops and unstructured single-stranded regions, represses transcription of mRNA in response to various stresses, including heat shock in mouse cells. The interaction of TLS (translocated in liposarcoma with CBP/p300 was induced by ncRNAs that bind to TLS, and this in turn results in inhibition of CBP/p300 histone acetyltransferase (HAT activity in human cells. Transcription regulator EWS (Ewing's sarcoma, which is highly related to TLS, and TLS specifically bind to G-quadruplex structures in vitro. The carboxy terminus containing the Arg-Gly-Gly (RGG repeat domains in these proteins are necessary for cis-repression of transcription activation and HAT activity by the N-terminal glutamine-rich domain. Especially, the RGG domain in the carboxy terminus of EWS is important for the G-quadruplex specific binding. Together, these data suggest that functions of EWS and TLS are modulated by specific structures of ncRNAs.

  13. The genetic signatures of noncoding RNAs.

    Directory of Open Access Journals (Sweden)

    John S Mattick


    Full Text Available The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non-protein-coding RNAs (ncRNAs, whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that

  14. Huntingtin gene repeat size variations affect risk of lifetime depression

    NARCIS (Netherlands)

    Gardiner, Sarah L.; van Belzen, Martine J.; Boogaard, Merel W.; van Roon-Mom, Willeke M. C.; Rozing, Maarten P.; van Hemert, Albert M.; Smit, Johannes H.; Beekman, Aartjan T. F.; van Grootheest, Gerard; Schoevers, Robert A.; Voshaar, Richard C. Oude; Roos, Raymund A. C.; Comijs, Hannie C.; Penninx, Brenda W. J. H.; van der Mast, Roos C.; Aziz, N. Ahmad


    Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect

  15. Huntingtin gene repeat size variations affect risk of lifetime depression

    DEFF Research Database (Denmark)

    Gardiner, Sarah L.; van Belzen, Martine J.; Boogaard, Merel W.


    Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect...

  16. Non-coding RNAs in skin cancers: An update

    Directory of Open Access Journals (Sweden)

    Shivani B. Kaushik, MD


    Full Text Available Skin cancers are the most common form of cancer in humans. They can largely be categorized into Melanoma and Non-melanoma skin cancers. The latter mainly includes Squamous Cell Carcinoma (SCC and Basal Cell Carcinoma (BCC, and have a higher incidence than melanomas. There has been a recent emergence of interest in the role of non-coding RNA's in pathogenesis of skin cancers. The transcripts which lack any protein coding capacity are called non-coding RNA. These non-coding RNA are further classified based on their length; small non-coding RNA (200 nucleotides. ncRNA They are involved at multiple transcriptional, post transcriptional and epigenetic levels, modulating cell proliferation, angiogenesis, senescence and apoptosis. Their expression pattern has also been linked to metastases, drug resistance and long term prognosis. They have both diagnostic and prognostic significance for skin cancers, and can also be a target for future therapies for cutaneous malignancies. More research is needed to further utilize their potential as therapeutic targets. Keywords: Skin cancer, Non-coding RNA's, miRNA, Cell proliferation, Invasion, Metastasis

  17. Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia


    David, Susana; Aguiar, Pedro; Antunes, Liliana; Dias, Alexandra; Morais, Anabela; Sakuntabhai, Anavaj; Lavinha, João


    Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) sev...

  18. Non-coding chloroplast regions analysis within the Orchidaceae family in Southern Ecuador

    Directory of Open Access Journals (Sweden)

    Ludeña Bertha


    Full Text Available Non-coding regions of the chloroplast genome offer interesting levels of nucleotide variation which are very useful for molecular genetics, population and phylogenetic analysis. The family Orchidaceae is represented by ca. 500 species in Southern Ecuador. In order to determine the genetic variability present in members of this family belonging to the genera Cyrtochilum, Masdevallia, Epidendrum, Polystachya, Stelis and Zelenchoa, we have analyzed four chloroplastic intergenic spacers: atpH - atpI, trnL - trnF, trnF- ndhJ and rps16 - trnQ. All these markers have shown high richness in simple sequence repeats (SSR, indels and substitutions. They resulted to be useful for species identification, phylogenetic analysis and population structure studies. Moreover the information provided by this analysis suggests that the endemic species Masdevallia deformis must be considered vulnerable and conservation strategies need to be adopted for its protection.

  19. Expression of a family of noncoding mitochondrial RNAs distinguishes normal from cancer cells. (United States)

    Burzio, Verónica A; Villota, Claudio; Villegas, Jaime; Landerer, Eduardo; Boccardo, Enrique; Villa, Luisa L; Martínez, Ronny; Lopez, Constanza; Gaete, Fancy; Toro, Viviana; Rodriguez, Ximena; Burzio, Luis O


    We reported the presence in human cells of a noncoding mitochondrial RNA that contains an inverted repeat (IR) of 815 nucleotides (nt) covalently linked to the 5' end of the mitochondrial 16S RNA (16S mtrRNA). The transcript contains a stem-loop structure and is expressed in human proliferating cells but not in resting cells. Here, we demonstrate that, in addition to this transcript, normal human proliferating cells in culture express 2 antisense mitochondrial transcripts. These transcripts also contain stem-loop structures but strikingly they are down-regulated in tumor cell lines and tumor cells present in 17 different tumor types. The differential expression of these transcripts distinguishes normal from tumor cells and might contribute a unique vision on cancer biology and diagnostics.

  20. New technologies accelerate the exploration of non-coding RNAs in horticultural plants

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Degao; Mewalal, Ritesh; Hu, Rongbin; Tuskan, Gerald A.; Yang, Xiaohan


    Non-coding RNAs (ncRNAs), that is, RNAs not translated into proteins, are crucial regulators of a variety of biological processes in plants. While protein-encoding genes have been relatively well-annotated in sequenced genomes, accounting for a small portion of the genome space in plants, the universe of plant ncRNAs is rapidly expanding. Recent advances in experimental and computational technologies have generated a great momentum for discovery and functional characterization of ncRNAs. Here we summarize the classification and known biological functions of plant ncRNAs, review the application of next-generation sequencing (NGS) technology and ribosome profiling technology to ncRNA discovery in horticultural plants and discuss the application of new technologies, especially the new genome-editing tool clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) systems, to functional characterization of plant ncRNAs.

  1. A-to-I editing of coding and non-coding RNAs by ADARs (United States)

    Nishikura, Kazuko


    Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference. PMID:26648264

  2. Selective Constraint on Noncoding Regions of Hominid Genomes.

    Directory of Open Access Journals (Sweden)


    Full Text Available An important challenge for human evolutionary biology is to understand the genetic basis of human-chimpanzee differences. One influential idea holds that such differences depend, to a large extent, on adaptive changes in gene expression. An important step in assessing this hypothesis involves gaining a better understanding of selective constraint on noncoding regions of hominid genomes. In noncoding sequence, functional elements are frequently small and can be separated by large nonfunctional regions. For this reason, constraint in hominid genomes is likely to be patchy. Here we use conservation in more distantly related mammals and amniotes as a way of identifying small sequence windows that are likely to be functional. We find that putatively functional noncoding elements defined in this manner are subject to significant selective constraint in hominids.


    Directory of Open Access Journals (Sweden)

    V. V. Tiguntsev


    Full Text Available The review presents the opening story, biogenesis and functions of basic groups of human’s small noncoding RNA: microRNA and short interfering RNA. These RNA molecules inhibit gene expression during translation by RNA interference. It was found that microRNA and short interfering RNA circulate in bioliquids and can serve as biomarkers of different human diseases because of its conservative sequences, tissue specificity and resistance to environment factors. The paper considers techniques to study noncoding RNA (cloning, bioinformatics analysis and hybridization methods: northern-blotting, RT-PCR, in situ hybridization, microarray analysis, reporter analysis. Possible noncoding RNA-targeted therapy can suggest delivery microRNA, anti-microRNA, antagomirs, microRNAsponges to target tissue by virus molecules, liposomes or nanoparticles. 

  4. Overexpression of long non-coding RNAs following exposure to xenobiotics in the aquatic midge Chironomus riparius

    Energy Technology Data Exchange (ETDEWEB)

    Martinez-Guitarte, Jose-Luis, E-mail: [Grupo de Biologia y Toxicologia Ambiental, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, UNED, Senda del Rey 9, 28040 Madrid (Spain); Planello, Rosario; Morcillo, Gloria [Grupo de Biologia y Toxicologia Ambiental, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, UNED, Senda del Rey 9, 28040 Madrid (Spain)


    Non-coding RNAs (ncRNAs) represent an important transcriptional output of eukaryotic genomes. In addition to their functional relevance as housekeeping and regulatory elements, recent studies have suggested their involvement in rather unexpected cellular functions. The aim of this work was to analyse the transcriptional behaviour of non-coding RNAs in the toxic response to pollutants in Chironomus riparius, a reference organism in aquatic toxicology. Three well-characterized long non-coding sequences were studied: telomeric repeats, Cla repetitive elements and the SINE CTRT1. Transcription levels were evaluated by RT-PCR after 24-h exposures to three current aquatic contaminants: bisphenol A (BPA), benzyl butyl phthalate (BBP) and the heavy metal cadmium (Cd). Upregulation of telomeric transcripts was found after BPA treatments. Moreover, BPA significantly activated Cla transcription, which also appeared to be increased by cadmium, whereas BBP did not affect the transcription levels of these sequences. Transcription of SINE CTRT1 was not altered by any of the chemicals tested. These data are discussed in the light of previous studies that have shown a response by long ncRNAS (lncRNAs) to cellular stressors, indicating a relationship with environmental stimuli. Our results demonstrated for the first time the ability of bisphenol A to activate non-coding sequences mainly located at telomeres and centromeres. Overall, this study provides evidence that xenobiotics can induce specific responses in ncRNAs derived from repetitive sequences that could be relevant in the toxic response, and also suggests that ncRNAs could represent a novel class of potential biomarkers in toxicological assessment.

  5. Overexpression of long non-coding RNAs following exposure to xenobiotics in the aquatic midge Chironomus riparius

    International Nuclear Information System (INIS)

    Martínez-Guitarte, José-Luis; Planelló, Rosario; Morcillo, Gloria


    Non-coding RNAs (ncRNAs) represent an important transcriptional output of eukaryotic genomes. In addition to their functional relevance as housekeeping and regulatory elements, recent studies have suggested their involvement in rather unexpected cellular functions. The aim of this work was to analyse the transcriptional behaviour of non-coding RNAs in the toxic response to pollutants in Chironomus riparius, a reference organism in aquatic toxicology. Three well-characterized long non-coding sequences were studied: telomeric repeats, Cla repetitive elements and the SINE CTRT1. Transcription levels were evaluated by RT-PCR after 24-h exposures to three current aquatic contaminants: bisphenol A (BPA), benzyl butyl phthalate (BBP) and the heavy metal cadmium (Cd). Upregulation of telomeric transcripts was found after BPA treatments. Moreover, BPA significantly activated Cla transcription, which also appeared to be increased by cadmium, whereas BBP did not affect the transcription levels of these sequences. Transcription of SINE CTRT1 was not altered by any of the chemicals tested. These data are discussed in the light of previous studies that have shown a response by long ncRNAS (lncRNAs) to cellular stressors, indicating a relationship with environmental stimuli. Our results demonstrated for the first time the ability of bisphenol A to activate non-coding sequences mainly located at telomeres and centromeres. Overall, this study provides evidence that xenobiotics can induce specific responses in ncRNAs derived from repetitive sequences that could be relevant in the toxic response, and also suggests that ncRNAs could represent a novel class of potential biomarkers in toxicological assessment.

  6. Targeting several CAG expansion diseases by a single antisense oligonucleotide.

    NARCIS (Netherlands)

    Evers, M.M.; Pepers, B.A.; Deutekom, J.C.T. van; Mulders, S.A.M.; Dunnen, J.T. den; Aartsma-Rus, A.; Ommen, G.J.B. van; Roon-Mom, W.M. van


    To date there are 9 known diseases caused by an expanded polyglutamine repeat, with the most prevalent being Huntington's disease. Huntington's disease is a progressive autosomal dominant neurodegenerative disorder for which currently no therapy is available. It is caused by a CAG repeat expansion

  7. Negative thermal expansion materials

    International Nuclear Information System (INIS)

    Evans, J.S.O.


    The recent discovery of negative thermal expansion over an unprecedented temperature range in ZrW 2 O 8 (which contracts continuously on warming from below 2 K to above 1000 K) has stimulated considerable interest in this unusual phenomenon. Negative and low thermal expansion materials have a number of important potential uses in ceramic, optical and electronic applications. We have now found negative thermal expansion in a large new family of materials with the general formula A 2 (MO 4 ) 3 . Chemical substitution dramatically influences the thermal expansion properties of these materials allowing the production of ceramics with negative, positive or zero coefficients of thermal expansion, with the potential to control other important materials properties such as refractive index and dielectric constant. The mechanism of negative thermal expansion and the phase transitions exhibited by this important new class of low-expansion materials will be discussed. (orig.)

  8. Deregulation of the non-coding genome in leukemia. (United States)

    Teppo, Susanna; Heinäniemi, Merja; Lohi, Olli


    Methodological advances that allow deeper characterization of non-coding elements in the genome have started to reveal the full spectrum of deregulation in cancer. We generated an inducible cell model to track transcriptional changes after induction of a well-known leukemia-inducing fusion gene, ETV6-RUNX1. Our data revealed widespread transcriptional alterations outside coding elements in the genome. This adds to the growing list of various alterations in the non-coding genome in cancer and pinpoints their role in diseased cellular state.

  9. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. (United States)

    Redon, Sophie; Reichenbach, Patrick; Lingner, Joachim


    Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in sequence the telomeric DNA substrate as they contain 5'-UUAGGG-3' repeats near their 3'-end which are complementary to the template sequence of telomerase RNA. Here we demonstrate that endogenous TERRA is bound to human telomerase in cell extracts. Using in vitro reconstituted telomerase and synthetic TERRA molecules we demonstrate that the 5'-UUAGGG-3' repeats of TERRA base pair with the RNA template of the telomerase RNA moiety (TR). In addition TERRA contacts the telomerase reverse transcriptase (TERT) protein subunit independently of hTR. In vitro studies further demonstrate that TERRA is not used as a telomerase substrate. Instead, TERRA acts as a potent competitive inhibitor for telomeric DNA in addition to exerting an uncompetitive mode of inhibition. Our data identify TERRA as a telomerase ligand and natural direct inhibitor of human telomerase. Telomerase regulation by the telomere substrate may be mediated via its transcription.

  10. Noncoding RNAs in protein clearance pathways: implications in ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 96; Issue 1. Noncoding RNAs in protein clearance pathways: implications in ... A class of small ncRNAs and miRNAs has gained much importance because of its involvement in human diseases such as cancer. Involvement of long ncRNAs have also been acknowledged in ...

  11. Noncoding RNAs in protein clearance pathways: implications in ...

    Indian Academy of Sciences (India)

    may provide protection against neurodegeneration. In this review, I summarize the importance of ncRNAs in protein quality .... in their oligoform and autophagy acts as a quality control mechanism in removal of these toxic ..... 2015 The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 47, 199–208.

  12. Non-coding RNAs in cancer brain metastasis (United States)

    Wu, Kerui; Sharma, Sambad; Venkat, Suresh; Liu, Keqin; Zhou, Xiaobo; Watabe, Kounosuke


    More than 90% of cancer death is attributed to metastatic disease, and the brain is one of the major metastatic sites of melanoma, colon, renal, lung and breast cancers. Despite the recent advancement of targeted therapy for cancer, the incidence of brain metastasis is increasing. One reason is that most therapeutic drugs can’t penetrate blood-brain-barrier and tumor cells find the brain as sanctuary site. In this review, we describe the pathophysiology of brain metastases to introduce the latest understandings of metastatic brain malignancies. This review also particularly focuses on non-coding RNAs and their roles in cancer brain metastasis. Furthermore, we discuss the roles of the extracellular vesicles as they are known to transport information between cells to initiate cancer cell-microenvironment communication. The potential clinical translation of non-coding RNAs as a tool for diagnosis and for treatment is also discussed in this review. At the end, the computational aspects of non-coding RNA detection, the sequence and structure calculation and epigenetic regulation of non-coding RNA in brain metastasis are discussed. PMID:26709907

  13. TERRA: telomeric repeat-containing RNA. (United States)

    Luke, Brian; Lingner, Joachim


    Telomeres, the physical ends of eukaryotic chromosomes, consist of tandem arrays of short DNA repeats and a large set of specialized proteins. A recent analysis has identified telomeric repeat-containing RNA (TERRA), a large non-coding RNA in animals and fungi, which forms an integral component of telomeric heterochromatin. TERRA transcription occurs at most or all chromosome ends and it is regulated by RNA surveillance factors and in response to changes in telomere length. TERRA functions that are emerging suggest important roles in the regulation of telomerase and in orchestrating chromatin remodelling throughout development and cellular differentiation. The accumulation of TERRA at telomeres can also interfere with telomere replication, leading to a sudden loss of telomere tracts. Such a phenotype can be observed upon impairment of the RNA surveillance machinery or in cells from ICF (Immunodeficiency, Centromeric region instability, Facial anomalies) patients, in which TERRA is upregulated because of DNA methylation defects in the subtelomeric region. Thus, TERRA may mediate several crucial functions at the telomeres, a region of the genome that had been considered to be transcriptionally silent.

  14. ATXN2 trinucleotide repeat length correlates with risk of ALS. (United States)

    Sproviero, William; Shatunov, Aleksey; Stahl, Daniel; Shoai, Maryam; van Rheenen, Wouter; Jones, Ashley R; Al-Sarraj, Safa; Andersen, Peter M; Bonini, Nancy M; Conforti, Francesca L; Van Damme, Philip; Daoud, Hussein; Del Mar Amador, Maria; Fogh, Isabella; Forzan, Monica; Gaastra, Ben; Gellera, Cinzia; Gitler, Aaron D; Hardy, John; Fratta, Pietro; La Bella, Vincenzo; Le Ber, Isabelle; Van Langenhove, Tim; Lattante, Serena; Lee, Yi-Chung; Malaspina, Andrea; Meininger, Vincent; Millecamps, Stéphanie; Orrell, Richard; Rademakers, Rosa; Robberecht, Wim; Rouleau, Guy; Ross, Owen A; Salachas, Francois; Sidle, Katie; Smith, Bradley N; Soong, Bing-Wen; Sorarù, Gianni; Stevanin, Giovanni; Kabashi, Edor; Troakes, Claire; van Broeckhoven, Christine; Veldink, Jan H; van den Berg, Leonard H; Shaw, Christopher E; Powell, John F; Al-Chalabi, Ammar


    We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10 -18 ), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R 2  = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Detecting non-coding selective pressure in coding regions

    Directory of Open Access Journals (Sweden)

    Blanchette Mathieu


    Full Text Available Abstract Background Comparative genomics approaches, where orthologous DNA regions are compared and inter-species conserved regions are identified, have proven extremely powerful for identifying non-coding regulatory regions located in intergenic or intronic regions. However, non-coding functional elements can also be located within coding region, as is common for exonic splicing enhancers, some transcription factor binding sites, and RNA secondary structure elements affecting mRNA stability, localization, or translation. Since these functional elements are located in regions that are themselves highly conserved because they are coding for a protein, they generally escaped detection by comparative genomics approaches. Results We introduce a comparative genomics approach for detecting non-coding functional elements located within coding regions. Codon evolution is modeled as a mixture of codon substitution models, where each component of the mixture describes the evolution of codons under a specific type of coding selective pressure. We show how to compute the posterior distribution of the entropy and parsimony scores under this null model of codon evolution. The method is applied to a set of growth hormone 1 orthologous mRNA sequences and a known exonic splicing elements is detected. The analysis of a set of CORTBP2 orthologous genes reveals a region of several hundred base pairs under strong non-coding selective pressure whose function remains unknown. Conclusion Non-coding functional elements, in particular those involved in post-transcriptional regulation, are likely to be much more prevalent than is currently known. With the numerous genome sequencing projects underway, comparative genomics approaches like that proposed here are likely to become increasingly powerful at detecting such elements.

  16. Long non-coding RNAs as emerging regulators of differentiation, development, and disease. (United States)

    Dey, Bijan K; Mueller, Adam C; Dutta, Anindya


    A significant portion of the mammalian genome encodes numerous transcripts that are not translated into proteins, termed long non-coding RNAs. Initial studies identifying long non-coding RNAs inferred these RNA sequences were a consequence of transcriptional noise or promiscuous RNA polymerase II activity. However, the last decade has seen a revolution in the understanding of regulation and function of long non-coding RNAs. Now it has become apparent that long non-coding RNAs play critical roles in a wide variety of biological processes. In this review, we describe the current understanding of long non-coding RNA-mediated regulation of cellular processes: differentiation, development, and disease.

  17. Convergence of mayer expansions

    International Nuclear Information System (INIS)

    Brydges, D.C.


    The tree graph bound of Battle and Federbush is extended and used to provide a simple criterion for the convergence of (iterated) Mayer expansions. As an application estimates on the radius of convergence of the Mayer expansion for the two-dimensional Yukawa gas (nonstable interaction) are obtained

  18. Shrub expansion in SW Greenland

    DEFF Research Database (Denmark)

    Jørgensen, Rasmus Halfdan

    Arctic regions have experienced higher temperatures in recent decades, and the warming trend is projected to continue in the coming years. Arctic ecosystems are considered to be particularly vulnerable to climate change. Expansion of shrubs has been observed widely in tundra areas across the Arctic...... to increasing shrub cover. Despite this, there is only limited experimental evidence that growth of the species responds to warming. Plant populations in fragmented and isolated locations could face problems adapting to a warming climate due to limited genetic variation and restricted migration from southern...... from more southerly habitats are better adapted to climatic conditions in a warmer Greenland compared with local provenances. To answer the first question historical photographs of vegetation in SW Greenland (1898–1974) were compiled. The photos were repeated in 2010 and 2011 and 64 photo pairs were...

  19. TFIIS-Dependent Non-coding Transcription Regulates Developmental Genome Rearrangements.

    Directory of Open Access Journals (Sweden)

    Kamila Maliszewska-Olejniczak


    Full Text Available Because of their nuclear dimorphism, ciliates provide a unique opportunity to study the role of non-coding RNAs (ncRNAs in the communication between germline and somatic lineages. In these unicellular eukaryotes, a new somatic nucleus develops at each sexual cycle from a copy of the zygotic (germline nucleus, while the old somatic nucleus degenerates. In the ciliate Paramecium tetraurelia, the genome is massively rearranged during this process through the reproducible elimination of repeated sequences and the precise excision of over 45,000 short, single-copy Internal Eliminated Sequences (IESs. Different types of ncRNAs resulting from genome-wide transcription were shown to be involved in the epigenetic regulation of genome rearrangements. To understand how ncRNAs are produced from the entire genome, we have focused on a homolog of the TFIIS elongation factor, which regulates RNA polymerase II transcriptional pausing. Six TFIIS-paralogs, representing four distinct families, can be found in P. tetraurelia genome. Using RNA interference, we showed that TFIIS4, which encodes a development-specific TFIIS protein, is essential for the formation of a functional somatic genome. Molecular analyses and high-throughput DNA sequencing upon TFIIS4 RNAi demonstrated that TFIIS4 is involved in all kinds of genome rearrangements, including excision of ~48% of IESs. Localization of a GFP-TFIIS4 fusion revealed that TFIIS4 appears specifically in the new somatic nucleus at an early developmental stage, before IES excision. RT-PCR experiments showed that TFIIS4 is necessary for the synthesis of IES-containing non-coding transcripts. We propose that these IES+ transcripts originate from the developing somatic nucleus and serve as pairing substrates for germline-specific short RNAs that target elimination of their homologous sequences. Our study, therefore, connects the onset of zygotic non coding transcription to the control of genome plasticity in Paramecium

  20. R-loops: targets for nuclease cleavage and repeat instability. (United States)

    Freudenreich, Catherine H


    R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias. Recently, it was found that R-loops at an expanded CAG/CTG repeat tract cause DNA breaks as well as repeat instability (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Two factors were identified as causing R-loop-dependent breaks at CAG/CTG tracts: deamination of cytosines and the MutLγ (Mlh1-Mlh3) endonuclease, defining two new mechanisms for how R-loops can generate DNA breaks (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Following R-loop-dependent nicking, base excision repair resulted in repeat instability. These results have implications for human repeat expansion diseases and provide a paradigm for how RNA:DNA hybrids can cause genome instability at structure-forming DNA sequences. This perspective summarizes mechanisms of R-loop-induced fragility at G-rich repeats and new links between DNA breaks and repeat instability.

  1. Reconfigurable multiport EPON repeater (United States)

    Oishi, Masayuki; Inohara, Ryo; Agata, Akira; Horiuchi, Yukio


    An extended reach EPON repeater is one of the solutions to effectively expand FTTH service areas. In this paper, we propose a reconfigurable multi-port EPON repeater for effective accommodation of multiple ODNs with a single OLT line card. The proposed repeater, which has multi-ports in both OLT and ODN sides, consists of TRs, BTRs with the CDR function and a reconfigurable electrical matrix switch, can accommodate multiple ODNs to a single OLT line card by controlling the connection of the matrix switch. Although conventional EPON repeaters require full OLT line cards to accommodate subscribers from the initial installation stage, the proposed repeater can dramatically reduce the number of required line cards especially when the number of subscribers is less than a half of the maximum registerable users per OLT. Numerical calculation results show that the extended reach EPON system with the proposed EPON repeater can save 17.5% of the initial installation cost compared with a conventional repeater, and can be less expensive than conventional systems up to the maximum subscribers especially when the percentage of ODNs in lightly-populated areas is higher.

  2. Quantum repeated games revisited

    International Nuclear Information System (INIS)

    Frąckiewicz, Piotr


    We present a scheme for playing quantum repeated 2 × 2 games based on Marinatto and Weber’s approach to quantum games. As a potential application, we study the twice repeated Prisoner’s Dilemma game. We show that results not available in the classical game can be obtained when the game is played in the quantum way. Before we present our idea, we comment on the previous scheme of playing quantum repeated games proposed by Iqbal and Toor. We point out the drawbacks that make their results unacceptable. (paper)

  3. Negative thermal expansion

    International Nuclear Information System (INIS)

    Barrera, G D; Bruno, J A O; Barron, T H K; Allan, N L


    There has been substantial renewed interest in negative thermal expansion following the discovery that cubic ZrW 2 O 8 contracts over a temperature range in excess of 1000 K. Substances of many different kinds show negative thermal expansion, especially at low temperatures. In this article we review the underlying thermodynamics, emphasizing the roles of thermal stress and elasticity. We also discuss vibrational and non-vibrational mechanisms operating on the atomic scale that are responsible for negative expansion, both isotropic and anisotropic, in a wide range of materials. (topical review)

  4. Function and Application Areas in Medicine of Non-Coding RNA

    Directory of Open Access Journals (Sweden)

    Figen Guzelgul


    Full Text Available RNA is the genetic material converting the genetic code that it gets from DNA into protein. While less than 2 % of RNA is converted into protein , more than 98 % of it can not be converted into protein and named as non-coding RNAs. 70 % of noncoding RNAs consists of introns , however, the rest part of them consists of exons. Non-coding RNAs are examined in two classes according to their size and functions. Whereas they are classified as long non-coding and small non-coding RNAs according to their size , they are grouped as housekeeping non-coding RNAs and regulating non-coding RNAs according to their function. For long years ,these non-coding RNAs have been considered as non-functional. However, today, it has been proved that these non-coding RNAs play role in regulating genes and in structural, functional and catalitic roles of RNAs converted into protein. Due to its taking a role in gene silencing mechanism, particularly in medical world , non-coding RNAs have led to significant developments. RNAi technolgy , which is used in designing drugs to be used in treatment of various diseases , is a ray of hope for medical world. [Archives Medical Review Journal 2009; 18(3.000: 141-155

  5. Functional long non-coding RNA transcription in Schizosaccharomyces pombe


    Ard, Ryan Anthony


    Eukaryotic genomes are pervasively transcribed and frequently generate long noncoding RNAs (lncRNAs). However, most lncRNAs remain uncharacterized. In this work, a set of positionally conserved intergenic lncRNAs in the fission yeast Schizosaccharomyces pombe genome are selected for further analysis. Deleting one of these lncRNA genes (ncRNA.1343) exhibited a clear phenotype: increased drug sensitivity. Further analyses revealed that deleting ncRNA.1343 also disrupted a prev...

  6. Therapeutic targeting of non-coding RNAs in cancer

    Czech Academy of Sciences Publication Activity Database

    Slabý, O.; Laga, Richard; Sedláček, Ondřej


    Roč. 474, č. 24 (2017), s. 4219-4251 ISSN 0264-6021 R&D Projects: GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : non-coding RNA * RNA delivery * polymer carriers Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemical research methods Impact factor: 3.797, year: 2016

  7. Right ventricular long noncoding RNA expression in human heart failure (United States)

    Guo, Yan; Su, Yan Ru; Clark, Travis; Brittain, Evan; Absi, Tarek; Maltais, Simon; Hemnes, Anna


    Abstract The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible functional roles using a variety of online tools. In HF hearts, RNA-Seq identified 84,793 total messenger RNA coding and noncoding different transcripts, including 13,019 protein-coding genes, 2,085 total lncRNA genes, and 1,064 pseudogenes. By Ensembl noncoding RNA categories, there were 48 lncRNAs, 27 pseudogenes, and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs in HF hearts. Compared with donor hearts, HF hearts exhibited differential expression of 7.7% of protein-coding genes, 3.7% of lncRNAs (including pseudogenes), and 2.5% of pseudogenes. There were not consistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent genes, implying differential regulation of expression. Exploratory in silico functional analyses using online tools suggested a variety of possible lncRNA regulatory roles. By providing a comprehensive profile of right ventricular polyadenylated messenger RNA transcriptome in HF, RNA-Seq provides an inventory of differentially expressed lncRNAs, including antisense transcripts and pseudogenes, for future mechanistic study. PMID:25992278

  8. Intragenic tandem repeats in Daphnia magna: structure, function and distribution

    Directory of Open Access Journals (Sweden)

    Du Pasquier Louis


    Full Text Available Abstract Background Expressed sequence tag (EST databases provide a valuable source of genetic data in organisms whose genome sequence information is not yet compiled. We used a published EST database for the waterflea Daphnia magna (Crustacea:Cladocera to isolate variable number of tandem repeat (VNTR markers for linkage mapping, Quantitative Trait Loci (QTL, and functional studies. Findings Seventy-four polymorphic markers were isolated and characterised. Analyses of repeat structure, putative gene function and polymorphism indicated that intragenic tandem repeats are not distributed randomly in the mRNA sequences; instead, dinucleotides are more frequent in non-coding regions, whereas trinucleotides (and longer motifs involving multiple-of-three nucleotide repeats are preferentially situated in coding regions. We also observed differential distribution of repeat motifs across putative genetic functions. This indicates differential selective constraints and possible functional significance of VNTR polymorphism in at least some genes. Conclusion Databases of VNTR markers situated in genes whose putative function can be inferred from homology searches will be a valuable resource for the genetic study of functional variation and selection.

  9. Repeat migration and disappointment. (United States)

    Grant, E K; Vanderkamp, J


    This article investigates the determinants of repeat migration among the 44 regions of Canada, using information from a large micro-database which spans the period 1968 to 1971. The explanation of repeat migration probabilities is a difficult task, and this attempt is only partly successful. May of the explanatory variables are not significant, and the overall explanatory power of the equations is not high. In the area of personal characteristics, the variables related to age, sex, and marital status are generally significant and with expected signs. The distance variable has a strongly positive effect on onward move probabilities. Variables related to prior migration experience have an important impact that differs between return and onward probabilities. In particular, the occurrence of prior moves has a striking effect on the probability of onward migration. The variable representing disappointment, or relative success of the initial move, plays a significant role in explaining repeat migration probabilities. The disappointment variable represents the ratio of actural versus expected wage income in the year after the initial move, and its effect on both repeat migration probabilities is always negative and almost always highly significant. The repeat probabilities diminish after a year's stay in the destination region, but disappointment in the most recent year still has a bearing on the delayed repeat probabilities. While the quantitative impact of the disappointment variable is not large, it is difficult to draw comparisons since similar estimates are not available elsewhere.

  10. Non-coding RNAs in the Ovarian Follicle

    Directory of Open Access Journals (Sweden)

    Rosalia Battaglia


    Full Text Available The mammalian ovarian follicle is the complex reproductive unit comprising germ cell, somatic cells (Cumulus and Granulosa cells, and follicular fluid (FF: paracrine communication among the different cell types through FF ensures the development of a mature oocyte ready for fertilization. This paper is focused on non-coding RNAs in ovarian follicles and their predicted role in the pathways involved in oocyte growth and maturation. We determined the expression profiles of microRNAs in human oocytes and FF by high-throughput analysis and identified 267 microRNAs in FF and 176 in oocytes. Most of these were FF microRNAs, while 9 were oocyte specific. By bioinformatic analysis, independently performed on FF and oocyte microRNAs, we identified the most significant Biological Processes and the pathways regulated by their validated targets. We found many pathways shared between the two compartments and some specific for oocyte microRNAs. Moreover, we found 41 long non-coding RNAs able to interact with oocyte microRNAs and potentially involved in the regulation of folliculogenesis. These data are important in basic reproductive research and could also be useful for clinical applications. In fact, the characterization of non-coding RNAs in ovarian follicles could improve reproductive disease diagnosis, provide biomarkers of oocyte quality in Assisted Reproductive Treatment, and allow the development of therapies for infertility disorders.

  11. Characterization of noncoding regulatory DNA in the human genome. (United States)

    Elkon, Ran; Agami, Reuven


    Genetic variants associated with common diseases are usually located in noncoding parts of the human genome. Delineation of the full repertoire of functional noncoding elements, together with efficient methods for probing their biological roles, is therefore of crucial importance. Over the past decade, DNA accessibility and various epigenetic modifications have been associated with regulatory functions. Mapping these features across the genome has enabled researchers to begin to document the full complement of putative regulatory elements. High-throughput reporter assays to probe the functions of regulatory regions have also been developed but these methods separate putative regulatory elements from the chromosome so that any effects of chromatin context and long-range regulatory interactions are lost. Definitive assignment of function(s) to putative cis-regulatory elements requires perturbation of these elements. Genome-editing technologies are now transforming our ability to perturb regulatory elements across entire genomes. Interpretation of high-throughput genetic screens that incorporate genome editors might enable the construction of an unbiased map of functional noncoding elements in the human genome.

  12. The human noncoding genome defined by genetic diversity. (United States)

    di Iulio, Julia; Bartha, Istvan; Wong, Emily H M; Yu, Hung-Chun; Lavrenko, Victor; Yang, Dongchan; Jung, Inkyung; Hicks, Michael A; Shah, Naisha; Kirkness, Ewen F; Fabani, Martin M; Biggs, William H; Ren, Bing; Venter, J Craig; Telenti, Amalio


    Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale.

  13. Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases

    Directory of Open Access Journals (Sweden)

    Nayra Soares do Amaral


    Full Text Available Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs and long noncoding RNAs (lncRNAs, is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways—primarily interleukin 6 (IL-6/signal transducer and activator of transcription 3 (STAT3, which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases.

  14. Controlled Thermal Expansion Alloys (United States)

    National Aeronautics and Space Administration — There has always been a need for controlled thermal expansion alloys suitable for mounting optics and detectors in spacecraft applications.  These alloys help...

  15. Weakly relativistic plasma expansion

    Energy Technology Data Exchange (ETDEWEB)

    Fermous, Rachid, E-mail:; Djebli, Mourad, E-mail: [Theoretical Physics Laboratory, Faculty of Physics, USTHB, B.P. 32 Bab-Ezzouar, 16079 Algiers (Algeria)


    Plasma expansion is an important physical process that takes place in laser interactions with solid targets. Within a self-similar model for the hydrodynamical multi-fluid equations, we investigated the expansion of both dense and under-dense plasmas. The weakly relativistic electrons are produced by ultra-intense laser pulses, while ions are supposed to be in a non-relativistic regime. Numerical investigations have shown that relativistic effects are important for under-dense plasma and are characterized by a finite ion front velocity. Dense plasma expansion is found to be governed mainly by quantum contributions in the fluid equations that originate from the degenerate pressure in addition to the nonlinear contributions from exchange and correlation potentials. The quantum degeneracy parameter profile provides clues to set the limit between under-dense and dense relativistic plasma expansions at a given density and temperature.

  16. Long noncoding RNA in prostate, bladder, and kidney cancer. (United States)

    Martens-Uzunova, Elena S; Böttcher, René; Croce, Carlo M; Jenster, Guido; Visakorpi, Tapio; Calin, George A


    Genomic regions without protein-coding potential give rise to millions of protein-noncoding RNA transcripts (noncoding RNA) that participate in virtually all cellular processes. Research over the last 10 yr has accumulated evidence that long noncoding RNAs (lncRNAs) are often altered in human urologic cancers. To review current progress in the biology and implication of lncRNAs associated with prostate, bladder, and kidney cancer. The PubMed database was searched for articles in the English language with combinations of the Medical Subject Headings terms long non coding RNA, long noncoding RNA, long untranslated RNA, cancer, neoplasms, prostate, bladder, and kidney. We summarise existing knowledge on the systematics, biology, and function of lncRNAs, particularly these involved in prostate, kidney, and bladder cancer. We also discuss the possible utilisation of lncRNAs as novel biomarkers and potential therapeutic targets in urologic malignancies and portray the major challenges and future perspectives of ongoing lncRNA research. LncRNAs are important regulators of gene expression interacting with the major pathways of cell growth, proliferation, differentiation, and survival. Alterations in the function of lncRNAs promote tumour formation, progression, and metastasis of prostate, bladder, and kidney cancer. LncRNAs can be used as noninvasive tumour markers in urologic malignancies. Increased knowledge of the molecular mechanisms by which lncRNAs perform their function in the normal and malignant cell will lead to a better understanding of tumour biology and could provide novel therapeutic targets for the treatment of urologic cancers. In this paper we reviewed current knowledge of long noncoding RNAs (lncRNAs) for the detection and treatment of urologic cancers. We conclude that lncRNAs can be used as novel biomarkers in prostate, kidney, or bladder cancer. LncRNAs hold promise as future therapeutic targets, but more research is needed to gain a better

  17. Long noncoding RNA PCA3 gene promoter region is related to the risk of prostate cancer on Chinese males. (United States)

    Zhou, Wu; Tao, Zhihua; Wang, Zhongyong; Hu, Wangqiang; Shen, Mo; Zhou, Lianlian; Wen, Zhiliang; Yu, Zhixian; Wu, Xiuling; Huang, Kate; Hu, Yuanping; Lin, Xiangyang


    Long noncoding RNA prostate cancer gene antigen 3 (PCA3) is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 RNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In this study, we investigated a short tandem repeat (STR) polymorphism of TAAA in the promoter region of PCA3 gene found in our previous study in prostate cancer (PCa) patients and benign prostatic hypertrophy (BPH) patients, aiming to evaluate the association between the STR and increased risk for PCa. 120 PCa cases and 120 benign prostatic hypertrophy (BPH) cases were identified among participants. The region encompassing the TAAA repeat was amplified with a specific primer set we designed and screened by PCR-based cloning and sequencing in paired peripheral blood leukocytes and prostate tissues. Genotype-specific risks were estimated as odds ratios (ORs) associated with 95% confidence intervals (CIs) and adjusted for age by means of unconditional logistic regression. 5 PCA3 TAAA STR polymorphisms and 8 genotypes were found in both peripheral blood leukocytes and prostate tissues, the carriers with more TAAA repeats were associated with increased risk for PCa than individuals having less TAAA repeats. Interestingly, 18 (15.0%) of 120 PCa patients had more (TAAA)n repeats in prostate tissues than that in peripheral blood leukocytes, and 3 (2.5%) of 120 had less (TAAA)n repeats in prostate tissues. The results of this study suggest that short tandem repeat polymorphism of TAAA in the promoter region of PCA3 gene is a risk-increasing factor for prostate cancer in the Chinese population. In addition to the hereditary factor, the insertion mutation of (TAAA)n in a local tissue maybe another mechanism of the onset of PCa. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Identifying noncoding risk variants using disease-relevant gene regulatory networks. (United States)

    Gao, Long; Uzun, Yasin; Gao, Peng; He, Bing; Ma, Xiaoke; Wang, Jiahui; Han, Shizhong; Tan, Kai


    Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.

  19. Resonant state expansions

    International Nuclear Information System (INIS)

    Lind, P.


    The completeness properties of the discrete set of bound state, virtual states and resonances characterizing the system of a single nonrelativistic particle moving in a central cutoff potential is investigated. From a completeness relation in terms of these discrete states and complex scattering states one can derive several Resonant State Expansions (RSE). It is interesting to obtain purely discrete expansion which, if valid, would significantly simplify the treatment of the continuum. Such expansions can be derived using Mittag-Leffler (ML) theory for a cutoff potential and it would be nice to see if one can obtain the same expansions starting from an eigenfunction theory that is not restricted to a finite sphere. The RSE of Greens functions is especially important, e.g. in the continuum RPA (CRPA) method of treating giant resonances in nuclear physics. The convergence of RSE is studied in simple cases using square well wavefunctions in order to achieve high numerical accuracy. Several expansions can be derived from each other by using the theory of analytic functions and one can the see how to obtain a natural discretization of the continuum. Since the resonance wavefunctions are oscillating with an exponentially increasing amplitude, and therefore have to be interpreted through some regularization procedure, every statement made about quantities involving such states is checked by numerical calculations.Realistic nuclear wavefunctions, generated by a Wood-Saxon potential, are used to test also the usefulness of RSE in a realistic nuclear calculation. There are some fundamental differences between different symmetries of the integral contour that defines the continuum in RSE. One kind of symmetry is necessary to have an expansion of the unity operator that is idempotent. Another symmetry must be used if we want purely discrete expansions. These are found to be of the same form as given by ML. (29 refs.)

  20. The Pentapeptide Repeat Proteins

    Energy Technology Data Exchange (ETDEWEB)

    Vetting,M.; Hegde, S.; Fajardo, J.; Fiser, A.; Roderick, S.; Takiff, H.; Blanchard, J.


    The Pentapeptide Repeat Protein (PRP) family has over 500 members in the prokaryotic and eukaryotic kingdoms. These proteins are composed of, or contain domains composed of, tandemly repeated amino acid sequences with a consensus sequence of [S, T,A, V][D, N][L, F]-[S, T,R][G]. The biochemical function of the vast majority of PRP family members is unknown. The three-dimensional structure of the first member of the PRP family was determined for the fluoroquinolone resistance protein (MfpA) from Mycobacterium tuberculosis. The structure revealed that the pentapeptide repeats encode the folding of a novel right-handed quadrilateral {beta}-helix. MfpA binds to DNA gyrase and inhibits its activity. The rod-shaped, dimeric protein exhibits remarkable size, shape and electrostatic similarity to DNA.

  1. Expansion joints for LMFBR

    International Nuclear Information System (INIS)

    Dzenus, M.; Hundhausen, W.; Jansing, W.


    This discourse recounts efforts put into the SNR-2 project; specifically the development of compensation devices. The various prototypes of these compensation devices are described and the state of the development reviewed. Large Na (sodium)-heat transfer systems require a lot of valuable space if the component lay-out does not include compensation devices. So, in order to condense the spatial requirement as much as possible, expansion joints must be integrated into the pipe system. There are two basic types to suit the purpose: axial expansion joints and angular expansion joints. The expansion joints were developed on the basis of specific design criteria whereby differentiation is made between expansion joints of small and large nominal diameter. Expansion joints for installation in the sodium-filled primary piping are equipped with safety bellows in addition to the actual working bellows. Expansion joints must be designed and mounted in a manner to completely withstand seismic forces. The design must exclude any damage to the bellows during intermittent operations, that is, when sodium is drained the bellows' folds must be completely empty; otherwise residual solidified sodium could destroy the bellows when restarting. The expansion joints must be engineered on the basis of the following design data for the secondary system of the SNR project: working pressure: 16 bar; failure mode pressure: 5 events; failure mode: 5 sec., 28.5 bar, 520 deg. C; working temperature: 520 deg. C; temperature transients: 30 deg. C/sec.; service life: 200,000 h; number of load cycles: 10 4 ; material: 1.4948 or 1.4919; layer thickness of folds: 0.5 mm; angular deflection (DN 800): +3 deg. C or; axial expansion absorption (DN 600): ±80 mm; calculation: ASME class. The bellows' development work is not handled within this scope. The bellows are supplied by leading manufacturers, and warrant highest quality. Multiple bellows were selected on the basis of maximum elasticity - a property

  2. Conformal expansions and renormalons

    Energy Technology Data Exchange (ETDEWEB)

    Rathsman, J.


    The coefficients in perturbative expansions in gauge theories are factorially increasing, predominantly due to renormalons. This type of factorial increase is not expected in conformal theories. In QCD conformal relations between observables can be defined in the presence of a perturbative infrared fixed-point. Using the Banks-Zaks expansion the authors study the effect of the large-order behavior of the perturbative series on the conformal coefficients. The authors find that in general these coefficients become factorially increasing. However, when the factorial behavior genuinely originates in a renormalon integral, as implied by a postulated skeleton expansion, it does not affect the conformal coefficients. As a consequence, the conformal coefficients will indeed be free of renormalon divergence, in accordance with previous observations concerning the smallness of these coefficients for specific observables. The authors further show that the correspondence of the BLM method with the skeleton expansion implies a unique scale-setting procedure. The BLM coefficients can be interpreted as the conformal coefficients in the series relating the fixed-point value of the observable with that of the skeleton effective charge. Through the skeleton expansion the relevance of renormalon-free conformal coefficients extends to real-world QCD.

  3. Sequence Variations in the Non-Coding Sequence of CTX Phages in Vibrio cholerae. (United States)

    Kim, Eun Jin; Yu, Hyun Jin; Kim, Dong Wook


    This study focused on the variations in the non-coding sequences between ctxB and rstR of various CTX phages. The non-coding sequences of CTX-1 and CTX-cla are phage type-specific. The length of the non-coding region of CTX-1 and CTX-cla is 601 and 730 nucleotides, respectively. The non-coding sequence of CTX phage could be divided into three regions. There is a phage type-specific Variable region between two homologous Common regions (Common regions 1 and 2). The non-coding sequence of RS1 element is similar to CTX-1 except that Common region 1 is replaced by a short RS1-specific sequence. The non-coding sequences of CTX-2 and CTX-cla are homologous, indicating the non-coding sequence of CTX-2 is derived from CTX-cla. The non-coding region of CTX-O139 is similar to CTX-cla and CTX-2; however, it contains an extra phage type-specific sequence between Common region 2 and rstR. The variations in the non-coding sequences of CTX phages might be associated with the difference in the replication efficiency and the directionality in the integration into the V. cholerae chromosome.

  4. Long non-coding RNAs: Mechanism of action and functional utility


    Bhat, Shakil Ahmad; Ahmad, Syed Mudasir; Mumtaz, Peerzada Tajamul; Malik, Abrar Ahad; Dar, Mashooq Ahmad; Urwat, Uneeb; Shah, Riaz Ahmad; Ganai, Nazir Ahmad


    Recent RNA sequencing studies have revealed that most of the human genome is transcribed, but very little of the total transcriptomes has the ability to encode proteins. Long non-coding RNAs (lncRNAs) are non-coding transcripts longer than 200 nucleotides. Members of the non-coding genome include microRNA (miRNA), small regulatory RNAs and other short RNAs. Most of long non-coding RNA (lncRNAs) are poorly annotated. Recent recognition about lncRNAs highlights their effects in many biological ...

  5. Uniform gradient expansions

    Directory of Open Access Journals (Sweden)

    Massimo Giovannini


    Full Text Available Cosmological singularities are often discussed by means of a gradient expansion that can also describe, during a quasi-de Sitter phase, the progressive suppression of curvature inhomogeneities. While the inflationary event horizon is being formed the two mentioned regimes coexist and a uniform expansion can be conceived and applied to the evolution of spatial gradients across the protoinflationary boundary. It is argued that conventional arguments addressing the preinflationary initial conditions are necessary but generally not sufficient to guarantee a homogeneous onset of the conventional inflationary stage.

  6. Uniform gradient expansions

    CERN Document Server

    Giovannini, Massimo


    Cosmological singularities are often discussed by means of a gradient expansion that can also describe, during a quasi-de Sitter phase, the progressive suppression of curvature inhomogeneities. While the inflationary event horizon is being formed the two mentioned regimes coexist and a uniform expansion can be conceived and applied to the evolution of spatial gradients across the protoinflationary boundary. It is argued that conventional arguments addressing the preinflationary initial conditions are necessary but generally not sufficient to guarantee a homogeneous onset of the conventional inflationary stage.

  7. Low-temperature thermal expansion

    International Nuclear Information System (INIS)

    Collings, E.W.


    This chapter discusses the thermal expansion of insulators and metals. Harmonicity and anharmonicity in thermal expansion are examined. The electronic, magnetic, an other contributions to low temperature thermal expansion are analyzed. The thermodynamics of the Debye isotropic continuum, the lattice-dynamical approach, and the thermal expansion of metals are discussed. Relative linear expansion at low temperatures is reviewed and further calculations of the electronic thermal expansion coefficient are given. Thermal expansions are given for Cu, Al and Ti. Phenomenologic thermodynamic relationships are also discussed

  8. Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. (United States)

    Nolte-'t Hoen, Esther N M; Buermans, Henk P J; Waasdorp, Maaike; Stoorvogel, Willem; Wauben, Marca H M; 't Hoen, Peter A C


    Cells release RNA-carrying vesicles and membrane-free RNA/protein complexes into the extracellular milieu. Horizontal vesicle-mediated transfer of such shuttle RNA between cells allows dissemination of genetically encoded messages, which may modify the function of target cells. Other studies used array analysis to establish the presence of microRNAs and mRNA in cell-derived vesicles from many sources. Here, we used an unbiased approach by deep sequencing of small RNA released by immune cells. We found a large variety of small non-coding RNA species representing pervasive transcripts or RNA cleavage products overlapping with protein coding regions, repeat sequences or structural RNAs. Many of these RNAs were enriched relative to cellular RNA, indicating that cells destine specific RNAs for extracellular release. Among the most abundant small RNAs in shuttle RNA were sequences derived from vault RNA, Y-RNA and specific tRNAs. Many of the highly abundant small non-coding transcripts in shuttle RNA are evolutionary well-conserved and have previously been associated to gene regulatory functions. These findings allude to a wider range of biological effects that could be mediated by shuttle RNA than previously expected. Moreover, the data present leads for unraveling how cells modify the function of other cells via transfer of specific non-coding RNA species.

  9. Incorporating Non-Coding Annotations into Rare Variant Analysis.

    Directory of Open Access Journals (Sweden)

    Tom G Richardson

    Full Text Available The success of collapsing methods which investigate the combined effect of rare variants on complex traits has so far been limited. The manner in which variants within a gene are selected prior to analysis has a crucial impact on this success, which has resulted in analyses conventionally filtering variants according to their consequence. This study investigates whether an alternative approach to filtering, using annotations from recently developed bioinformatics tools, can aid these types of analyses in comparison to conventional approaches.We conducted a candidate gene analysis using the UK10K sequence and lipids data, filtering according to functional annotations using the resource CADD (Combined Annotation-Dependent Depletion and contrasting results with 'nonsynonymous' and 'loss of function' consequence analyses. Using CADD allowed the inclusion of potentially deleterious intronic variants, which was not possible when filtering by consequence. Overall, different filtering approaches provided similar evidence of association, although filtering according to CADD identified evidence of association between ANGPTL4 and High Density Lipoproteins (P = 0.02, N = 3,210 which was not observed in the other analyses. We also undertook genome-wide analyses to determine how filtering in this manner compared to conventional approaches for gene regions. Results suggested that filtering by annotations according to CADD, as well as other tools known as FATHMM-MKL and DANN, identified association signals not detected when filtering by variant consequence and vice versa.Incorporating variant annotations from non-coding bioinformatics tools should prove to be a valuable asset for rare variant analyses in the future. Filtering by variant consequence is only possible in coding regions of the genome, whereas utilising non-coding bioinformatics annotations provides an opportunity to discover unknown causal variants in non-coding regions as well. This should allow

  10. Cigarette smoke exposure-associated alterations to noncoding RNA

    Directory of Open Access Journals (Sweden)

    Matthew Alan Maccani


    Full Text Available Environmental exposures vary by timing, severity, and frequency and may have a number of deleterious effects throughout the life course. The period of in utero development, for example, is one of the most crucial stages of development during which adverse environmental exposures can both alter the growth and development of the fetus as well as lead to aberrant fetal programming, increasing disease risk. During fetal development and beyond, the plethora of exposures, including nutrients, drugs, stress, and trauma, influence health, development, and survival. Recent research in environmental epigenetics has investigated the roles of environmental exposures in influencing epigenetic modes of gene regulation during pregnancy and at various stages of life. Many relatively common environmental exposures, such as cigarette smoking, alcohol consumption, and drug use, may have consequences for the expression and function of noncoding RNA (ncRNA, important post-transcriptional regulators of gene expression. A number of ncRNA have been discovered, including microRNA (miRNA, Piwi-interacting RNA (piRNA, and long noncoding RNA (long ncRNA. The best-characterized species of ncRNA are miRNA, the mature forms of which are ~22 nucleotides in length and capable of post-transcriptionally regulating target mRNA utilizing mechanisms based largely on the degree of complementarity between miRNA and target mRNA. Because miRNA can still negatively regulate gene expression when imperfectly base-paired with a target mRNA, a single miRNA can have a large number of potential mRNA targets and can regulate many different biological processes critical for health and development. The following review analyzes the current literature detailing links between cigarette smoke exposure and aberrant expression and function of noncoding RNA, assesses how such alterations may have consequences throughout the life course, and proposes future directions for this intriguing field of

  11. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis

    DEFF Research Database (Denmark)

    Pauli, Andrea; Valen, Eivind; Lin, Michael F.


    Long non-coding RNAs (lncRNAs) comprise a diverse class of transcripts that structurally resemble mRNAs but do not encode proteins. Recent genome-wide studies in human and mouse have annotated lncRNAs expressed in cell lines and adult tissues, but a systematic analysis of lncRNAs expressed during...... and distinct subcellular localization patterns. Integrative computational analyses associated individual lncRNAs with specific pathways and functions, ranging from cell cycle regulation to morphogenesis. Our study provides the first systematic identification of lncRNAs in a vertebrate embryo and forms...

  12. Circadian changes in long noncoding RNAs in the pineal gland


    Coon, Steven L.; Munson, Peter J.; Cherukuri, Praveen F.; Sugden, David; Rath, Martin F.; Møller, Morten; Clokie, Samuel J. H.; Fu, Cong; Olanich, Mary E.; Rangel, Zoila; Werner, Thomas; Mullikin, James C.; Klein, David C.; Benjamin, Betty; Blakesley, Robert


    Long noncoding RNAs (lncRNAs) play a broad range of biological roles, including regulation of expression of genes and chromosomes. Here, we present evidence that lncRNAs are involved in vertebrate circadian biology. Differential night/day expression of 112 lncRNAs (0.3 to >50 kb) occurs in the rat pineal gland, which is the source of melatonin, the hormone of the night. Approximately one-half of these changes reflect nocturnal increases. Studies of eight lncRNAs with 2- to >100-fold daily rhy...

  13. Annotating non-coding regions of the genome. (United States)

    Alexander, Roger P; Fang, Gang; Rozowsky, Joel; Snyder, Michael; Gerstein, Mark B


    Most of the human genome consists of non-protein-coding DNA. Recently, progress has been made in annotating these non-coding regions through the interpretation of functional genomics experiments and comparative sequence analysis. One can conceptualize functional genomics analysis as involving a sequence of steps: turning the output of an experiment into a 'signal' at each base pair of the genome; smoothing this signal and segmenting it into small blocks of initial annotation; and then clustering these small blocks into larger derived annotations and networks. Finally, one can relate functional genomics annotations to conserved units and measures of conservation derived from comparative sequence analysis.

  14. Alteration of Epigenetic Regulation by Long Noncoding RNAs in Cancer

    Directory of Open Access Journals (Sweden)

    Mariangela Morlando


    Full Text Available Long noncoding RNAs (lncRNAs are important regulators of the epigenetic status of the human genome. Besides their participation to normal physiology, lncRNA expression and function have been already associated to many diseases, including cancer. By interacting with epigenetic regulators and by controlling chromatin topology, their misregulation may result in an aberrant regulation of gene expression that may contribute to tumorigenesis. Here, we review the functional role and mechanisms of action of lncRNAs implicated in the aberrant epigenetic regulation that has characterized cancer development and progression.

  15. Alanine repeats influence protein localization in splicing speckles and paraspeckles. (United States)

    Chang, Shuo-Hsiu; Chang, Wei-Lun; Lu, Chia-Chen; Tarn, Woan-Yuh


    Mammalian splicing regulatory protein RNA-binding motif protein 4 (RBM4) has an alanine repeat-containing C-terminal domain (CAD) that confers both nuclear- and splicing speckle-targeting activities. Alanine-repeat expansion has pathological potential. Here we show that the alanine-repeat tracts influence the subnuclear targeting properties of the RBM4 CAD in cultured human cells. Notably, truncation of the alanine tracts redistributed a portion of RBM4 to paraspeckles. The alanine-deficient CAD was sufficient for paraspeckle targeting. On the other hand, alanine-repeat expansion reduced the mobility of RBM4 and impaired its splicing activity. We further took advantage of the putative coactivator activator (CoAA)-RBM4 conjoined splicing factor, CoAZ, to investigate the function of the CAD in subnuclear targeting. Transiently expressed CoAZ formed discrete nuclear foci that emerged and subsequently separated-fully or partially-from paraspeckles. Alanine-repeat expansion appeared to prevent CoAZ separation from paraspeckles, resulting in their complete colocalization. CoAZ foci were dynamic but, unlike paraspeckles, were resistant to RNase treatment. Our results indicate that the alanine-rich CAD, in conjunction with its conjoined RNA-binding domain(s), differentially influences the subnuclear localization and biogenesis of RBM4 and CoAZ. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. Wake Expansion Models

    DEFF Research Database (Denmark)

    Branlard, Emmanuel Simon Pierre


    Different models of wake expansion are presented in this chapter: the 1D momentum theory model, the cylinder analog model and Theodorsen’s model. Far wake models such as the ones from Frandsen or Rathmann or only briefly mentioned. The different models are compared to each other. Results from...

  17. AUTO-EXPANSIVE FLOW (United States)

    Physics suggests that the interplay of momentum, continuity, and geometry in outward radial flow must produce density and concomitant pressure reductions. In other words, this flow is intrinsically auto-expansive. It has been proposed that this process is the key to understanding...

  18. Static gas expansion cooler (United States)

    Guzek, J.C.; Lujan, R.A.


    Disclosed is a cooler for television cameras and other temperature sensitive equipment. The cooler uses compressed gas ehich is accelerated to a high velocity by passing it through flow passageways having nozzle portions which expand the gas. This acceleration and expansion causes the gas to undergo a decrease in temperature thereby cooling the cooler body and adjacent temperature sensitive equipment.

  19. Expression of a novel non-coding mitochondrial RNA in human proliferating cells. (United States)

    Villegas, Jaime; Burzio, Veronica; Villota, Claudio; Landerer, Eduardo; Martinez, Ronny; Santander, Marcela; Martinez, Rodrigo; Pinto, Rodrigo; Vera, María I; Boccardo, Enrique; Villa, Luisa L; Burzio, Luis O


    Previously, we reported the presence in mouse cells of a mitochondrial RNA which contains an inverted repeat (IR) of 121 nucleotides (nt) covalently linked to the 5' end of the mitochondrial 16S RNA (16S mtrRNA). Here, we report the structure of an equivalent transcript of 2374 nt which is over-expressed in human proliferating cells but not in resting cells. The transcript contains a hairpin structure comprising an IR of 815 nt linked to the 5' end of the 16S mtrRNA and forming a long double-stranded structure or stem and a loop of 40 nt. The stem is resistant to RNase A and can be detected and isolated after digestion with the enzyme. This novel transcript is a non-coding RNA (ncRNA) and several evidences suggest that the transcript is synthesized in mitochondria. The expression of this transcript can be induced in resting lymphocytes stimulated with phytohaemagglutinin (PHA). Moreover, aphidicolin treatment of DU145 cells reversibly blocks proliferation and expression of the transcript. If the drug is removed, the cells re-assume proliferation and over-express the ncmtRNA. These results suggest that the expression of the ncmtRNA correlates with the replicative state of the cell and it may play a role in cell proliferation.

  20. CAG trinucleotide RNA repeats interact with RNA-binding proteins

    Energy Technology Data Exchange (ETDEWEB)

    McLaughlin, B.A.; Eberwine, J.; Spencer, C. [Univ. of Pennsylvania, Philadelphia, PA (United States)


    Genes associated with several neurological diseases are characterized by the presence of an abnormally long trinucleotide repeat sequence. By way of example, Huntington`s disease (HD), is characterized by selective neuronal degeneration associated with the expansion of a polyglutamine-encoding CAG tract. Normally, this CAG tract is comprised of 11-34 repeats, but in HD it is expanded to >37 repeats in affected individuals. The mechanism by which CAG repeats cause neuronal degeneration is unknown, but it has been speculated that the expansion primarily causes abnormal protein functioning, which in turn causes HD pathology. Other mechanisms, however, have not been ruled out. Interactions between RNA and RNA-binding proteins have previously been shown to play a role in the expression of several eukaryotic genes. Herein, we report the association of cytoplasmic proteins with normal length and extended CAG repeats, using gel shift and LJV crosslinking assays. Cytoplasmic protein extracts from several rat brain regions, including the striatum and cortex, sites of neuronal degeneration in HD, contain a 63-kD RNA-binding protein that specifically interacts with these CAG-repeat sequences. These protein-RNA interactions are dependent on the length of the CAG repeat, with longer repeats binding substantially more protein. Two CAG repeat-binding proteins are present in human cortex and striatum; one comigrates with the rat protein at 63 kD, while the other migrates at 49 kD. These data suggest mechanisms by which RNA-binding proteins may be involved in the pathological course of trinucleotide repeat-associated neurological diseases. 47 refs., 5 figs.

  1. Alu repeats: A source for the genesis of primate microsatellites

    Energy Technology Data Exchange (ETDEWEB)

    Arcot, S.S.; Batzer, M.A. [Lawrence Livermore National Lab., CA (United States); Wang, Zhenyuan [Marshfield Medical Research Foundation, WI (United States)] [and others


    As a result of their abundance, relatively uniform distribution, and high degree of polymorphism, microsatellites and minisatellites have become valuable tools in genetic mapping, forensic identity testing, and population studies. In recent years, a number of microsatellite repeats have been found to be associated with Alu interspersed repeated DNA elements. The association of an Alu element with a microsatellite repeat could result from the integration of an Alu element within a preexisting microsatellite repeat. Alternatively, Alu elements could have a direct role in the origin of microsatellite repeats. Errors introduced during reverse transcription of the primary transcript derived from an Alu {open_quotes}master{close_quote} gene or the accumulation of random mutations in the middle A-rich regions and oligo(dA)-rich tails of Alu elements after insertion and subsequent expansion and contraction of these sequences could result in the genesis of a microsatellite repeat. We have tested these hypotheses by a direct evolutionary comparison of the sequences of some recent Alu elements that are found only in humans and are absent from nonhuman primates, as well as some older Alu elements that are present at orthologous positions in a number of nonhuman primates. The origin of {open_quotes}young{close_quotes} Alu insertions, absence of sequences that resemble microsatellite repeats at the orthologous loci in chimpanzees, and the gradual expansion of microsatellite repeats in some old Alu repeats at orthologous positions within the genomes of a number of nonhuman primates suggest that Alu elements are a source for the genesis of primate microsatellite repeats. 48 refs., 5 figs., 3 tabs.

  2. Duct Leakage Repeatability Testing

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Iain [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sherman, Max [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)


    Duct leakage often needs to be measured to demonstrate compliance with requirements or to determine energy or Indoor Air Quality (IAQ) impacts. Testing is often done using standards such as ASTM E1554 (ASTM 2013) or California Title 24 (California Energy Commission 2013 & 2013b), but there are several choices of methods available within the accepted standards. Determining which method to use or not use requires an evaluation of those methods in the context of the particular needs. Three factors that are important considerations are the cost of the measurement, the accuracy of the measurement and the repeatability of the measurement. The purpose of this report is to evaluate the repeatability of the three most significant measurement techniques using data from the literature and recently obtained field data. We will also briefly discuss the first two factors. The main question to be answered by this study is to determine if differences in the repeatability of these tests methods is sufficient to indicate that any of these methods is so poor that it should be excluded from consideration as an allowed procedure in codes and standards.

  3. Junk DNA and the long non-coding RNA twist in cancer genetics

    NARCIS (Netherlands)

    H. Ling (Hui); K. Vincent; M. Pichler; R. Fodde (Riccardo); I. Berindan-Neagoe (Ioana); F.J. Slack (Frank); G.A. Calin (George)


    textabstractThe central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs

  4. Dynamic Epigenetic Control of Highly Conserved Noncoding Elements

    KAUST Repository

    Seridi, Loqmane


    Background Many noncoding genomic loci have remained constant over long evolutionary periods, suggesting that they are exposed to strong selective pressures. The molecular functions of these elements have been partially elucidated, but the fundamental reason for their extreme conservation is still unknown. Results To gain new insights into the extreme selection of highly conserved noncoding elements (HCNEs), we used a systematic analysis of multi-omic data to study the epigenetic regulation of such elements during the development of Drosophila melanogaster. At the sequence level, HCNEs are GC-rich and have a characteristic oligomeric composition. They have higher levels of stable nucleosome occupancy than their flanking regions, and lower levels of mononucleosomes and H3.3, suggesting that these regions reside in compact chromatin. Furthermore, these regions showed remarkable modulations in histone modification and the expression levels of adjacent genes during development. Although HCNEs are primarily initiated late in replication, about 10% were related to early replication origins. Finally, HCNEs showed strong enrichment within lamina-associated domains. Conclusion HCNEs have distinct and protective sequence properties, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. These observations indicate that such elements are likely to have essential cellular functions, and offer insights into their epigenetic properties.

  5. [Non-coding RNA in fungi--a review]. (United States)

    Li, Liping; Luo, Yuping; Li, Siguang


    Non-coding RNAs (ncRNAs) existing widely in many living organisms are functional RNA molecules, function directly as structural or regulatory RNAs in organisms. Although large and diverse populations of ncRNAs have been extensively studied and well understood in animals and plants, few reports could be found about ncRNAs in fungi. Recently, with the development of modern biological techniques, a number of ncRNAs have been identified in fungi, including snoRNA-derived RNAs, long non-coding RNAs, small interfering RNAs (siRNAs), dsRNA Killer viruses, and novel classes of ncRNAs discovered in filamentous fungi. These ncRNAs play important roles in gene transcription and translation, RNA processing and modifying, chromatin structure, and even fungal pathogenicity. Therefore, studies on ncRNAs in fungi may shed light on the regulatory system of gene expression and the characteristics of fungal growth, and even provide some clues towards understanding pathogenic mechanisms of pathogenic fungi, which will contribute to the treatment of fungal diseases. Here, we reviewed the discovery of fungal ncRNAs, their origins and processing, classification, and biological functions, aiming to establish a theoretical foundation and basis for deep understanding of fungal ncRNAs in future.

  6. Comprehensive reconstruction andvisualization of non-coding regulatorynetworks in human

    Directory of Open Access Journals (Sweden)

    Vincenzo eBonnici


    Full Text Available Research attention has been powered to understand the functional roles of non-coding RNAs (ncRNAs. Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established online repositories. The interactions involve RNA, DNA, proteins and diseases. ncRNA-DB is available at It is equipped with three interfaces: web based, command line and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape.

  7. Long non-coding RNAs in aging organs and tissues. (United States)

    Xing, Wenmin; Gao, Wenyan; Mao, Genxiang; Zhang, Jing; Lv, Xiaoling; Wang, Guofu; Yan, Jing


    The aging process directly impacts bodily functions on multiple levels, including a reduced ability to resist stress, damage and disease. Besides changes in metabolic control, the aging process coincides with the altered long non-coding RNAs (lncRNAs) expression, which are ≥200nt long class of non-protein coding RNAs. The majority of non-coding transcripts of mammalian organs and tissues are expressed in developmentally regulated and cell-type specific manners. Specific altered lncRNA level has been involved in induction and maintenance of the whole human body aging with highly specific spatial andtemporal expression patterns. Furthermore, many lncRNAs are transcribed in sense, antisense and bidirectional manners in the mammalian genome. They play a vital role in regulating organ or tissue differentiation during aging by binding with miRNA or proteins to act as a decoy. Recently, the correlation between lncRNAs and aging has been studied intensely. Here, we have summarized some examples of known and novel lncRNAs that have been implicated in the aging process in the whole mammalian body and we discuss these patterns, conservation and characters during aging. This may further promote the development of research on lncRNAs and the aging process. © 2017 John Wiley & Sons Australia, Ltd.

  8. Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets? (United States)

    Boon, Reinier A; Jaé, Nicolas; Holdt, Lesca; Dimmeler, Stefanie


    Recent studies suggest that the majority of the human genome is transcribed, but only about 2% accounts for protein-coding exons. Long noncoding RNAs (lncRNAs) constitute a heterogenic class of RNAs that includes, for example, intergenic lncRNAs, antisense transcripts, and enhancer RNAs. Moreover, alternative splicing can lead to the formation of circular RNAs. In support of putative functions, GWAS for cardiovascular diseases have shown predictive single-nucleotide polymorphisms in lncRNAs, such as the 9p21 susceptibility locus that encodes the lncRNA antisense noncoding RNA in the INK4 locus (ANRIL). Many lncRNAs are regulated during disease. For example, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and myocardial infarction-associated transcript (MIAT) were shown to affect endothelial cell functions and diabetic retinopathy, whereas lincRNA-p21 controls neointima formation. In the heart, several lncRNAs were shown to act as microRNA sponges and to control ischemia-reperfusion injury or act as epigenetic regulators. In this review, the authors summarize the current understanding of lncRNA functions and their role as biomarkers in cardiovascular diseases. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. Long Noncoding RNAs as a Key Player in Hepatocellular Carcinoma (United States)

    Mehra, Mrigaya; Chauhan, Ranjit


    Hepatocellular carcinoma (HCC) is a major malignancy in the liver and has emerged as one of the main cancers in the world with a high mortality rate. However, the molecular mechanisms of HCC are still poorly understood. Long noncoding RNAs (lncRNAs) have recently come to the forefront as functional non–protein-coding RNAs that are involved in a variety of cellular processes ranging from maintaining the structural integrity of chromosomes to gene expression regulation in a spatiotemporal manner. Many recent studies have reported the involvement of lncRNAs in HCC which has led to a better understanding of the underlying molecular mechanisms operating in HCC. Long noncoding RNAs have been shown to regulate development and progression of HCC, and thus, lncRNAs have both diagnostic and therapeutic potentials. In this review, we present an overview of the lncRNAs involved in different stages of HCC and their potential in clinical applications which have been studied so far. PMID:29147078

  10. Noncoding RNAs as Novel Biomarkers in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    C. G. H. Rönnau


    Full Text Available Prostate cancer (PCa is the second most common diagnosed malignant disease in men worldwide. Although serum PSA test dramatically improved the early diagnosis of PCa, it also led to an overdiagnosis and as a consequence to an overtreatment of patients with an indolent disease. New biomarkers for diagnosis, prediction, and monitoring of the disease are needed. These biomarkers would enable the selection of patients with aggressive or progressive disease and, hence, would contribute to the implementation of individualized therapy of the cancer patient. Since the FDA approval of the long noncoding PCA3 RNA-based urine test for the diagnosis of PCa patients, many new noncoding RNAs (ncRNAs associated with PCa have been discovered. According to their size and function, ncRNAs can be divided into small and long ncRNAs. NcRNAs are expressed in (tumor tissue, but many are also found in circulating tumor cells and in all body fluids as protein-bound or incorporated in extracellular vesicles. In these protected forms they are stable and so they can be easily analyzed, even in archival specimens. In this review, the authors will focus on ncRNAs as novel biomarker candidates for PCa diagnosis, prediction, prognosis, and monitoring of therapeutic response and discuss their potential for an implementation into clinical practice.

  11. Gene conversion homogenizes the CMT1A paralogous repeats

    Directory of Open Access Journals (Sweden)

    Hurles Matthew E


    Full Text Available Abstract Background Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. It has recently been shown empirically that gene conversion can homogenize such repeats, resulting in longer stretches of absolute identity that may increase the rate of non-allelic homologous recombination. Results Here, a statistical test to detect gene conversion between pairs of non-coding sequences is presented. It is shown that the 24 kb Charcot-Marie-Tooth type 1A paralogous repeats (CMT1A-REPs exhibit the imprint of gene conversion processes whilst control orthologous sequences do not. In addition, Monte Carlo simulations of the evolutionary divergence of the CMT1A-REPs, incorporating two alternative models for gene conversion, generate repeats that are statistically indistinguishable from the observed repeats. Bounds are placed on the rate of these conversion processes, with central values of 1.3 × 10-4 and 5.1 × 10-5 per generation for the alternative models. Conclusions This evidence presented here suggests that gene conversion may have played an important role in the evolution of the CMT1A-REP paralogous repeats. The rates of these processes are such that it is probable that homogenized CMT1A-REPs are polymorphic within modern populations. Gene conversion processes are similarly likely to play an important role in the evolution of other segmental duplications and may influence the rate of non-allelic homologous recombination between them.

  12. Bistability in self-activating genes regulated by non-coding RNAs

    International Nuclear Information System (INIS)

    Miro-Bueno, Jesus


    Non-coding RNA molecules are able to regulate gene expression and play an essential role in cells. On the other hand, bistability is an important behaviour of genetic networks. Here, we propose and study an ODE model in order to show how non-coding RNA can produce bistability in a simple way. The model comprises a single gene with positive feedback that is repressed by non-coding RNA molecules. We show how the values of all the reaction rates involved in the model are able to control the transitions between the high and low states. This new model can be interesting to clarify the role of non-coding RNA molecules in genetic networks. As well, these results can be interesting in synthetic biology for developing new genetic memories and biomolecular devices based on non-coding RNAs

  13. The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease

    Directory of Open Access Journals (Sweden)

    Clarissa P.C. Gomes


    Full Text Available The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus.

  14. Expansion tube test time predictions (United States)

    Gourlay, Christopher M.


    The interaction of an interface between two gases and strong expansion is investigated and the effect on flow in an expansion tube is examined. Two mechanisms for the unsteady Pitot-pressure fluctuations found in the test section of an expansion tube are proposed. The first mechanism depends on the Rayleigh-Taylor instability of the driver-test gas interface in the presence of a strong expansion. The second mechanism depends on the reflection of the strong expansion from the interface. Predictions compare favorably with experimental results. The theory is expected to be independent of the absolute values of the initial expansion tube filling pressures.

  15. Expansion at Olympic Dam

    International Nuclear Information System (INIS)

    Lewis, C.


    The Olympic Dam orebody is the 6th largest copper and the single largest uranium orebody in the world. Mine production commenced in June 1988, at an annual production rate of around 45,000 tonnes of copper and 1,000 tonnes of uranium. Western Mining Corporation announced in 1996 a proposed $1.25 billion expansion of the Olympic Dam operation to raise the annual production capacity of the mine to 200,000 tonnes of copper, approximately 3,700 tonnes of uranium, 75,000 ounces of gold and 950,000 ounces of silver by 2001. Further optimisation work has identified a faster track expansion route, with an increase in the capital cost to $1.487 billion but improved investment outcome, a new target completion date of end 1999, and a new uranium output of 4,600 tonnes per annum from that date

  16. Symmetric eikonal expansion

    International Nuclear Information System (INIS)

    Matsuki, Takayuki


    Symmetric eikonal expansion for the scattering amplitude is formulated for nonrelativistic and relativistic potential scatterings and also for the quantum field theory. The first approximations coincide with those of Levy and Sucher. The obtained scattering amplitudes are time reversal invariant for all cases and are crossing symmetric for the quantum field theory in each order of approximation. The improved eikonal phase introduced by Levy and Sucher is also derived from the different approximation scheme from the above. (auth.)

  17. Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

    DEFF Research Database (Denmark)

    Lindquist, Sg; Duno, M; Batbayli, M


    Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical...

  18. Molecular analysis of the eTG trinucleotide repeat in South African ...

    African Journals Online (AJOL)

    -4 When amplified, this trinucleotide repeat is responsible for DNA instability and molecular pathology. A similar mechanism of trinucleotide repeat expansion has been described in fragile X mental retardation syndrome. (CGG):·· spinobulbar muscular atrophy (CAG)' and, more. MRC Human Ecogenetics Research Unit, ...

  19. Analysis of CAG/CTG triplet repeats in the human genome ...

    Indian Academy of Sciences (India)

    Instability and polymorphism at several CAG/CTG trinucleotide repeat loci have been associated with human genetic disorders. In an attempt to identify novel sites that may be possible loci for expansion of CAG/CTG repeats, we searched all human sequences in the EMBL nucleotide sequence database for (CAG)5 and ...

  20. Repeatability of Cryogenic Multilayer Insulation (United States)

    Johnson, W. L.; Vanderlaan, M.; Wood, J. J.; Rhys, N. O.; Guo, W.; Van Sciver, S.; Chato, D. J.


    Due to the variety of requirements across aerospace platforms, and one off projects, the repeatability of cryogenic multilayer insulation (MLI) has never been fully established. The objective of this test program is to provide a more basic understanding of the thermal performance repeatability of MLI systems that are applicable to large scale tanks. There are several different types of repeatability that can be accounted for: these include repeatability between identical blankets, repeatability of installation of the same blanket, and repeatability of a test apparatus. The focus of the work in this report is on the first two types of repeatability. Statistically, repeatability can mean many different things. In simplest form, it refers to the range of performance that a population exhibits and the average of the population. However, as more and more identical components are made (i.e. the population of concern grows), the simple range morphs into a standard deviation from an average performance. Initial repeatability testing on MLI blankets has been completed at Florida State University. Repeatability of five Glenn Research Center (GRC) provided coupons with 25 layers was shown to be +/- 8.4% whereas repeatability of repeatedly installing a single coupon was shown to be +/- 8.0%. A second group of 10 coupons has been fabricated by Yetispace and tested by Florida State University, the repeatability between coupons has been shown to be +/- 15-25%. Based on detailed statistical analysis, the data has been shown to be statistically significant.

  1. Duct Leakage Repeatability Testing

    Energy Technology Data Exchange (ETDEWEB)

    Walker, Iain [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sherman, Max [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)


    The purpose of this report is to evaluate the repeatability of the three most significant measurement techniques for duct leakage using data from the literature and recently obtained field data. We will also briefly discuss the first two factors. The main question to be answered by this study is to determine if differences in the repeatability of these tests methods is sufficient to indicate that any of these methods is so poor that it should be excluded from consideration as an allowed procedure in codes and standards. The three duct leak measurement methods assessed in this report are the two duct pressurization methods that are commonly used by many practitioners and the DeltaQ technique. These are methods B, C and A, respectively of the ASTM E1554 standard. Although it would be useful to evaluate other duct leak test methods, this study focused on those test methods that are commonly used and are required in various test standards, such as BPI (2010), RESNET (2014), ASHRAE 62.2 (2013), California Title 24 (CEC 2012), DOE Weatherization and many other energy efficiency programs.

  2. Chromatin, Non-Coding RNAs, and the Expression of HIV

    Directory of Open Access Journals (Sweden)

    Jessica N. Groen


    Full Text Available HIV is a chronic viral infection affecting an estimated 34 million people worldwide. Current therapies employ the use of a cocktail of antiretroviral medications to reduce the spread and effects of HIV, however complete eradication from an individual currently remains unattainable. Viral latency and regulation of gene expression is a key consideration when developing effective treatments. While our understanding of these processes remains incomplete new developments suggest that non-coding RNA (ncRNA mediated regulation may provide an avenue to controlling both viral expression and latency. Here we discuss the importance of known regulatory mechanisms and suggest directions for further study, in particular the use ncRNAs in controlling HIV expression.

  3. Identification of expressed and conserved human noncoding RNAs

    DEFF Research Database (Denmark)

    Nielsen, Morten Muhlig; Tehler, Disa; Vang, Søren


    The past decade has shown mammalian genomes to be pervasively transcribed and identified thousands of noncoding (nc) transcripts. It is currently unclear to what extent these transcripts are of functional importance, as experimental functional evidence exists for only a small fraction. Here, we...... characterize the expression and evolutionary conservation properties of 12,115 known and novel nc transcripts, including structural RNAs, long nc RNAs (lncRNAs), antisense RNAs, EvoFold predictions, ultraconserved elements, and expressed nc regions. Expression levels are evaluated across 12 human tissues using...... a custom-designed microarray, supplemented with RNAseq. Conservation levels are evaluated at both the base level and at the syntenic level. We combine these measures with epigenetic mark annotations to identify subsets of novel nc transcripts that show characteristics similar to known functional nc...

  4. Long Non-coding RNAs and Drug Resistance. (United States)

    Pan, Jing-Jing; Xie, Xiao-Juan; Li, Xu; Chen, Wei


    Long non-coding RNAs (lncRNAs) are emerging as key players in gene expression that govern cell developmental processes, and thus contributing to diseases, especially cancers. Many studies have suggested that aberrant expression of lncRNAs is responsible for drug resistance, a substantial obstacle for cancer therapy. Drug resistance not only results from individual variations in patients, but also from genetic and epigenetic differences in tumors. It is reported that drug resistance is tightly modulated by lncRNAs which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, and drug metabolism. In this review, we summarize recent advances in research on lncRNAs associated with drug resistance and underlying molecular or cellular mechanisms, which may contribute helpful approaches for the development of new therapeutic strategies to overcome treatment failure.

  5. Long noncoding RNAs in Innate and Adaptive Immunity (United States)

    Fitzgerald, Katherine A.; Caffrey, Daniel R.


    The differentiation and activation of both innate and adaptive immune cells is highly dependent on a coordinated set of transcriptional and post-transcriptional events. Chromatin-modifiers and transcription factors regulate the accessibility and transcription of immune genes, respectively. Immune cells also express miRNA and RNA-binding proteins that provide an additional layer of regulation at the mRNA level. However, long noncoding RNA (lncRNA), which have been primarily studied in the context of genomic imprinting, cancer, and cell differentiation, are now emerging as important regulators of immune cell differentiation and activation. In this review, we provide a brief overview of lncRNA, their known functions in immunity, and discuss their potential to be more broadly involved in other aspects of the immune response. PMID:24556411

  6. Evaluation of Agency Non-Code Layered Pressure Vessels (LPVs) (United States)

    Prosser, William H.


    In coordination with the Office of Safety and Mission Assurance and the respective Center Pressure System Managers (PSMs), the NASA Engineering and Safety Center (NESC) was requested to formulate a consensus draft proposal for the development of additional testing and analysis methods to establish the technical validity, and any limitation thereof, for the continued safe operation of facility non-code layered pressure vessels. The PSMs from each NASA Center were asked to participate as part of the assessment team by providing, collecting, and reviewing data regarding current operations of these vessels. This report contains the outcome of the assessment and the findings, observations, and NESC recommendations to the Agency and individual NASA Centers.

  7. Long noncoding RNAs: Novel insights into hepatocelluar carcinoma. (United States)

    He, Yong; Meng, Xiao-Ming; Huang, Cheng; Wu, Bao-Ming; Zhang, Lei; Lv, Xiong-Wen; Li, Jun


    Recent advances in non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack of coding protein function, termed long noncoding RNAs (lncRNAs). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNAs world. Moreover, accumulating studies have demonstrated that a class of lncRNAs are dysregulated in hepatocellular carcinoma(HCC) and closely related with tumorigenesis, metastasis, prognosis or diagnosis. In this review, we will briefly discuss the regulation and functional role of lncRNAs in HCC, therefore evaluating the potential of lncRNAs as prospective novel therapeutic targets in HCC. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  8. Gene regulation in the immune system by long noncoding RNAs. (United States)

    Chen, Y Grace; Satpathy, Ansuman T; Chang, Howard Y


    Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression in the immune system. Studies have shown that lncRNAs are expressed in a highly lineage-specific manner and control the differentiation and function of innate and adaptive cell types. In this Review, we focus on mechanisms used by lncRNAs to regulate genes encoding products involved in the immune response, including direct interactions with chromatin, RNA and proteins. In addition, we address new areas of lncRNA biology, such as the functions of enhancer RNAs, circular RNAs and chemical modifications to RNA in cellular processes. We emphasize critical gaps in knowledge and future prospects for the roles of lncRNAs in the immune system and autoimmune disease.

  9. Noncoding RNAs: Regulators of the Mammalian Transcription Machinery. (United States)

    Eidem, Tess M; Kugel, Jennifer F; Goodrich, James A


    Transcription by RNA polymerase II (Pol II) is required to produce mRNAs and some noncoding RNAs (ncRNAs) within mammalian cells. This coordinated process is precisely regulated by multiple factors, including many recently discovered ncRNAs. In this perspective, we will discuss newly identified ncRNAs that facilitate DNA looping, regulate transcription factor binding, mediate promoter-proximal pausing of Pol II, and/or interact with Pol II to modulate transcription. Moreover, we will discuss new roles for ncRNAs, as well as a novel Pol II RNA-dependent RNA polymerase activity that regulates an ncRNA inhibitor of transcription. As the multifaceted nature of ncRNAs continues to be revealed, we believe that many more ncRNA species and functions will be discovered. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Rfam: annotating families of non-coding RNA sequences. (United States)

    Daub, Jennifer; Eberhardt, Ruth Y; Tate, John G; Burge, Sarah W


    The primary task of the Rfam database is to collate experimentally validated noncoding RNA (ncRNA) sequences from the published literature and facilitate the prediction and annotation of new homologues in novel nucleotide sequences. We group homologous ncRNA sequences into "families" and related families are further grouped into "clans." We collate and manually curate data cross-references for these families from other databases and external resources. Our Web site offers researchers a simple interface to Rfam and provides tools with which to annotate their own sequences using our covariance models (CMs), through our tools for searching, browsing, and downloading information on Rfam families. In this chapter, we will work through examples of annotating a query sequence, collating family information, and searching for data.

  11. Inhibition of Cell Growth and Shoot Development by a Specific Nucleotide Sequence in a Noncoding Viroid RNA (United States)

    Qi, Yijun; Ding, Biao


    Viroids are small noncoding and infectious RNAs that replicate autonomously and move systemically throughout an infected plant. The RNAs of the family Pospiviroidae contain a central conserved region (CCR) that has long been thought to be involved in replication. Here, we report that the CCR of Potato spindle tuber viroid (PSTVd) also plays a role in pathogenicity. A U257A change in the CCR converted the intermediate strain PSTVdInt to a lethal strain that caused severe growth stunting and premature death of infected plants. PSTVd with nucleotide U257 changed to C or G did not cause such symptoms. The pathogenic effect of the U257A substitution was abolished by a C259U substitution in the same RNA. Analyses of the pathogenic effects of the U257A substitution in three other PSTVd variants established A257 as a new pathogenicity determinant that functions independently and synergistically with the classic pathogenicity domain. The U257A substitution did not alter PSTVd secondary structure, replication levels, or tissue tropism. The stunted growth of PSTVdIntU257A-infected tomato plants resulted from restricted cell expansion but not cell division or differentiation. This was correlated positively with the downregulated expression of an expansin gene, LeExp2. Our results demonstrate that specific nucleotides in a noncoding, pathogenic RNA have a profound effect in altering distinct cellular responses, which then lead to well-defined alterations in plant growth and developmental patterns. The feasibility of correlating viroid RNA sequence/structure with the altered expression of specific host genes, cellular processes, and developmental patterns makes viroid infection a valuable system in which to investigate host factors for symptom expression and perhaps also to characterize the mechanisms of RNA regulation of gene expression in plants. PMID:12782729

  12. Facts and updates about cardiovascular non-coding RNAs in heart failure. (United States)

    Thum, Thomas


    About 11% of all deaths include heart failure as a contributing cause. The annual cost of heart failure amounts to US $34,000,000,000 in the United States alone. With the exception of heart transplantation, there is no curative therapy available. Only occasionally there are new areas in science that develop into completely new research fields. The topic on non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, is such a field. In this short review, we will discuss the latest developments about non-coding RNAs in cardiovascular disease. MicroRNAs are short regulatory non-coding endogenous RNA species that are involved in virtually all cellular processes. Long non-coding RNAs also regulate gene and protein levels; however, by much more complicated and diverse mechanisms. In general, non-coding RNAs have been shown to be of great value as therapeutic targets in adverse cardiac remodelling and also as diagnostic and prognostic biomarkers for heart failure. In the future, non-coding RNA-based therapeutics are likely to enter the clinical reality offering a new treatment approach of heart failure.

  13. Long Noncoding RNA Expression during Human B-Cell Development.

    Directory of Open Access Journals (Sweden)

    Andreas Petri

    Full Text Available Long noncoding RNAs (lncRNAs have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7, and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6, respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as "guilt by association". By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations.

  14. Ups and Downs: Mechanisms of Repeat Instability in the Fragile X-Related Disorders

    Directory of Open Access Journals (Sweden)

    Xiao-Nan Zhao


    Full Text Available The Fragile X-related disorders (FXDs are a group of clinical conditions resulting from the expansion of a CGG/CCG-repeat tract in exon 1 of the Fragile X mental retardation 1 (FMR1 gene. While expansions of the repeat tract predominate, contractions are also seen with the net result being that individuals can show extensive repeat length heterogeneity in different tissues. The mechanisms responsible for expansion and contraction are still not well understood. This review will discuss what is known about these processes and current evidence that supports a model in which expansion arises from the interaction of components of the base excision repair, mismatch repair and transcription coupled repair pathways.

  15. Load regulating expansion fixture

    International Nuclear Information System (INIS)

    Wagner, L.M.; Strum, M.J.


    A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils is disclosed. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located there between. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components. 1 fig

  16. Repeat Customer Success in Extension (United States)

    Bess, Melissa M.; Traub, Sarah M.


    Four multi-session research-based programs were offered by two Extension specialist in one rural Missouri county. Eleven participants who came to multiple Extension programs could be called "repeat customers." Based on the total number of participants for all four programs, 25% could be deemed as repeat customers. Repeat customers had…

  17. Non-coding sequence retrieval system for comparative genomic analysis of gene regulatory elements

    Directory of Open Access Journals (Sweden)

    Temple Matthew H


    Full Text Available Abstract Background Completion of the human genome sequence along with other species allows for greater understanding of the biochemical mechanisms and processes that govern healthy as well as diseased states. The large size of the genome sequences has made them difficult to study using traditional methods. There are many studies focusing on the protein coding sequences, however, not much is known about the function of non-coding regions of the genome. It has been demonstrated that parts of the non-coding region play a critical role as gene regulatory elements. Enhancers that regulate transcription processes have been found in intergenic regions. Furthermore, it is observed that regulatory elements found in non-coding regions are highly conserved across different species. However, the analysis of these regulatory elements is not as straightforward as it may first seem. The development of a centralized resource that allows for the quick and easy retrieval of non-coding sequences from multiple species and is capable of handing multi-gene queries is critical for the analysis of non-coding sequences. Here we describe the development of a web-based non-coding sequence retrieval system. Results This paper presents a Non-Coding Sequences Retrieval System (NCSRS. The NCSRS is a web-based bioinformatics tool that performs fast and convenient retrieval of non-coding and coding sequences from multiple species related to a specific gene or set of genes. This tool has compiled resources from multiple sources into one easy to use and convenient web based interface. With no software installation necessary, the user needs only internet access to use this tool. Conclusion The unique features of this tool will be very helpful for those studying gene regulatory elements that exist in non-coding regions. The web based application can be accessed on the internet at:

  18. Tissue expansion in burn sequelae repair. (United States)

    Tavares Filho, João Medeiros; Belerique, Manoel; Franco, Diogo; Porchat, Carlos Alberto; Franco, Talita


    Burns may cause emotional, aesthetic and functional sequelae. Extended or hypertrophic scars are usually difficult to repair using local tissues, and the use of skin grafts may cause further injuries to the donor sites. The use of tissue expanders may offer a better option in the treatment of burn sequelae. This is a report on our experience using tissue expanders in 54 cases (23 patients) of burn sequelae located in different anatomical areas. Fourteen of the patients were female and nine male ranging in age between 5 and 48. The expanders were placed in the subgaleal, submuscular, subfascial or subcutaneous planes. Skin expansion was completed in 50 cases (92.5%). The injured area was removed by advancement flaps in 44 cases and by transposition flaps in 6 of them. Primary expansion was performed in 42 cases and reexpansion in 12. The rate of complications was 24.07%, of which 30.8% were considered to be absolute and 69.2% relative. Tissue expansion is an excellent option for burn sequelae treatment because it provides skin of similar local characteristics and does not damage the donor site. The procedure can be repeated in the event of major sequelae (reexpansion).

  19. Thermal expansion of granite rocks

    International Nuclear Information System (INIS)

    Stephansson, O.


    The thermal expansion of rocks is strongly controlled by the thermal expansion of the minerals. The theoretical thermal expansion of the Stripa Granite is gound to be 21 . 10 -6 [deg C] -1 at 25 deg C and 38 . 10 -6 [deg C] -1 at 400 deg C. The difference in expansion for the rock forming minerals causes micro cracking at heating. The expansion due to micro cracks is found to be of the same order as the mineral expansion. Most of the micro cracks will close at pressures of the order of 10 - 20 MPa. The thermal expansion of a rock mass including the effect of joints is determined in the pilot heater test in the Stripa Mine

  20. The Non-Coding RNA Ontology (NCRO): a comprehensive resource for the unification of non-coding RNA biology. (United States)

    Huang, Jingshan; Eilbeck, Karen; Smith, Barry; Blake, Judith A; Dou, Dejing; Huang, Weili; Natale, Darren A; Ruttenberg, Alan; Huan, Jun; Zimmermann, Michael T; Jiang, Guoqian; Lin, Yu; Wu, Bin; Strachan, Harrison J; He, Yongqun; Zhang, Shaojie; Wang, Xiaowei; Liu, Zixing; Borchert, Glen M; Tan, Ming


    In recent years, sequencing technologies have enabled the identification of a wide range of non-coding RNAs (ncRNAs). Unfortunately, annotation and integration of ncRNA data has lagged behind their identification. Given the large quantity of information being obtained in this area, there emerges an urgent need to integrate what is being discovered by a broad range of relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a systematically structured and precisely defined controlled vocabulary for the domain of ncRNAs, thereby facilitating the discovery, curation, analysis, exchange, and reasoning of data about structures of ncRNAs, their molecular and cellular functions, and their impacts upon phenotypes. The goal of NCRO is to serve as a common resource for annotations of diverse research in a way that will significantly enhance integrative and comparative analysis of the myriad resources currently housed in disparate sources. It is our belief that the NCRO ontology can perform an important role in the comprehensive unification of ncRNA biology and, indeed, fill a critical gap in both the Open Biological and Biomedical Ontologies (OBO) Library and the National Center for Biomedical Ontology (NCBO) BioPortal. Our initial focus is on the ontological representation of small regulatory ncRNAs, which we see as the first step in providing a resource for the annotation of data about all forms of ncRNAs. The NCRO ontology is free and open to all users, accessible at:

  1. Targeting non-coding RNAs in Plants with the CRISPR-Cas technology is a challenge yet worth accepting

    Directory of Open Access Journals (Sweden)

    Jolly eBasak


    Full Text Available Non-coding RNAs (ncRNAs have emerged as versatile master regulator of biological functions in recent years. MicroRNAs (miRNAs are small endogenous ncRNAs of 18-24 nucleotides in length that originates from long self-complementary precursors. Besides their direct involvement in developmental processes, plant miRNAs play key roles in gene regulatory networks and varied biological processes. Alternatively, long ncRNAs (lncRNAs are a large and diverse class of transcribed ncRNAs whose length exceed that of 200 nucleotides. Plant lncRNAs are transcribed by different RNA polymerases, showing diverse structural features. Plant lncRNAs also are important regulators of gene expression in diverse biological processes. There has been a breakthrough in the technology of genome editing, the CRISPR-Cas9 (clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 technology, in the last decade. CRISPR loci are transcribed into ncRNA and eventually form a functional complex with Cas9 and further guide the complex to cleave complementary invading DNA. The CRISPR-Cas technology has been successfully applied in model plants such as Arabidopsis and tobacco and important crops like wheat, maize and rice. However, all these studies are focused on protein coding genes. Information about targeting non-coding genes is scarce. Hitherto, the CRISPR-Cas technology has been exclusively used in vertebrate systems to engineer miRNA/lncRNAs, but it is still relatively unexplored in plants. While briefing miRNAs, lncRNAs and applications of the CRISPR-Cas technology in human and animals, this review essentially elaborates several strategies to overcome the challenges of applying the CRISPR-Cas technology in editing ncRNAs in plants and the future perspective of this field.

  2. Replication Stalling and Heteroduplex Formation within CAG/CTG Trinucleotide Repeats by Mismatch Repair

    KAUST Repository

    Viterbo, David


    Trinucleotide repeat expansions are responsible for at least two dozen neurological disorders. Mechanisms leading to these large expansions of repeated DNA are still poorly understood. It was proposed that transient stalling of the replication fork by the repeat tract might trigger slippage of the newly-synthesized strand over its template, leading to expansions or contractions of the triplet repeat. However, such mechanism was never formally proven. Here we show that replication fork pausing and CAG/CTG trinucleotide repeat instability are not linked, stable and unstable repeats exhibiting the same propensity to stall replication forks when integrated in a yeast natural chromosome. We found that replication fork stalling was dependent on the integrity of the mismatch-repair system, especially the Msh2p-Msh6p complex, suggesting that direct interaction of MMR proteins with secondary structures formed by trinucleotide repeats in vivo, triggers replication fork pauses. We also show by chromatin immunoprecipitation that Msh2p is enriched at trinucleotide repeat tracts, in both stable and unstable orientations, this enrichment being dependent on MSH3 and MSH6. Finally, we show that overexpressing MSH2 favors the formation of heteroduplex regions, leading to an increase in contractions and expansions of CAG/CTG repeat tracts during replication, these heteroduplexes being dependent on both MSH3 and MSH6. These heteroduplex regions were not detected when a mutant msh2-E768A gene in which the ATPase domain was mutated was overexpressed. Our results unravel two new roles for mismatch-repair proteins: stabilization of heteroduplex regions and transient blocking of replication forks passing through such repeats. Both roles may involve direct interactions between MMR proteins and secondary structures formed by trinucleotide repeat tracts, although indirect interactions may not be formally excluded.

  3. [Determination of major expansion properties of refractory die material compatible with slip casting core of sintered titanium powder]. (United States)

    Chao, Y; Kuang, X; Liao, Y; Wang, H


    To determinate major expansion properties of refractory die material. The setting expansion ratio of refractory die material for slip casting core of sintered titanium powder at room temperature was performed, as well as thermal expansion ratio from room temperature to 800 degrees C. The maximum setting expansion ratio in 2 hours reached 0.3407%; The final setting expansion ratio in 24 hours was 0.3117%; The mean thermal expansion coefficient was mainly in range of 8 x 10(-6)-11 x 10(-6)/degree C; The expansion property seemed very stable after sintering repeatedly and the small shrinkage after sintering could be compensated with the die spacer and setting expansion. The expansion properties of the refractory die material that we synthesized can fulfil the application requirements of slip casting core of sintered titanium powder.


    Directory of Open Access Journals (Sweden)

    A. I. Sushkov


    Full Text Available Nowadays, kidney transplantation is the best approach of renal replacement therapy for the majority of patients with end-stage renal disease that significantly improves the quality and length of life. Advances in the field of organ donation, immunosuppression, transplant surgery and immunology have improved short-term graft and patient survival. But the long-term graft survival remains static over last two decades. The disparity between low graft and high patient long-term survival led to increasing number of transplant recipients with failed grafts. Repeat renal transplant is presumed to be a good option for many patients losing their grafts, but it is associated with higher complication rates. Unfortunately, there are no evidence-based recommendations or guidelines for renal retransplantation procedure. This review is based on 100 scientifi c publications related to various aspects of the kidney retransplantation and provides the recent data on this matter.

  5. Rethinking expansive learning

    DEFF Research Database (Denmark)

    Kolbæk, Ditte; Lundh Snis, Ulrika

    in their professional organisation and how they developed their identity to become more skilled practitioners. We discuss the effects of the written discussions and reflections on the students’ endeavour to become authors in practice. Our contribution to the research consists of considerations of changing the spoken......Abstract: This paper analyses an online community of master’s students taking a course in ICT and organisational learning. The students initiated and facilitated an educational design for organisational learning called Proactive Review in the organisation where they are employed. By using an online...... discussion forum on Google groups, they created new ways of reflecting and learning. We used netnography to select qualitative postings from the online community and expansive learning concepts for data analysis. The findings show how students changed practices of organisational learning...

  6. Toward understanding non-coding RNA roles in intracranial aneurysms and subarachnoid hemorrhage

    Directory of Open Access Journals (Sweden)

    Huang Fengzhen


    Full Text Available Subarachnoid hemorrhage (SAH is a common and frequently life-threatening cerebrovascular disease, which is mostly related with a ruptured intracranial aneurysm. Its complications include rebleeding, early brain injury, cerebral vasospasm, delayed cerebral ischemia, chronic hydrocephalus, and also non neurological problems. Non-coding RNAs (ncRNAs, comprising of microRNAs (miRNAs, small interfering RNAs (siRNAs and long non-coding RNAs (lncRNAs, play an important role in intracranial aneurysms and SAH. Here, we review the non-coding RNAs expression profile and their related mechanisms in intracranial aneurysms and SAH. Moreover, we suggest that these non-coding RNAs function as novel molecular biomarkers to predict intracranial aneurysms and SAH, and may yield new therapies after SAH in the future.

  7. Non-Coding Transcript Heterogeneity in Mesothelioma: Insights from Asbestos-Exposed Mice. (United States)

    Felley-Bosco, Emanuela; Rehrauer, Hubert


    Mesothelioma is an aggressive, rapidly fatal cancer and a better understanding of its molecular heterogeneity may help with making more efficient therapeutic strategies. Non-coding RNAs represent a larger part of the transcriptome but their contribution to diseases is not fully understood yet. We used recently obtained RNA-seq data from asbestos-exposed mice and performed data mining of publicly available datasets in order to evaluate how non-coding RNA contribute to mesothelioma heterogeneity. Nine non-coding RNAs are specifically elevated in mesothelioma tumors and contribute to human mesothelioma heterogeneity. Because some of them have known oncogenic properties, this study supports the concept of non-coding RNAs as cancer progenitor genes.

  8. Neurodevelopmental disabilities in children with intermediate and premutation range fragile X cytosine-guanine-guanine expansions. (United States)

    Renda, Meredith M; Voigt, Robert G; Babovic-Vuksanovic, Dusica; Highsmith, W Edward; Vinson, Sherry S; Sadowski, Christine M; Hagerman, Randi J


    To determine the range of neurodevelopmental diagnoses associated with intermediate (45-54 repeats) and premutation (55-200 repeats) range cytosine-guanine-guanine fragile X expansions, the medical records of children with intermediate or premutation range expansions were retrospectively reviewed, and all neurodevelopmental diagnoses were abstracted. Twenty-nine children (9 female, 20 male; age, 13 months to 17 years) with intermediate (n = 25) or premutation (n = 4) range expansions were identified with neurodevelopmental diagnoses, including global developmental delay/intellectual disability (n = 15), language and learning disorders (n = 9), attention-deficit hyperactivity disorder (n = 5), epilepsy (n = 5), and motor disorders (n = 12), including 2 boys younger than 4 years of age with tremor and ataxia. Thus, children with intermediate or premutation range fragile X cytosine-guanine-guanine expansions may be more susceptible than children without such expansions to other processes, both genetic and environmental, that contribute to neurodevelopmental disability.

  9. Noncoding RNAs in DNA Damage Response: Opportunities for Cancer Therapeutics. (United States)

    Arjumand, Wani; Asiaf, Asia; Ahmad, Shiekh Tanveer


    DNA repair machinery preserves genomic integrity, which is frequently challenged through endogenous and exogenous toxic insults, and any sort of repair machinery malfunctioning ultimately manifests in the form of several types of terrible human diseases such as cancers (Hoeijmakers, Nature 411(6835): 366-374, 2001). Noncoding RNAs (ncRNAs) are crucial players of DNA repair machinery in a cell and play a vital role in maintaining genomic stability, which is essential for its survival and normal functioning thus preventing tumorigenesis. To preserve the integrity of the genome, cells initiate a specific cellular response, recognized as DNA damage response (DDR), which includes several distinct DNA repair pathways. These repair pathways permit normal cells to repair DNA damage or induce apoptosis and cell cycle arrest in case the damage is irreparable. Disruption of these pathways in cancer leads to an increase in genomic instability and mutagenesis. Recently, emerging evidence suggests that ncRNAs play a critical role in the regulation of DDR. There is an extensive crosstalk between ncRNAs and the canonical DDR signaling pathway. DDR-induced expression of ncRNAs can provide a regulatory mechanism to accurately control the expression of DNA damage responsive genes in a spatio-temporal manner. DNA damage alters expression of a variety of ncRNAs at multiple levels including transcriptional regulation, post-transcriptional regulation, and RNA degradation and vice versa, wherein ncRNAs can directly regulate cellular processes involved in DDR by altering expression of their targeting genes, with a particular emphasis on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Relationship between the defects in the DDR and deregulation of related ncRNAs in human cancers is one of the established, which is growing stronger with the advent of high-throughput sequencing techniques such as next-generation sequencing. Understanding of the mechanisms that explain the association

  10. Non-coding RNAs in endometriosis: a narrative review. (United States)

    Panir, Kavita; Schjenken, John E; Robertson, Sarah A; Hull, M Louise


    Endometriosis is a benign gynaecological disorder, which affects 10% of reproductive-aged women and is characterized by endometrial cells from the lining of the uterus being found outside the uterine cavity. However, the pathophysiological mechanisms causing the development of this heterogeneous disease remain enigmatic, and a lack of effective biomarkers necessitates surgical intervention for diagnosis. There is international recognition that accurate non-invasive diagnostic tests and more effective therapies are urgently needed. Non-coding RNA (ncRNA) molecules, which are important regulators of cellular function, have been implicated in many chronic conditions. In endometriosis, transcriptome profiling of tissue samples and functional in vivo and in vitro studies demonstrate that ncRNAs are key contributors to the disease process. In this review, we outline the biogenesis of various ncRNAs relevant to endometriosis and then summarize the evidence indicating their roles in regulatory pathways that govern disease establishment and progression. Articles from 2000 to 2016 were selected for relevance, validity and quality, from results obtained in PubMed, MEDLINE and Google Scholar using the following search terms: ncRNA and reproduction; ncRNA and endometriosis; miRNA and endometriosis; lncRNA and endometriosis; siRNA and endometriosis; endometriosis; endometrial; cervical; ovary; uterus; reproductive tract. All articles were independently screened for eligibility by the authors. This review integrates extensive information from all relevant published studies focusing on microRNAs, long ncRNAs and short inhibitory RNAs in endometriosis. We outline the biological function and synthesis of microRNAs, long ncRNAs and short inhibitory RNAs and provide detailed findings from human research as well as functional studies carried out both in vitro and in vivo, including animal models. Although variability in findings between individual studies exists, collectively, the

  11. Thermal expansion of beryllium oxide

    International Nuclear Information System (INIS)

    Solodukhin, A.V.; Kruzhalov, A.V.; Mazurenko, V.G.; Maslov, V.A.; Medvedev, V.A.; Polupanova, T.I.


    Precise measurements of temperature dependence of the coefficient of linear expansion in the 22-320 K temperature range on beryllium oxide monocrystals are conducted. A model of thermal expansion is suggested; the range of temperature dependence minimum of the coefficient of thermal expansion is well described within the frames of this model. The results of the experiment may be used for investigation of thermal stresses in crystals

  12. Permissible limit for mandibular expansion. (United States)

    Motoyoshi, Mitsuru; Shirai, Sawa; Yano, Shinya; Nakanishi, Kotoe; Shimizu, Noriyoshi


    In recent years, mandibular expansion has been increasingly performed in conjunction with orthodontic treatment. Lateral tipping of the molars associated with mandibular expansion should, however, be considered, because excessive expansion may result in excessive buccal tooth inclination, which may disturb the occlusal relationship. This study was conducted to quantitatively clarify molar movement during mandibular expansion using the Schwarz appliance to determine the permissible limit of mandibular expansion as a clinical index for inclination movement. Inclinations in the masticatory surface of the first molar and intermolar width were measured before expansion (T1), after expansion (T2), and before edgewise treatment (T3). Lower plaster models from 29 subjects treated with expansion plates were used and compared with models from 11 control subjects with normal occlusion. The average treatment change (T1-T2) in intermolar width was 5.42 mm (standard deviation 1.98), and the average angle of buccal tooth inclination was 10.16 degrees (standard deviation 3.83). No significant correlation was found between age prior to treatment and the treatment period when they were compared with the intermolar width increments and inclination angles. There was a significant positive correlation between retention duration and the amount of expansion. The regression coefficient of the angle of buccal tooth inclination during expansion to the increment of the intermolar width was approximately 0.2. This means that 1 mm of expansion is accompanied by 5 degrees of molar lateral tipping. This coefficient is clinically useful for estimating the permissible limit for mandibular expansion.

  13. Purifying selection acts on coding and non-coding sequences of paralogous genes in Arabidopsis thaliana. (United States)

    Hoffmann, Robert D; Palmgren, Michael


    Whole-genome duplications in the ancestors of many diverse species provided the genetic material for evolutionary novelty. Several models explain the retention of paralogous genes. However, how these models are reflected in the evolution of coding and non-coding sequences of paralogous genes is unknown. Here, we analyzed the coding and non-coding sequences of paralogous genes in Arabidopsis thaliana and compared these sequences with those of orthologous genes in Arabidopsis lyrata. Paralogs with lower expression than their duplicate had more nonsynonymous substitutions, were more likely to fractionate, and exhibited less similar expression patterns with their orthologs in the other species. Also, lower-expressed genes had greater tissue specificity. Orthologous conserved non-coding sequences in the promoters, introns, and 3' untranslated regions were less abundant at lower-expressed genes compared to their higher-expressed paralogs. A gene ontology (GO) term enrichment analysis showed that paralogs with similar expression levels were enriched in GO terms related to ribosomes, whereas paralogs with different expression levels were enriched in terms associated with stress responses. Loss of conserved non-coding sequences in one gene of a paralogous gene pair correlates with reduced expression levels that are more tissue specific. Together with increased mutation rates in the coding sequences, this suggests that similar forces of purifying selection act on coding and non-coding sequences. We propose that coding and non-coding sequences evolve concurrently following gene duplication.

  14. Robust identification of noncoding RNA from transcriptomes requires phylogenetically-informed sampling.

    Directory of Open Access Journals (Sweden)

    Stinus Lindgreen


    Full Text Available Noncoding RNAs are integral to a wide range of biological processes, including translation, gene regulation, host-pathogen interactions and environmental sensing. While genomics is now a mature field, our capacity to identify noncoding RNA elements in bacterial and archaeal genomes is hampered by the difficulty of de novo identification. The emergence of new technologies for characterizing transcriptome outputs, notably RNA-seq, are improving noncoding RNA identification and expression quantification. However, a major challenge is to robustly distinguish functional outputs from transcriptional noise. To establish whether annotation of existing transcriptome data has effectively captured all functional outputs, we analysed over 400 publicly available RNA-seq datasets spanning 37 different Archaea and Bacteria. Using comparative tools, we identify close to a thousand highly-expressed candidate noncoding RNAs. However, our analyses reveal that capacity to identify noncoding RNA outputs is strongly dependent on phylogenetic sampling. Surprisingly, and in stark contrast to protein-coding genes, the phylogenetic window for effective use of comparative methods is perversely narrow: aggregating public datasets only produced one phylogenetic cluster where these tools could be used to robustly separate unannotated noncoding RNAs from a null hypothesis of transcriptional noise. Our results show that for the full potential of transcriptomics data to be realized, a change in experimental design is paramount: effective transcriptomics requires phylogeny-aware sampling.

  15. Burial Ground Expansion Hydrogeologic Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Gaughan , T.F.


    Sirrine Environmental Consultants provided technical oversight of the installation of eighteen groundwater monitoring wells and six exploratory borings around the location of the Burial Ground Expansion.

  16. The Asian Rice Gall Midge (Orseolia oryzae Mitogenome Has Evolved Novel Gene Boundaries and Tandem Repeats That Distinguish Its Biotypes.

    Directory of Open Access Journals (Sweden)

    Isha Atray

    Full Text Available The complete mitochondrial genome of the Asian rice gall midge, Orseolia oryzae (Diptera; Cecidomyiidae was sequenced, annotated and analysed in the present study. The circular genome is 15,286 bp with 13 protein-coding genes, 22 tRNAs and 2 ribosomal RNA genes, and a 578 bp non-coding control region. All protein coding genes used conventional start codons and terminated with a complete stop codon. The genome presented many unusual features: (1 rearrangement in the order of tRNAs as well as protein coding genes; (2 truncation and unusual secondary structures of tRNAs; (3 presence of two different repeat elements in separate non-coding regions; (4 presence of one pseudo-tRNA gene; (5 inversion of the rRNA genes; (6 higher percentage of non-coding regions when compared with other insect mitogenomes. Rearrangements of the tRNAs and protein coding genes are explained on the basis of tandem duplication and random loss model and why intramitochondrial recombination is a better model for explaining rearrangements in the O. oryzae mitochondrial genome is discussed. Furthermore, we evaluated the number of iterations of the tandem repeat elements found in the mitogenome. This led to the identification of genetic markers capable of differentiating rice gall midge biotypes and the two Orseolia species investigated.

  17. Hematoma Expansion is Common after Spontaneous Intracerebral Hemorrhage in Children (United States)

    Beslow, Lauren A.; Ichord, Rebecca N.; Gindville, Melissa C.; Kleinman, Jonathan T.; Bastian, Rachel A.; Smith, Sabrina E.; Licht, Daniel J.; Hillis, Argye E.; Jordan, Lori C.


    outcome. Compared to children with only one head CT within 48 hours, children with two head CTs had larger baseline hemorrhage volumes (p=.05) and were more likely to receive treatment for elevated intracranial pressure (pHematoma expansion occurs in children with intracerebral hemorrhage and may require urgent treatment. Repeat CT should be considered in children with either large hemorrhage or increased intracranial pressure. PMID:24296993

  18. Long Non-Coding RNAs in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Lucia Nobili


    Full Text Available Multiple myeloma (MM is an incurable disease caused by the malignant proliferation of bone marrow plasma cells, whose pathogenesis remains largely unknown. Although a large fraction of the genome is actively transcribed, most of the transcripts do not serve as templates for proteins and are referred to as non-coding RNAs (ncRNAs, broadly divided into short and long transcripts on the basis of a 200-nucleotide threshold. Short ncRNAs, especially microRNAs, have crucial roles in virtually all types of cancer, including MM, and have gained importance in cancer diagnosis and prognosis, predicting the response to therapy and, notably, as innovative therapeutic targets. Long ncRNAs (lncRNAs are a very heterogeneous group, involved in many physiological cellular and genomic processes as well as in carcinogenesis, cancer metastasis, and invasion. LncRNAs are aberrantly expressed in various types of cancers, including hematological malignancies, showing either oncogenic or tumor suppressive functions. However, the mechanisms of the related disease-causing events are not yet revealed in most cases. Besides emerging as key players in cancer initiation and progression, lncRNAs own many interesting features as biomarkers with diagnostic and prognostic importance and, possibly, for their utility in therapeutic terms as druggable molecules. This review focuses on the role of lncRNAs in the pathogenesis of MM and summarizes the recent literature.

  19. Strategies to identify long noncoding RNAs involved in gene regulation

    Directory of Open Access Journals (Sweden)

    Lee Catherine


    Full Text Available Abstract Long noncoding RNAs (lncRNAs have been detected in nearly every cell type and found to be fundamentally involved in many biological processes. The characterization of lncRNAs has immense potential to advance our comprehensive understanding of cellular processes and gene regulation, along with implications for the treatment of human disease. The recent ENCODE (Encyclopedia of DNA Elements study reported 9,640 lncRNA loci in the human genome, which corresponds to around half the number of protein-coding genes. Because of this sheer number and their functional diversity, it is crucial to identify a pool of potentially relevant lncRNAs early on in a given study. In this review, we evaluate the methods for isolating lncRNAs by immunoprecipitation and review the advantages, disadvantages, and applications of three widely used approaches – microarray, tiling array, and RNA-seq – for identifying lncRNAs involved in gene regulation. We also look at ways in which data from publicly available databases such as ENCODE can support the study of lncRNAs.

  20. Dynamic Nature of Noncoding RNA Regulation of Adaptive Immune Response

    Directory of Open Access Journals (Sweden)

    Franca Citarella


    Full Text Available Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically. For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs in regulating development, activation and homeostasis of the immune system. Although microRNAs (miRNAs are the most comprehensive and well-studied, a number of reports suggest the exciting possibility that long ncRNAs (lncRNAs could mediate host response and immune function. Finally, evidence is also accumulating that suggests a role for miRNAs and other small ncRNAs in autocrine, paracrine and exocrine signaling events, thus highlighting an elaborate network of regulatory interactions mediated by different classes of ncRNAs during immune response. This review will explore the multifaceted roles of ncRNAs in the adaptive immune response. In particular, we will focus on the well-established role of miRNAs and on the emerging role of lncRNAs and circulating ncRNAs, which all make indispensable contributions to the understanding of the multilayered modulation of the adaptive immune response.

  1. The noncoding-RNA landscape in cardiovascular health and disease

    Directory of Open Access Journals (Sweden)

    Vittoria Di Mauro


    Full Text Available The cardiovascular system plays a pivotal role in regulating and maintaining homeostasis in the human body. Therefore any alteration in regulatory networks that orchestrate heart development as well as adaptation to physiological and environmental stress might result in pathological conditions, which represent the leading cause of death worldwide [1]. The latest advances in genome-wide techniques challenged the “protein-central dogma” with the discovery of the so-called non-coding RNAs (ncRNAs. Despite their lack of protein coding potential, ncRNAs have been largely demonstrated to regulate the majority of biological processes and have also been largely implicated in cardiovascular disorders. This review will first discuss the important mechanistic aspects of some of the classes of ncRNAs such as biogenesis, mechanism of action, as well as their involvement in cardiac diseases. The ncRNA potential uses as therapeutic molecules, with a specific focus on the latest technologies for their in vivo delivery as drug targets, will be described.

  2. Rethinking the central dogma: noncoding RNAs are biologically relevant. (United States)

    Robinson, Victoria L


    Non-coding RNAs (ncRNAs) are a large class of functional molecules with over 100 unique classes described to date. ncRNAs are diverse in terms of their function and size. A relatively new class of small ncRNA, called microRNAs (miRNA), have received a great deal of attention in the literature in recent years. miRNAs are endogenously encoded gene families that demonstrate striking evolutionary conservation. miRNAs serve essential and diverse physiological functions such as differentiation and development, proliferation, maintaining cell type phenotypes, and many others. The discovery and ongoing investigation of miRNAs is part of a revolution in biology that is changing the basic concepts of gene expression and RNA functionality. A single miRNA can participate in controlling the expression of up to several hundred protein-coding genes by interacting with mRNAs, generally in 3' untranslated regions. Our new and developing understanding of miRNAs, and other ncRNAs, promises to lead to significant contributions to medicine. Specifically, miRNAs are likely to serve as the basis for novel therapies and diagnostic tools.

  3. Non-Coding RNA in Brain Development and Disorder. (United States)

    Subhramanyam, Charannya Sozheesvari; Hu, Qidong


    Although up to 90% of the eukaryotic genome can be transcribed, only 1-2% of the resultant transcripts encode for proteins, while the remaining can be classified as non-coding RNAs (ncRNAs) which mostly consist of long ncRNAs (lncRNAs) and small ncRNAs. In overall, they have been suggested to target specific regions in the genome and play multi-faceted roles in many important biological processes. Recent evidence has shown that ncRNAs are abundantly expressed in the brain and many of them are aberrantly regulated in neural disorders. Yet their functional relevance in related physiological and pathological processes has not been adequately understood. Thus, the elucidation of the role of ncRNAs in the brain would greatly enhance the current understanding of neural development and ultimately lead to novel strategies to treat neural diseases. In this report, we reviewed the structure and mechanism of lncRNAs and various classes of small ncRNAs in brain development and neural disorders. We hope that extensive studies of these ncRNAs would unravel and characterize novel molecular circuits in the brain, and facilitate the development of RNA-based therapeutics for people suffering from neural disorders. Copyright© Bentham Science Publishers; For any queries, please email at

  4. Long Noncoding RNA Ceruloplasmin Promotes Cancer Growth by Altering Glycolysis

    Directory of Open Access Journals (Sweden)

    Rajesha Rupaimoole


    Full Text Available Long noncoding RNAs (lncRNAs significantly influence the development and regulation of genome expression in cells. Here, we demonstrate the role of lncRNA ceruloplasmin (NRCP in cancer metabolism and elucidate functional effects leading to increased tumor progression. NRCP was highly upregulated in ovarian tumors, and knockdown of NRCP resulted in significantly increased apoptosis, decreased cell proliferation, and decreased glycolysis compared with control cancer cells. In an orthotopic mouse model of ovarian cancer, siNRCP delivered via a liposomal carrier significantly reduced tumor growth compared with control treatment. We identified NRCP as an intermediate binding partner between STAT1 and RNA polymerase II, leading to increased expression of downstream target genes such as glucose-6-phosphate isomerase. Collectively, we report a previously unrecognized role of the lncRNA NRCP in modulating cancer metabolism. As demonstrated, DOPC nanoparticle-incorporated siRNA-mediated silencing of this lncRNA in vivo provides therapeutic avenue toward modulating lncRNAs in cancer.

  5. DNA watermarks in non-coding regulatory sequences

    Directory of Open Access Journals (Sweden)

    Pyka Martin


    Full Text Available Abstract Background DNA watermarks can be applied to identify the unauthorized use of genetically modified organisms. It has been shown that coding regions can be used to encrypt information into living organisms by using the DNA-Crypt algorithm. Yet, if the sequence of interest presents a non-coding DNA sequence, either the function of a resulting functional RNA molecule or a regulatory sequence, such as a promoter, could be affected. For our studies we used the small cytoplasmic RNA 1 in yeast and the lac promoter region of Escherichia coli. Findings The lac promoter was deactivated by the integrated watermark. In addition, the RNA molecules displayed altered configurations after introducing a watermark, but surprisingly were functionally intact, which has been verified by analyzing the growth characteristics of both wild type and watermarked scR1 transformed yeast cells. In a third approach we introduced a second overlapping watermark into the lac promoter, which did not affect the promoter activity. Conclusion Even though the watermarked RNA and one of the watermarked promoters did not show any significant differences compared to the wild type RNA and wild type promoter region, respectively, it cannot be generalized that other RNA molecules or regulatory sequences behave accordingly. Therefore, we do not recommend integrating watermark sequences into regulatory regions.

  6. Genome-wide analyses of small noncoding RNAs in streptococci

    Directory of Open Access Journals (Sweden)

    Nadja ePatenge


    Full Text Available Streptococci represent a diverse group of Gram-positive bacteria, which colonize a wide range of hosts among animals and humans. Streptococcal species occur as commensal as well as pathogenic organisms. Many of the pathogenic species can cause severe, invasive infections in their hosts leading to a high morbidity and mortality. The consequence is a tremendous suffering on the part of men and livestock besides the significant financial burden in the agricultural and healthcare sectors. An environmentally stimulated and tightly controlled expression of virulence factor genes is of fundamental importance for streptococcal pathogenicity. Bacterial small noncoding RNAs (sRNAs modulate the expression of genes involved in stress response, sugar metabolism, surface composition, and other properties that are related to bacterial virulence. Even though the regulatory character is shared by this class of RNAs, variation on the molecular level results in a high diversity of functional mechanisms. The knowledge about the role of sRNAs in streptococci is still limited, but in recent years, genome-wide screens for sRNAs have been conducted in an increasing number of species. Bioinformatics prediction approaches have been employed as well as expression analyses by classical array techniques or next generation sequencing. This review will give an overview of whole genome screens for sRNAs in streptococci with a focus on describing the different methods and comparing their outcome considering sRNA conservation among species, functional similarities, and relevance for streptococcal infection.

  7. Adaptive evolution of conserved noncoding elements in mammals.

    Directory of Open Access Journals (Sweden)

    Su Yeon Kim


    Full Text Available Conserved noncoding elements (CNCs are an abundant feature of vertebrate genomes. Some CNCs have been shown to act as cis-regulatory modules, but the function of most CNCs remains unclear. To study the evolution of CNCs, we have developed a statistical method called the "shared rates test" to identify CNCs that show significant variation in substitution rates across branches of a phylogenetic tree. We report an application of this method to alignments of 98,910 CNCs from the human, chimpanzee, dog, mouse, and rat genomes. We find that approximately 68% of CNCs evolve according to a null model where, for each CNC, a single parameter models the level of constraint acting throughout the phylogeny linking these five species. The remaining approximately 32% of CNCs show departures from the basic model including speed-ups and slow-downs on particular branches and occasionally multiple rate changes on different branches. We find that a subset of the significant CNCs have evolved significantly faster than the local neutral rate on a particular branch, providing strong evidence for adaptive evolution in these CNCs. The distribution of these signals on the phylogeny suggests that adaptive evolution of CNCs occurs in occasional short bursts of evolution. Our analyses suggest a large set of promising targets for future functional studies of adaptation.

  8. On the classification of long non-coding RNAs

    KAUST Repository

    Ma, Lina


    Long non-coding RNAs (lncRNAs) have been found to perform various functions in a wide variety of important biological processes. To make easier interpretation of lncRNA functionality and conduct deep mining on these transcribed sequences, it is convenient to classify lncRNAs into different groups. Here, we summarize classification methods of lncRNAs according to their four major features, namely, genomic location and context, effect exerted on DNA sequences, mechanism of functioning and their targeting mechanism. In combination with the presently available function annotations, we explore potential relationships between different classification categories, and generalize and compare biological features of different lncRNAs within each category. Finally, we present our view on potential further studies. We believe that the classifications of lncRNAs as indicated above are of fundamental importance for lncRNA studies, helpful for further investigation of specific lncRNAs, for formulation of new hypothesis based on different features of lncRNA and for exploration of the underlying lncRNA functional mechanisms. © 2013 Landes Bioscience.

  9. Community structure of non-coding RNA interaction network

    Directory of Open Access Journals (Sweden)

    Nacher Jose C.


    Full Text Available Rapid technological advances have shown that the ratio of non-protein coding genes rises to 98.5% in humans, suggesting that current knowledge on genetic information processing might be largely incomplete. It implies that protein-coding sequences only represent a small fraction of cellular transcriptional information. Here, we examine the community structure of the network defined by functional interactions between noncoding RNAs (ncRNAs and proteins related bio-macrolecules (PRMs using a two-fold approach: modularity in bipartite network and k-clique community detection. First, the high modularity scores as well as the distribution of community sizes showing a scaling-law revealed manifestly non-random features. Second, the k-clique sub-graphs and overlaps show that the identified communities of the ncRNA molecules of H. sapiens can potentially be associated with certain functions. These findings highlight the complex modular structure of ncRNA interactions and its possible regulatory roles in the cell.

  10. The noncoding human genome and the future of personalised medicine. (United States)

    Cowie, Philip; Hay, Elizabeth A; MacKenzie, Alasdair


    Non-coding cis-regulatory sequences act as the 'eyes' of the genome and their role is to perceive, organise and relay cellular communication information to RNA polymerase II at gene promoters. The evolution of these sequences, that include enhancers, silencers, insulators and promoters, has progressed in multicellular organisms to the extent that cis-regulatory sequences make up as much as 10% of the human genome. Parallel evidence suggests that 75% of polymorphisms associated with heritable disease occur within predicted cis-regulatory sequences that effectively alter the 'perception' of cis-regulatory sequences or render them blind to cell communication cues. Cis-regulatory sequences also act as major functional targets of epigenetic modification thus representing an important conduit through which changes in DNA-methylation affects disease susceptibility. The objectives of the current review are (1) to describe what has been learned about identifying and characterising cis-regulatory sequences since the sequencing of the human genome; (2) to discuss their role in interpreting cell signalling pathways pathways; and (3) outline how this role may be altered by polymorphisms and epigenetic changes. We argue that the importance of the cis-regulatory genome for the interpretation of cellular communication pathways cannot be overstated and understanding its role in health and disease will be critical for the future development of personalised medicine.

  11. The Role of Long Noncoding RNAs in Neurodegenerative Diseases. (United States)

    Wan, Peixing; Su, Wenru; Zhuo, Yehong


    Long noncoding RNAs (lncRNAs) are transcripts with low protein-coding potential but occupy a large part of transcriptional output. Their roles include regulating gene expression at the epigenetic, transcriptional, and post-transcriptional level in cellular homeostasis. However, lncRNA studies are still in their infancy and the functions of the vast majority of lncRNA transcripts remain unknown. It is generally known that the function of the human nervous system largely relies on the precise regulation of gene expression. Various studies have shown that lncRNAs have a significant impact on normal neural development and on the development and progression of neurodegenerative diseases. In this review, we focused on recent studies associated with lncRNAs in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), frontotemporal lobar degeneration (FTLD), and glaucoma. Glaucoma, caused by unexplained ganglion cell lesion and apoptosis, is now labeled as a chronic neurodegenerative disorder [1], and therefore, we discussed the association of lncRNAs with glaucoma as well. We illustrate the role of some specific lncRNAs, which may provide new insights into our understanding of the etiology and pathophysiology of the neurodegenerative diseases mentioned above.

  12. In Vivo Enhancer Analysis Chromosome 16 Conserved NoncodingSequences

    Energy Technology Data Exchange (ETDEWEB)

    Pennacchio, Len A.; Ahituv, Nadav; Moses, Alan M.; Nobrega,Marcelo; Prabhakar, Shyam; Shoukry, Malak; Minovitsky, Simon; Visel,Axel; Dubchak, Inna; Holt, Amy; Lewis, Keith D.; Plajzer-Frick, Ingrid; Akiyama, Jennifer; De Val, Sarah; Afzal, Veena; Black, Brian L.; Couronne, Olivier; Eisen, Michael B.; Rubin, Edward M.


    The identification of enhancers with predicted specificitiesin vertebrate genomes remains a significant challenge that is hampered bya lack of experimentally validated training sets. In this study, weleveraged extreme evolutionary sequence conservation as a filter toidentify putative gene regulatory elements and characterized the in vivoenhancer activity of human-fish conserved and ultraconserved1 noncodingelements on human chromosome 16 as well as such elements from elsewherein the genome. We initially tested 165 of these extremely conservedsequences in a transgenic mouse enhancer assay and observed that 48percent (79/165) functioned reproducibly as tissue-specific enhancers ofgene expression at embryonic day 11.5. While driving expression in abroad range of anatomical structures in the embryo, the majority of the79 enhancers drove expression in various regions of the developingnervous system. Studying a set of DNA elements that specifically droveforebrain expression, we identified DNA signatures specifically enrichedin these elements and used these parameters to rank all ~;3,400human-fugu conserved noncoding elements in the human genome. The testingof the top predictions in transgenic mice resulted in a three-foldenrichment for sequences with forebrain enhancer activity. These datadramatically expand the catalogue of in vivo-characterized human geneenhancers and illustrate the future utility of such training sets for avariety of iological applications including decoding the regulatoryvocabulary of the human genome.

  13. Decapping of long noncoding RNAs regulates inducible genes. (United States)

    Geisler, Sarah; Lojek, Lisa; Khalil, Ahmad M; Baker, Kristian E; Coller, Jeff


    Decapping represents a critical control point in regulating expression of protein coding genes. Here, we demonstrate that decapping also modulates expression of long noncoding RNAs (lncRNAs). Specifically, levels of >100 lncRNAs in yeast are controlled by decapping and are degraded by a pathway that occurs independent of decapping regulators. We find many lncRNAs degraded by DCP2 are expressed proximal to inducible genes. Of these, we show several genes required for galactose utilization are associated with lncRNAs that have expression patterns inversely correlated with their mRNA counterpart. Moreover, decapping of these lncRNAs is critical for rapid and robust induction of GAL gene expression. Failure to destabilize a lncRNA known to exert repressive histone modifications results in perpetuation of a repressive chromatin state that contributes to reduced plasticity of gene activation. We propose that decapping and lncRNA degradation serve a vital role in transcriptional regulation specifically at inducible genes. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Identification of expressed and conserved human noncoding RNAs (United States)

    Nielsen, Morten Muhlig; Tehler, Disa; Vang, Søren; Sudzina, Frantisek; Hedegaard, Jakob; Nordentoft, Iver; Ørntoft, Torben Falck; Lund, Anders H.; Pedersen, Jakob Skou


    The past decade has shown mammalian genomes to be pervasively transcribed and identified thousands of noncoding (nc) transcripts. It is currently unclear to what extent these transcripts are of functional importance, as experimental functional evidence exists for only a small fraction. Here, we characterize the expression and evolutionary conservation properties of 12,115 known and novel nc transcripts, including structural RNAs, long nc RNAs (lncRNAs), antisense RNAs, EvoFold predictions, ultraconserved elements, and expressed nc regions. Expression levels are evaluated across 12 human tissues using a custom-designed microarray, supplemented with RNAseq. Conservation levels are evaluated at both the base level and at the syntenic level. We combine these measures with epigenetic mark annotations to identify subsets of novel nc transcripts that show characteristics similar to known functional ncRNAs. Few novel nc transcripts show both high expression and conservation levels. However, overall, we observe a positive correlation between expression and both conservation and epigenetic annotations, suggesting that a subset of the expressed transcripts are under purifying selection and likely functional. The identified subsets of expressed and conserved novel nc transcripts may form the basis for further functional characterization. PMID:24344320

  15. Long Noncoding RNA PANDA Positively Regulates Proliferation of Osteosarcoma Cells. (United States)

    Kotake, Yojiro; Goto, Taiki; Naemura, Madoka; Inoue, Yasutoshi; Okamoto, Haruna; Tahara, Keiichiro


    A long noncoding RNA, p21-associated ncRNA DNA damage-activated (PANDA), associates with nuclear transcription factor Y subunit alpha (NF-YA) and inhibits its binding to promoters of apoptosis-related genes, thereby repressing apoptosis in normal human fibroblasts. Here, we show that PANDA is involved in regulating proliferation in the U2OS human osteosarcoma cell line. U2OS cells were transfected with siRNAs against PANDA 72 h later and they were subjected to reverse transcription-polymerase chain reaction (RT-PCR), quantitative RT-PCR and cell-cycle analysis. PANDA was highly expressed in U2OS cells, and its expression was induced by DNA damage. Silencing PANDA caused arrest at the G 1 phase of the cell cycle, leading to inhibition of cell proliferation. Quantitative RT-PCR showed that silencing PANDA increased mRNA levels of the cyclin-dependent kinase inhibitor p18, which caused G 1 phase arrest. These results suggest that PANDA promotes G 1 -S transition by repressing p18 transcription, and thus promotes U2OS cell proliferation. Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. Potentials and limitations of histone repeat sequences for phylogenetic reconstruction of Sophophora. (United States)

    Baldo, A M; Les, D H; Strausbaugh, L D


    Simplified DNA sequence acquisition has provided many new data sets that are useful for phylogenetic reconstruction, including single- and multiple-copy nuclear and organellar genes. Although transcribed regions receive much attention, nontranscribed regions have recently been added to the repertoire of sequences suitable for phylogenetic studies, especially for closely related taxa. We evaluated the efficacy of a small portion of the histone repeat for phylogenetic reconstruction among Drosophila species. Histone repeats in invertebrates offer distinct advantages similar to those of widely used ribosomal repeats. First, the units are tandemly repeated and undergo concerted evolution. Second, histone repeats include both highly conserved coding and variable intergenic regions. This composition facilitates application of "universal" primers spanning potentially informative sites. We examined a small region of the histone repeat, including the intergenic spacer segments of coding regions from the divergently transcribed H2A and H2B histone genes. The spacer (about 230 bp) exists as a mosaic with highly conserved functional motifs interspersed with rapidly diverging regions; the former aid in alignment of the spacer. There are no ambiguities in alignment of coding regions. Coding and noncoding regions were analyzed together and separately for phylogenetic information. Parsimony, distance, and maximum-likelihood methods successfully retrieve the corroborated phylogeny for the taxa examined. This study demonstrates the resolving power of a small histone region which may now be added to the growing collection of phylogenetically useful DNA sequences.

  17. On summation of perturbation expansions

    International Nuclear Information System (INIS)

    Horzela, A.


    The problem of the restoration of physical quantities defined by divergent perturbation expansions is analysed. The Pad'e and Borel summability is proved for alternating perturbation expansions with factorially growing coefficients. The proof is based on the methods of the classical moments theory. 17 refs. (author)

  18. Renormalization group and mayer expansions

    International Nuclear Information System (INIS)

    Mack, G.


    Mayer expansions promise to become a powerful tool in exact renormalization group calculations. Iterated Mayer expansions were sucessfully used in the rigorous analysis of 3-dimensional U (1) lattice gauge theory by Gopfert and the author, and it is hoped that they will also be useful in the 2-dimensional nonlinear σ-model, and elsewhere

  19. Renormalization group and Mayer expansions

    International Nuclear Information System (INIS)

    Mack, G.


    Mayer expansions promise to become a powerful tool in exact renormalization group calculations. Iterated Mayer expansions were sucessfully used in the rigorous analysis of 3-dimensional U(1) lattice gauge theory by Goepfert and the author, and it is hoped that they will also be useful in the 2-dimensional nonlinear sigma-model, and elsewhere. (orig.)

  20. Exponential Expansion in Evolutionary Economics

    DEFF Research Database (Denmark)

    Frederiksen, Peter; Jagtfelt, Tue


    to this problem is proposed in the form of a model of exponential expansion. The model outlines the overall structure and function of the economy as exponential expansion. The pictographic model describes four axiomatic concepts and their exponential nature. The interactive, directional, emerging and expanding...

  1. Isotropic Negative Thermal Expansion Metamaterials. (United States)

    Wu, Lingling; Li, Bo; Zhou, Ji


    Negative thermal expansion materials are important and desirable in science and engineering applications. However, natural materials with isotropic negative thermal expansion are rare and usually unsatisfied in performance. Here, we propose a novel method to achieve two- and three-dimensional negative thermal expansion metamaterials via antichiral structures. The two-dimensional metamaterial is constructed with unit cells that combine bimaterial strips and antichiral structures, while the three-dimensional metamaterial is fabricated by a multimaterial 3D printing process. Both experimental and simulation results display isotropic negative thermal expansion property of the samples. The effective coefficient of negative thermal expansion of the proposed models is demonstrated to be dependent on the difference between the thermal expansion coefficient of the component materials, as well as on the circular node radius and the ligament length in the antichiral structures. The measured value of the linear negative thermal expansion coefficient of the three-dimensional sample is among the largest achieved in experiments to date. Our findings provide an easy and practical approach to obtaining materials with tunable negative thermal expansion on any scale.

  2. 78 FR 65594 - Vehicular Repeaters (United States)


    ... comment on Industrial/ Business licensees' usage of mobile repeaters. Telemetry Channels We seek comment... mobile repeater applications, e.g., by listing active, co-channel incumbent call signs and associated... Rulemaking, including this IRFA, to the Chief Counsel for Advocacy of the Small Business Administration (SBA...

  3. Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)(n) Repeats by PNA or LNA Targeting

    DEFF Research Database (Denmark)

    Bergquist, Helen; Rocha, Cristina S. J.; Alvarez-Asencio, Ruben


    Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigen...

  4. Genetic variation in the non-coding genome : Involvement of micro-RNAs and long non-coding RNAs in disease

    NARCIS (Netherlands)

    Hrdlickova, Barbara; de Almeida, Rodrigo Coutinho; Borek, Zuzanna; Withoff, Sebo


    It has been found that the majority of disease-associated genetic variants identified by genome-wide association studies are located outside of protein-coding regions, where they seem to affect regions that control transcription (promoters, enhancers) and non-coding RNAs that also can influence gene

  5. Repeatability of visual acuity measurement. (United States)

    Raasch, T W; Bailey, I L; Bullimore, M A


    This study investigates features of visual acuity chart design and acuity testing scoring methods which affect the validity and repeatability of visual acuity measurements. Visual acuity was measured using the Sloan and British Standard letter series, and Landolt rings. Identifiability of the different letters as a function of size was estimated, and expressed in the form of frequency-of-seeing curves. These functions were then used to simulate acuity measurements with a variety of chart designs and scoring criteria. Systematic relationships exist between chart design parameters and acuity score, and acuity score repeatability. In particular, an important feature of a chart, that largely determines the repeatability of visual acuity measurement, is the amount of size change attributed to each letter. The methods used to score visual acuity performance also affect repeatability. It is possible to evaluate acuity score validity and repeatability using the statistical principles discussed here.

  6. All-photonic quantum repeaters (United States)

    Azuma, Koji; Tamaki, Kiyoshi; Lo, Hoi-Kwong


    Quantum communication holds promise for unconditionally secure transmission of secret messages and faithful transfer of unknown quantum states. Photons appear to be the medium of choice for quantum communication. Owing to photon losses, robust quantum communication over long lossy channels requires quantum repeaters. It is widely believed that a necessary and highly demanding requirement for quantum repeaters is the existence of matter quantum memories. Here we show that such a requirement is, in fact, unnecessary by introducing the concept of all-photonic quantum repeaters based on flying qubits. In particular, we present a protocol based on photonic cluster-state machine guns and a loss-tolerant measurement equipped with local high-speed active feedforwards. We show that, with such all-photonic quantum repeaters, the communication efficiency scales polynomially with the channel distance. Our result paves a new route towards quantum repeaters with efficient single-photon sources rather than matter quantum memories. PMID:25873153

  7. Tevatron serial data repeater system

    International Nuclear Information System (INIS)

    Ducar, R.J.


    A ten megabit per second serial data repeater system has been developed for the 6.28km Tevatron accelerator. The repeaters are positioned at each of the thirty service buildings and accommodate control and abort system communications as well as distribution of the Tevatron time and energy clocks. The repeaters are transparent to the particular protocol of the transmissions. Serial data are encoded locally as unipolar two volt signals employing the self-clocking Manchester Bi-Phase code. The repeaters modulate the local signals to low-power bursts of 50 MHz rf carrier for the 260m transmission between service buildings. The repeaters also demodulate the transmission and restructure the data for local utilization. The employment of frequency discrimination techniques yields high immunity to the characteristic noise spectrum

  8. Genomic origin and nuclear localization of TERRA telomeric repeat-containing RNA: from Darkness to Dawn. (United States)

    Diman, Aurélie; Decottignies, Anabelle


    Long noncoding RNAs, produced from distinct regions of the chromosomes, are emerging as new key players in several important biological processes. The long noncoding RNAs add a new layer of complexity to cellular regulatory pathways, from transcription to cellular trafficking or chromatin remodeling. More than 25 years ago, the discovery of a transcriptional activity at telomeres of protozoa ended the long-lasting belief that telomeres were transcriptionally silent. Since then, progressively accumulating evidences established that production of TElomeric Repeat-containing RNA (TERRA) was a general feature of eukaryotic cells. Whether TERRA molecules always originate from the telomeres or whether they can be transcribed from internal telomeric repeats as well is however still a matter of debate. Whether TERRA transcripts always localize to telomeres and play similar roles in all eukaryotic cells is also unclear. We review the studies on TERRA localization in the cell, its composition and some aspects of its transcriptional regulation to summarize the current knowledge and controversies about the genomic origin of TERRA, with a focus on human and mouse TERRA. © 2017 Federation of European Biochemical Societies.

  9. Targeting Promoter-Associated Noncoding RNA In Vivo. (United States)

    Civenni, Gianluca


    There are many classes of noncoding RNAs (ncRNAs), with wide-ranging functionalities (e.g., RNA editing, mediation of mRNA splicing, ribosomal function). MicroRNAs (miRNAs) and long ncRNAs (lncRNAs) are implicated in a wide variety of cellular processes, including the regulation of gene expression. Incorrect expression or mutation of lncRNAs has been reported to be associated with several disease conditions, such a malignant transformation in humans. Importantly, pivotal players in tumorigenesis and cancer progression, such as c-Myc, may be regulated by lncRNA at promoter level. The function of lncRNA can be reduced with antisense oligonucleotides that sequester or degrade mature lncRNAs. In alternative, lncRNA transcription can be blocked by small interference RNA (RNAi), which had acquired, recently, broad interested in clinical applications. In vivo-jetPEI™ is a linear polyethylenimine mediating nucleic acid (DNA, shRNA, siRNA, oligonucelotides) delivery with high efficiency. Different in vivo delivery routes have been validated: intravenous (IV), intraperitoneal (IP), intratumoral, subcutaneous, topical, and intrathecal. High levels of nucleic acid delivery are achieved into a broad range of tissues, such as lung, salivary glands, heart, spleen, liver, and prostate upon systemic administration. In addition, in vivo-jetPEI™ is also an efficient carrier for local gene and siRNA delivery such as intratumoral or topical application on the skin. After systemic injection, siRNA can be detected and the levels can be validated in target tissues by qRT-PCR. Targeting promoter-associated lncRNAs with siRNAs (small interfering RNAs) in vivo is becoming an exciting breakthrough for the treatment of human disease.

  10. Novel classes of non-coding RNAs and cancer

    Directory of Open Access Journals (Sweden)

    Sana Jiri


    Full Text Available Abstract For the many years, the central dogma of molecular biology has been that RNA functions mainly as an informational intermediate between a DNA sequence and its encoded protein. But one of the great surprises of modern biology was the discovery that protein-coding genes represent less than 2% of the total genome sequence, and subsequently the fact that at least 90% of the human genome is actively transcribed. Thus, the human transcriptome was found to be more complex than a collection of protein-coding genes and their splice variants. Although initially argued to be spurious transcriptional noise or accumulated evolutionary debris arising from the early assembly of genes and/or the insertion of mobile genetic elements, recent evidence suggests that the non-coding RNAs (ncRNAs may play major biological roles in cellular development, physiology and pathologies. NcRNAs could be grouped into two major classes based on the transcript size; small ncRNAs and long ncRNAs. Each of these classes can be further divided, whereas novel subclasses are still being discovered and characterized. Although, in the last years, small ncRNAs called microRNAs were studied most frequently with more than ten thousand hits at PubMed database, recently, evidence has begun to accumulate describing the molecular mechanisms by which a wide range of novel RNA species function, providing insight into their functional roles in cellular biology and in human disease. In this review, we summarize newly discovered classes of ncRNAs, and highlight their functioning in cancer biology and potential usage as biomarkers or therapeutic targets.

  11. Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders. (United States)

    Usdin, Karen; Kumari, Daman


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

  12. Exploration of CAG triplet repeat in nontranslated region of SCA12 ...

    Indian Academy of Sciences (India)

    Out of these five cases, three cases had expansion at different SCA loci, i.e. SCA12 and SCA1. The other two cases had age at onset in the second decade of their life and could not be categorized as SCA12 type since their repeats at. SCA12 locus do not fall in the expanded range based on the published expansion range.

  13. AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission


    Yrigollen, Carolyn M; Martorell, Loreto; Durbin-Johnson, Blythe; Naudo, Montserrat; Genoves, Jordi; Murgia, Alessandra; Polli, Roberta; Zhou, Lili; Barbouth, Deborah; Rupchock, Abigail; Finucane, Brenda; Latham, Gary J; Hadd, Andrew; Berry-Kravis, Elizabeth; Tassone, Flora


    Background The presence of AGG interruptions in the CGG repeat locus of the fragile X mental retardation 1 (FMR1) gene decreases the instability of the allele during transmission from parent to child, and decreases the risk of expansion of a premutation allele to a full mutation allele (the predominant cause of fragile X syndrome) during maternal transmission. Methods To strengthen recent findings on the utility of AGG interruptions in predicting instability or expansion to a full mutation of...

  14. Plasma expansion: fundamentals and applications

    International Nuclear Information System (INIS)

    Engeln, R; Mazouffre, S; Vankan, P; Bakker, I; Schram, D C


    The study of plasma expansion is interesting from a fundamental point of view as well as from a more applied point of view. We here give a short overview of the way properties like density, velocity and temperature behave in an expanding thermal plasma. Experimental data show that the basic phenomena of plasma expansion are to some extent similar to those of the expansion of a hot neutral gas. From the application point of view, we present first results on the use of an expanding thermal plasma in the plasma-activated catalysis of ammonia, from N 2 -H 2 mixtures

  15. Thermal Expansion of Polyurethane Foam (United States)

    Lerch, Bradley A.; Sullivan, Roy M.


    Closed cell foams are often used for thermal insulation. In the case of the Space Shuttle, the External Tank uses several thermal protection systems to maintain the temperature of the cryogenic fuels. A few of these systems are polyurethane, closed cell foams. In an attempt to better understand the foam behavior on the tank, we are in the process of developing and improving thermal-mechanical models for the foams. These models will start at the microstructural level and progress to the overall structural behavior of the foams on the tank. One of the key properties for model characterization and verification is thermal expansion. Since the foam is not a material, but a structure, the modeling of the expansion is complex. It is also exacerbated by the anisoptropy of the material. During the spraying and foaming process, the cells become elongated in the rise direction and this imparts different properties in the rise direction than in the transverse directions. Our approach is to treat the foam as a two part structure consisting of the polymeric cell structure and the gas inside the cells. The polymeric skeleton has a thermal expansion of its own which is derived from the basic polymer chemistry. However, a major contributor to the thermal expansion is the volume change associated with the gas inside of the closed cells. As this gas expands it exerts pressure on the cell walls and changes the shape and size of the cells. The amount that this occurs depends on the elastic and viscoplastic properties of the polymer skeleton. The more compliant the polymeric skeleton, the more influence the gas pressure has on the expansion. An additional influence on the expansion process is that the polymeric skeleton begins to breakdown at elevated temperatures and releases additional gas species into the cell interiors, adding to the gas pressure. The fact that this is such a complex process makes thermal expansion ideal for testing the models. This report focuses on the thermal

  16. Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers

    Directory of Open Access Journals (Sweden)

    Alejandra Sandoval-Bórquez


    Full Text Available Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori and Epstein-Barr virus (EBV, host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs, regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

  17. Impact of nutrition on noncoding RNA epigenetics in breast and gynecological cancer

    Directory of Open Access Journals (Sweden)

    Rosanna H. E. Krakowsky


    Full Text Available Cancer is the second leading cause of death in females. According to the American Cancer Society, there are 327,660 new cases in breast and gynecological cancers estimated in 2014, placing emphasis on the need for cancer prevention and new cancer treatment strategies. One important approach to cancer prevention involves phytochemicals, biologically active compounds derived from plants. A variety of studies on the impact of dietary compounds found in cruciferous vegetables, green tea and spices like curry and black pepper have revealed epigenetic changes in female cancers. Thus, an important emerging topic comprises epigenetic changes due to the modulation of noncoding RNA levels. Since it has been shown that noncoding RNAs such as microRNAs and long noncoding RNAs are aberrantly expressed in cancer and furthermore are linked to distinct cancer phenotypes, understanding the effects of dietary compounds and supplements on the epigenetic modulator noncoding RNA is of great interest. This article reviews the current findings on nutrition-induced changes in breast and gynecological cancers at the noncoding RNA level.

  18. Accurate discrimination of conserved coding and non-coding regions through multiple indicators of evolutionary dynamics

    Directory of Open Access Journals (Sweden)

    Pesole Graziano


    Full Text Available Abstract Background The conservation of sequences between related genomes has long been recognised as an indication of functional significance and recognition of sequence homology is one of the principal approaches used in the annotation of newly sequenced genomes. In the context of recent findings that the number non-coding transcripts in higher organisms is likely to be much higher than previously imagined, discrimination between conserved coding and non-coding sequences is a topic of considerable interest. Additionally, it should be considered desirable to discriminate between coding and non-coding conserved sequences without recourse to the use of sequence similarity searches of protein databases as such approaches exclude the identification of novel conserved proteins without characterized homologs and may be influenced by the presence in databases of sequences which are erroneously annotated as coding. Results Here we present a machine learning-based approach for the discrimination of conserved coding sequences. Our method calculates various statistics related to the evolutionary dynamics of two aligned sequences. These features are considered by a Support Vector Machine which designates the alignment coding or non-coding with an associated probability score. Conclusion We show that our approach is both sensitive and accurate with respect to comparable methods and illustrate several situations in which it may be applied, including the identification of conserved coding regions in genome sequences and the discrimination of coding from non-coding cDNA sequences.

  19. Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation. (United States)

    Harmston, Nathan; Ing-Simmons, Elizabeth; Tan, Ge; Perry, Malcolm; Merkenschlager, Matthias; Lenhard, Boris


    Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.

  20. Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation

    DEFF Research Database (Denmark)

    Nordin, Angelica; Akimoto, Chizuru; Wuolikainen, Anna


    A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting R...

  1. Analysis of repeated measures data

    CERN Document Server

    Islam, M Ataharul


    This book presents a broad range of statistical techniques to address emerging needs in the field of repeated measures. It also provides a comprehensive overview of extensions of generalized linear models for the bivariate exponential family of distributions, which represent a new development in analysing repeated measures data. The demand for statistical models for correlated outcomes has grown rapidly recently, mainly due to presence of two types of underlying associations: associations between outcomes, and associations between explanatory variables and outcomes. The book systematically addresses key problems arising in the modelling of repeated measures data, bearing in mind those factors that play a major role in estimating the underlying relationships between covariates and outcome variables for correlated outcome data. In addition, it presents new approaches to addressing current challenges in the field of repeated measures and models based on conditional and joint probabilities. Markov models of first...

  2. Estimates of expansion time scales

    International Nuclear Information System (INIS)

    Jones, E.M.


    Monte Carlo simulations of the expansion of a spacefaring civilization show that descendants of that civilization should be found near virtually every useful star in the Galaxy in a time much less than the current age of the Galaxy. Only extreme assumptions about local population growth rates, emigration rates, or ship ranges can slow or halt an expansion. The apparent absence of extraterrestrials from the solar system suggests that no such civilization has arisen in the Galaxy. 1 figure

  3. Expansion lyre-shaped tube

    International Nuclear Information System (INIS)

    Andro, Jean.


    The invention relates the expansion lyre-shaped tube portions formed in dudgeoned tubular bundles between two bottom plates. An expansion lyre comprises at least two sets of tubes of unequal lengths coplanar and symmetrical with respect to the main tube axis, with connecting portions between the tubes forming said sets. The invention applies to apparatus such as heat exchangers, heaters, superheaters or breeders [fr

  4. Strategic Complexity and Global Expansion

    DEFF Research Database (Denmark)

    Oladottir, Asta Dis; Hobdari, Bersant; Papanastassiou, Marina


    The purpose of this paper is to analyse the determinants of global expansion strategies of newcomer Multinational Corporations (MNCs) by focusing on Iceland, Israel and Ireland. We argue that newcomer MNCs from small open economies pursue complex global expansion strategies (CGES). We distinguish....... The empirical evidence suggests that newcomer MNCs move away from simplistic dualities in the formulation of their strategic choices towards more complex options as a means of maintaining and enhancing their global competitiveness....

  5. Impediment of Replication Forks by Long Non-coding RNA Provokes Chromosomal Rearrangements by Error-Prone Restart

    Directory of Open Access Journals (Sweden)

    Takaaki Watanabe


    Full Text Available Naturally stalled replication forks are considered to cause structurally abnormal chromosomes in tumor cells. However, underlying mechanisms remain speculative, as capturing naturally stalled forks has been a challenge. Here, we captured naturally stalled forks in tumor cells and delineated molecular processes underlying the structural evolution of circular mini-chromosomes (double-minute chromosomes; DMs. Replication forks stalled on the DM by the co-directional collision with the transcription machinery for long non-coding RNA. RPA, BRCA2, and DNA polymerase eta (Polη were recruited to the stalled forks. The recruitment of Polη was critical for replication to continue, as Polη knockdown resulted in DM loss. Rescued stalled forks were error-prone and switched replication templates repeatedly to create complex fusions of multiple short genomic segments. In mice, such complex fusions circularized the genomic region surrounding MYC to create a DM during tumorigenesis. Our results define a molecular path that guides stalled replication forks to complex chromosomal rearrangements.

  6. Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers. (United States)

    Kim, Tae-Kyung; Hemberg, Martin; Gray, Jesse M


    Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription. Emerging studies, showing that eRNAs function in controlling mRNA transcription, challenge the idea that enhancers are merely sites of transcription factor assembly. Instead, communication between promoters and enhancers can be bidirectional with promoters required to activate enhancer transcription. Reciprocally, eRNAs may then facilitate enhancer-promoter interaction or activate promoter-driven transcription. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  7. Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5. (United States)

    Kim, Taewan; Cui, Ri; Jeon, Young-Jun; Lee, Ji-Hoon; Lee, Ju Hee; Sim, Hosung; Park, Jong Kook; Fadda, Paolo; Tili, Esmerina; Nakanishi, Hiroshi; Huh, Man-Il; Kim, Sung-Hak; Cho, Ju Hwan; Sung, Bong Hwan; Peng, Yong; Lee, Tae Jin; Luo, Zhenghua; Sun, Hui-Lung; Wei, Huijun; Alder, Hansjuerg; Oh, Jeong Su; Shim, Kang Sup; Ko, Sang-Bong; Croce, Carlo M


    The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.


    Directory of Open Access Journals (Sweden)

    Elena eCarnero


    Full Text Available Interferons (IFNs are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long noncoding RNAs (lncRNAs. To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs. Further validation showed that ISR2, 8 and 12 expression mimics that of their neighboring genes GBP1, IRF1 and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8 or later (ISR12 time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8 and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.

  9. Long noncoding RNAs coordinate functions between mitochondria and the nucleus. (United States)

    Dong, Yaru; Yoshitomi, Takeshi; Hu, Ji-Fan; Cui, Jizhe


    In animal cells, mitochondria are the primary powerhouses and metabolic factories. They also contain genomes and can produce mitochondrial-specific nucleic acids and proteins. To maintain homeostasis of the entire cell, an intense cross-talk between mitochondria and the nucleus, mediated by encoded noncoding RNAs (ncRNAs), as well as proteins, is required. Long ncRNAs (lncRNAs) contain characteristic structures, and they are involved in the regulation of almost every stage of gene expression, as well as being implicated in a variety of disease states, such as cancer. In the coordinated signaling system, several lncRNAs, transcribed in the nucleus but residing in mitochondria, play a key role in regulating mitochondrial functions or dynamics. For example, RMRP, a component of the mitochondrial RNase MRP, is important for mitochondrial DNA replication and RNA processing, and the steroid receptor RNA activator, SRA, is a key modulator of hormone signaling and is present in both the nucleus and mitochondria. Some RNA-binding proteins maybe play a role in the lncRNAs transport system, such as HuR, GRSF1, SHARP, SLIRP, PPR, and PNPASE. Furthermore, a series of nuclear DNA-encoded lncRNAs were implicated in mitochondria-mediated apoptosis, mitochondrial bioenergetics and biosynthesis, and glutamine metabolism. The mitochondrial genome can also encode a set of lncRNAs, and they are divided into three categories: (1) lncND5, lncND6, and lncCyt b RNA; (2) chimeric mitochondrial DNA-encoded lncRNAs; and (3) putative mitochondrial DNA-encoded lncRNAs. It has been reported that the mitochondrial DNA-encoded lncRNAs appear to operate in the nucleus. The molecular mechanisms underlying trafficking of the mitochondrial DNA-encoded lncRNAs to the nucleus in mammals are only now beginning to emerge. In conclusion, both nuclear- and mitochondrial DNA-encoded lncRNAs mediate an intense intercompartmental cross-talk, which opens a rich field for investigation of the mechanism

  10. The diversity and evolution of Wolbachia ankyrin repeat domain genes.

    Directory of Open Access Journals (Sweden)

    Stefanos Siozios

    Full Text Available Ankyrin repeat domain-encoding genes are common in the eukaryotic and viral domains of life, but they are rare in bacteria, the exception being a few obligate or facultative intracellular Proteobacteria species. Despite having a reduced genome, the arthropod strains of the alphaproteobacterium Wolbachia contain an unusually high number of ankyrin repeat domain-encoding genes ranging from 23 in wMel to 60 in wPip strain. This group of genes has attracted considerable attention for their astonishing large number as well as for the fact that ankyrin proteins are known to participate in protein-protein interactions, suggesting that they play a critical role in the molecular mechanism that determines host-Wolbachia symbiotic interactions. We present a comparative evolutionary analysis of the wMel-related ankyrin repeat domain-encoding genes present in different Drosophila-Wolbachia associations. Our results show that the ankyrin repeat domain-encoding genes change in size by expansion and contraction mediated by short directly repeated sequences. We provide examples of intra-genic recombination events and show that these genes are likely to be horizontally transferred between strains with the aid of bacteriophages. These results confirm previous findings that the Wolbachia genomes are evolutionary mosaics and illustrate the potential that these bacteria have to generate diversity in proteins potentially involved in the symbiotic interactions.

  11. Long intervening non-coding RNA 00320 is human brain-specific and highly expressed in the cortical white matter

    NARCIS (Netherlands)

    Mills, James D.; Chen, Jieqiong; Kim, Woojin S.; Waters, Paul D.; Prabowo, Avanita S.; Aronica, Eleonora; Halliday, Glenda M.; Janitz, Michael


    Pervasive transcription of the genome produces a diverse array of functional non-coding RNAs (ncRNAs). One particular class of ncRNAs, long intervening non-coding RNAs (lincRNAs) are thought to play a role in regulating gene expression and may be a major contributor to organism and tissue

  12. Investigation of SCA10 in the Cypriot population: further exclusion of SCA dynamic repeat mutations. (United States)

    Votsi, Christina; Zamba-Papanicolaou, Eleni; Georghiou, Anthi; Kyriakides, Theodoros; Papacostas, Savvas; Kleopa, Kleopas A; Pantzaris, Marios; Christodoulou, Kyproula


    Autosomal dominant cerebellar ataxias (ADCAs) encompass a heterogeneous group of rare diseases that affect the cerebellum and its connections. The most common forms have been associated with dynamic mutations while some rarer forms with conventional mutations. Studies in different populations revealed differences in their relative frequencies both within and between the studied populations, showing that the frequencies are depended on ethnic and geographical factors. Previous investigation of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in the Cypriot population, revealed no pathogenic expansion in the Cypriot SCA patients. We hereby present our recent investigation of the SCA10 pentanucleotide repeat expansion. Forty-two ascertained Cypriot sporadic ataxia patients, the index case from 1 ADCA and 14 ARCA families and a cohort of normal population individuals were included in the study. All our patients have normal range ATXN10 gene ATTCT repeat numbers (10-19). In the normal population group, repeat lengths ranged from 11 to 20 with the 14 repeats allele being the most frequent. Therefore, all currently established dynamic repeat SCA mutations are absent from the Cypriot population, indicating distinct genetic causes. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. On genus expansion of superpolynomials (United States)

    Mironov, Andrei; Morozov, Alexei; Sleptsov, Alexei; Smirnov, Andrey


    Recently it was shown that the (Ooguri-Vafa) generating function of HOMFLY polynomials is the Hurwitz partition function, i.e. that the dependence of the HOMFLY polynomials on representation R is naturally captured by symmetric group characters (cut-and-join eigenvalues). The genus expansion and expansion through Vassiliev invariants explicitly demonstrate this phenomenon. In the present paper we claim that the superpolynomials are not functions of such a type: symmetric group characters do not provide an adequate linear basis for their expansions. Deformation to superpolynomials is, however, straightforward in the multiplicative basis: the Casimir operators are β-deformed to Hamiltonians of the Calogero-Moser-Sutherland system. Applying this trick to the genus and Vassiliev expansions, we observe that the deformation is fully straightforward only for the thin knots. Beyond the family of thin knots additional algebraically independent terms appear in the Vassiliev and genus expansions. This can suggest that the superpolynomials do in fact contain more information about knots than the colored HOMFLY and Kauffman polynomials. However, even for the thin knots the beta-deformation is non-innocent: already in the simplest examples it seems inconsistent with the positivity of colored superpolynomials in non-(anti)symmetric representations, which also happens in I. Cherednik's (DAHA-based) approach to the torus knots.

  14. On genus expansion of superpolynomials

    International Nuclear Information System (INIS)

    Mironov, Andrei; Morozov, Alexei; Sleptsov, Alexei; Smirnov, Andrey


    Recently it was shown that the (Ooguri–Vafa) generating function of HOMFLY polynomials is the Hurwitz partition function, i.e. that the dependence of the HOMFLY polynomials on representation R is naturally captured by symmetric group characters (cut-and-join eigenvalues). The genus expansion and expansion through Vassiliev invariants explicitly demonstrate this phenomenon. In the present paper we claim that the superpolynomials are not functions of such a type: symmetric group characters do not provide an adequate linear basis for their expansions. Deformation to superpolynomials is, however, straightforward in the multiplicative basis: the Casimir operators are β-deformed to Hamiltonians of the Calogero–Moser–Sutherland system. Applying this trick to the genus and Vassiliev expansions, we observe that the deformation is fully straightforward only for the thin knots. Beyond the family of thin knots additional algebraically independent terms appear in the Vassiliev and genus expansions. This can suggest that the superpolynomials do in fact contain more information about knots than the colored HOMFLY and Kauffman polynomials. However, even for the thin knots the beta-deformation is non-innocent: already in the simplest examples it seems inconsistent with the positivity of colored superpolynomials in non-(anti)symmetric representations, which also happens in I. Cherednik's (DAHA-based) approach to the torus knots

  15. Hysteresis of magnetostructural transitions: Repeatable and non-repeatable processes (United States)

    Provenzano, Virgil; Della Torre, Edward; Bennett, Lawrence H.; ElBidweihy, Hatem


    The Gd5Ge2Si2 alloy and the off-stoichiometric Ni50Mn35In15 Heusler alloy belong to a special class of metallic materials that exhibit first-order magnetostructural transitions near room temperature. The magnetic properties of this class of materials have been extensively studied due to their interesting magnetic behavior and their potential for a number of technological applications such as refrigerants for near-room-temperature magnetic refrigeration. The thermally driven first-order transitions in these materials can be field-induced in the reverse order by applying a strong enough field. The field-induced transitions are typically accompanied by the presence of large magnetic hysteresis, the characteristics of which are a complicated function of temperature, field, and magneto-thermal history. In this study we show that the virgin curve, the major loop, and sequentially measured MH loops are the results of both repeatable and non-repeatable processes, in which the starting magnetostructural state, prior to the cycling of field, plays a major role. Using the Gd5Ge2Si2 and Ni50Mn35In15 alloys, as model materials, we show that a starting single phase state results in fully repeatable processes and large magnetic hysteresis, whereas a mixed phase starting state results in non-repeatable processes and smaller hysteresis.

  16. Hysteresis of magnetostructural transitions: Repeatable and non-repeatable processes

    International Nuclear Information System (INIS)

    Provenzano, Virgil; Della Torre, Edward; Bennett, Lawrence H.; ElBidweihy, Hatem


    The Gd 5 Ge 2 Si 2 alloy and the off-stoichiometric Ni 50 Mn 35 In 15 Heusler alloy belong to a special class of metallic materials that exhibit first-order magnetostructural transitions near room temperature. The magnetic properties of this class of materials have been extensively studied due to their interesting magnetic behavior and their potential for a number of technological applications such as refrigerants for near-room-temperature magnetic refrigeration. The thermally driven first-order transitions in these materials can be field-induced in the reverse order by applying a strong enough field. The field-induced transitions are typically accompanied by the presence of large magnetic hysteresis, the characteristics of which are a complicated function of temperature, field, and magneto-thermal history. In this study we show that the virgin curve, the major loop, and sequentially measured MH loops are the results of both repeatable and non-repeatable processes, in which the starting magnetostructural state, prior to the cycling of field, plays a major role. Using the Gd 5 Ge 2 Si 2 and Ni 50 Mn 35 In 15 alloys, as model materials, we show that a starting single phase state results in fully repeatable processes and large magnetic hysteresis, whereas a mixed phase starting state results in non-repeatable processes and smaller hysteresis

  17. Non-coding RNAs in schistosomes: an unexplored world

    Directory of Open Access Journals (Sweden)

    Katia C Oliveira


    Full Text Available Non-coding RNAs (ncRNAs were recently given much higher attention due to technical advances in sequencing which expanded the characterization of transcriptomes in different organisms. ncRNAs have different lengths (22 nt to >1, 000 nt and mechanisms of action that essentially comprise a sophisticated gene expression regulation network. Recent publication of schistosome genomes and transcriptomes has increased the description and characterization of a large number of parasite genes. Here we review the number of predicted genes and the coverage of genomic bases in face of the public ESTs dataset available, including a critical appraisal of the evidence and characterization of ncRNAs in schistosomes. We show expression data for ncRNAs in Schistosoma mansoni. We analyze three different microarray experiment datasets: (1 adult worms' large-scale expression measurements; (2 differentially expressed S. mansoni genes regulated by a human cytokine (TNF-α in a parasite culture; and (3 a stage-specific expression of ncRNAs. All these data point to ncRNAs involved in different biological processes and physiological responses that suggest functionality of these new players in the parasite's biology. Exploring this world is a challenge for the scientists under a new molecular perspective of host-parasite interactions and parasite development.RNAs não codificadores (ncRNAs têm sido recentemente objeto de atenção muito maior devido aos avanços técnicos no sequenciamento que expandiram a caracterização dos transcritomas em diferentes organismos. ncRNAs possuem diferentes comprimentos (22 nt a >1.000 nt e mecanismos de ação que essencialmente compreendem uma sofisticada rede de regulação de expressão gênica. A publicação recente dos genomas e transcritomas dos esquistossomos aumentou a descrição e caracterização de um grande número de genes do parasita. Aqui nós revisamos o número de genes preditos e a cobertura das bases do genoma em face

  18. Low thermal expansion glass ceramics

    CERN Document Server


    This book is one of a series reporting on international research and development activities conducted by the Schott group of companies With the series, Schott aims to provide an overview of its activities for scientists, engineers, and managers from all branches of industry worldwide where glasses and glass ceramics are of interest Each volume begins with a chapter providing a general idea of the current problems, results, and trends relating to the subjects treated This volume describes the fundamental principles, the manufacturing process, and applications of low thermal expansion glass ceramics The composition, structure, and stability of polycrystalline materials having a low thermal expansion are described, and it is shown how low thermal expansion glass ceramics can be manufactured from appropriately chosen glass compositions Examples illustrate the formation of this type of glass ceramic by utilizing normal production processes together with controlled crystallization Thus glass ceramics with thermal c...

  19. An expansion for Neutrino Phenomenology

    CERN Document Server

    Grinstein, Benjamin


    We develop a formalism for constructing the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) matrix and neutrino masses using an expansion that originates when a sequence of heavy right handed neutrinos are integrated out, assuming a seesaw mechanism for the origin of neutrino masses. The expansion establishes relationships between the structure of the PMNS matrix and the mass differences of neutrinos, and allows symmetry implications for measured deviations from tri-bimaximal form to be studied systematically. Our approach does not depend on choosing the rotation between the weak and mass eigenstates of the charged lepton fields to be diagonal. We comment on using this expansion to examine the symmetry implications of the recent results from the Daya-Bay collaboration reporting the discovery of a non zero value for theta_{13}, indicating a deviation from tri-bimaximal form, with a significance of 5.2 sigma.

  20. Differential expansion for link polynomials (United States)

    Bai, C.; Jiang, J.; Liang, J.; Mironov, A.; Morozov, A.; Morozov, An.; Sleptsov, A.


    The differential expansion is one of the key structures reflecting group theory properties of colored knot polynomials, which also becomes an important tool for evaluation of non-trivial Racah matrices. This makes highly desirable its extension from knots to links, which, however, requires knowledge of the 6j-symbols, at least, for the simplest triples of non-coincident representations. Based on the recent achievements in this direction, we conjecture a shape of the differential expansion for symmetrically-colored links and provide a set of examples. Within this study, we use a special framing that is an unusual extension of the topological framing from knots to links. In the particular cases of Whitehead and Borromean rings links, the differential expansions are different from the previously discovered.

  1. Characterization of conservative somatic instability of the CAG repeat region in Huntington`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Schaefer, F.V.; Calikoglu, A.S.; Whetsell, L.H. [H.A. Chapman Research Institute of Medical Genetics, Tulsa, OK (United States)


    Instability and enlargement of a CAG repeat region at the beginning of the huntingtin gene (IT-15) has been linked with Huntington`s disease. The CAG repeat size shows a highly significant correlation with age-of-onset of clinicial features in individuals with 40 or more repeats who have Huntington disease. The clinical status of nonsymptomatic individuals with 30 to 39 CAG repeats is considered ambiguous. In order to define more carefully the nature of the HD expansion instability, we examined patients in our HD population using a discriminating fluorescence-based PCR approach. The degree of somatic mutation increases with both earlier age of onset and the size of the inherited allele. A single prominent band one repeat larger than the index peak was typical in individuals with 40-41 CAG repeats. Three to four larger bands are typically discerned in individuals with 50 or more repeats. In an extreme example, an individual with approximately 95 repeats had at least 8 prominent bands. Plotting the degree of somatic mutation relative to the size of the HD allele shows somatic mutation activity increases with size. By this approach 40-60% of the alleles in a 40-41 CAG repeat HD loci is represented in the primary allele. In contrast, the primary allele represents a relatively minor proportion of the total alleles for expansions greater than 50 CAG repeats (10-20%). The limited range of somatic mutation suggest that the instability is restricted to very early stages of embryogenesis before tissue development diverges or that persistent somatic instability occurs at a slow rate. Therefore, the properties of somatic instability in Huntington`s disease have aspects that are both in common but also different from that found in other trinucleotide repeat expanding diseases such as myotonic muscular dystrophy and fragile X syndrome.

  2. Expansion-based passive ranging (United States)

    Barniv, Yair


    This paper describes a new technique of passive ranging which is based on utilizing the image-plane expansion experienced by every object as its distance from the sensor decreases. This technique belongs in the feature/object-based family. The motion and shape of a small window, assumed to be fully contained inside the boundaries of some object, is approximated by an affine transformation. The parameters of the transformation matrix are derived by initially comparing successive images, and progressively increasing the image time separation so as to achieve much larger triangulation baseline than currently possible. Depth is directly derived from the expansion part of the transformation. To a first approximation, image-plane expansion is independent of image-plane location with respect to the focus of expansion (FOE) and of platform maneuvers. Thus, an expansion-based method has the potential of providing a reliable range in the difficult image area around the FOE. In areas far from the FOE the shift parameters of the affine transformation can provide more accurate depth information than the expansion alone, and can thus be used similarly to the way they have been used in conjunction with the Inertial Navigation Unit (INU) and Kalman filtering. However, the performance of a shift-based algorithm, when the shifts are derived from the affine transformation, would be much improved compared to current algorithms because the shifts--as well as the other parameters--can be obtained between widely separated images. Thus, the main advantage of this new approach is that, allowing the tracked window to expand and rotate, in addition to moving laterally, enables one to correlate images over a very long time span which, in turn, translates into a large spatial baseline resulting in a proportionately higher depth accuracy.

  3. Abnormal Base Excision Repair at Trinucleotide Repeats Associated with Diseases: A Tissue-Selective Mechanism

    Directory of Open Access Journals (Sweden)

    Agathi-Vasiliki Goula


    Full Text Available More than fifteen genetic diseases, including Huntington’s disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression. DNA damage and base excision repair (BER are involved in repeat instability and might contribute to the tissue selectivity of the process. In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.

  4. Relativistic effects on plasma expansion

    Energy Technology Data Exchange (ETDEWEB)

    Benkhelifa, El-Amine; Djebli, Mourad, E-mail: [USTHB, Faculty of Physics, Theoretical Physics Laboratory, B.P. 32 Bab-Ezzouar, 16079 Algiers (Algeria)


    The expansion of electron-ion plasma is studied through a fully relativistic multi-fluids plasma model which includes thermal pressure, ambipolar electrostatic potential, and internal energy conversion. Numerical investigation, based on quasi-neutral assumption, is performed for three different regimes: nonrelativistic, weakly relativistic, and relativistic. Ions' front in weakly relativistic regime exhibits spiky structure associated with a break-down of quasi-neutrality at the expanding front. In the relativistic regime, ion velocity is found to reach a saturation limit which occurs at earlier stages of the expansion. This limit is enhanced by higher electron velocity.

  5. Non-coding RNA may be associated with cytoplasmic male sterility in Silene vulgaris

    Czech Academy of Sciences Publication Activity Database

    Stone, James D.; Koloušková, Pavla; Sloan, D.B.; Štorchová, Helena


    Roč. 68, č. 7 (2017), s. 1599-1612 ISSN 0022-0957 R&D Projects: GA ČR(CZ) GA16-09220S Institutional support: RVO:61389030 Keywords : Cytoplasmic male sterility * Editing * Mitochondrion * Non-coding RNA * Silene vulgaris * Splicing * Transcriptome Subject RIV: EF - Botanics OBOR OECD: Plant sciences, botany Impact factor: 5.830, year: 2016

  6. allele of the noncoding hsrω gene of Drosophila melanogaster is not ...

    Indian Academy of Sciences (India)

    , Martinez P. et al. 2000 Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–. 106. Lakhotia S. C. 2003 The non-coding, developmentally active and stress inducible hsrω gene of Drosophila melanogaster ...

  7. Use of tiling array data and RNA secondary structure predictions to identify noncoding RNA genes

    DEFF Research Database (Denmark)

    Weile, Christian; Gardner, Paul P; Hedegaard, Mads M


    BACKGROUND: Within the last decade a large number of noncoding RNA genes have been identified, but this may only be the tip of the iceberg. Using comparative genomics a large number of sequences that have signals concordant with conserved RNA secondary structures have been discovered in the human...

  8. Transcriptome sequencing of a large human family identifies the impact of rare noncoding variants. (United States)

    Li, Xin; Battle, Alexis; Karczewski, Konrad J; Zappala, Zach; Knowles, David A; Smith, Kevin S; Kukurba, Kim R; Wu, Eric; Simon, Noah; Montgomery, Stephen B


    Recent and rapid human population growth has led to an excess of rare genetic variants that are expected to contribute to an individual's genetic burden of disease risk. To date, much of the focus has been on rare protein-coding variants, for which potential impact can be estimated from the genetic code, but determining the impact of rare noncoding variants has been more challenging. To improve our understanding of such variants, we combined high-quality genome sequencing and RNA sequencing data from a 17-individual, three-generation family to contrast expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) within this family to eQTLs and sQTLs within a population sample. Using this design, we found that eQTLs and sQTLs with large effects in the family were enriched with rare regulatory and splicing variants (minor allele frequency impact of rare noncoding variants. We found that distance to the transcription start site, evolutionary constraint, and epigenetic annotation were considerably more informative for predicting the impact of rare variants than for predicting the impact of common variants. These results highlight that rare noncoding variants are important contributors to individual gene-expression profiles and further demonstrate a significant capability for genomic annotation to predict the impact of rare noncoding variants. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Male sterility associated with overexpression of the noncoding hsrω ...

    Indian Academy of Sciences (India)


    To examine if the abnormal sperm development was associated with altered expression patterns of hsrω transcripts and/or various nuclear proteins that may interact with these noncoding transcripts, we examined the in situ localization of hsrω-n transcripts and several nuclear RNA-binding proteins in various cell types of.

  10. p53-dependent non-coding RNA networks in chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Blume, C. J.; Hotz-Wagenblatt, A.; Hüllein, J.; Sellner, L.; Jethwa, A.; Stolz, T.; Slabicki, M.; Lee, K.; Sharathchandra, A.; Benner, A.; Dietrich, S.; Oakes, C. C.; Dreger, P.; te Raa, D.; Kater, A. P.; Jauch, A.; Merkel, O.; Oren, M.; Hielscher, T.; Zenz, T.


    Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We

  11. The Role of Non-coding RNAs and Isothiocyanates in Cancer. (United States)

    Martin, Samantha L; Royston, Kendra J; Tollefsbol, Trygve O


    Cancer is the second leading cause of mortalities in the United States, only exceeded by heart disease. Current cancer treatments include chemotherapy, surgery and/or radiation. Due to the often harsh effects of current cancer therapies, investigators are focusing their efforts on cancer prevention mediated by dietary phytochemicals. Since the discovery that cancer can be initiated by and progress through both genetic and epigenetic pathways, there has been a significant surge in studies on epigenetic effects mediated by nutritive compounds. Isothiocyanates, naturally occurring molecules found in cruciferous vegetables, have been documented to exhibit many anticarcinogenic activities. Although isothiocyanates have been extensively documented as key players in epigenetic processes such as DNA methylation and histone modifications, their effects on non-coding RNAs is understudied. Non-coding RNAs are molecules that target mRNA production and repress protein translation and are known to be dysregulated in various human malignancies. Studies have used non-coding RNAs as novel targets for exploration in cancer therapy. This review focuses on the exploration of isothiocyanates and their effect on non-coding RNAs in cancer prevention and therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. Extracellular vesicle associated long non-coding RNAs functionally enhance cell viability

    Directory of Open Access Journals (Sweden)

    Chris Hewson


    Full Text Available Cells communicate with one another to create microenvironments and share resources. One avenue by which cells communicate is through the action of exosomes. Exosomes are extracellular vesicles that are released by one cell and taken up by neighbouring cells. But how exosomes instigate communication between cells has remained largely unknown. We present evidence here that particular long non-coding RNA molecules are preferentially packaged into exosomes. We also find that a specific class of these exosome associated non-coding RNAs functionally modulate cell viability by direct interactions with l-lactate dehydrogenase B (LDHB, high-mobility group protein 17 (HMG-17, and CSF2RB, proteins involved in metabolism, nucleosomal architecture and cell signalling respectively. Knowledge of this endogenous cell to cell pathway, those proteins interacting with exosome associated non-coding transcripts and their interacting domains, could lead to a better understanding of not only cell to cell interactions but also the development of exosome targeted approaches in patient specific cell-based therapies. Keywords: Non-coding RNA, Extracellular RNA, Exosomes, Retroelement, Pseudogene

  13. The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning

    NARCIS (Netherlands)

    Briz, Victor; Restivo, Leonardo; Pasciuto, Emanuela; Juczewski, Konrad; Mercaldo, Valentina; Lo, Adrian C; Baatsen, Pieter; Gounko, Natalia V; Borreca, Antonella; Girardi, Tiziana; Luca, Rossella; Nys, Julie; Poorthuis, Rogier B; Mansvelder, Huibert D; Fisone, Gilberto; Ammassari-Teule, Martine; Arckens, Lutgarde; Krieger, Patrik; Meredith, Rhiannon; Bagni, Claudia


    The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger

  14. Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation

    NARCIS (Netherlands)

    Alvarez-Dominguez, Juan R; Hu, Wenqian; Yuan, Bingbing; Shi, Jiahai; Park, Staphany S; Gromatzky, Austin A; van Oudenaarden, Alexander; Lodish, Harvey F


    Erythropoiesis is regulated at multiple levels to ensure the proper generation of mature red cells under multiple physiological conditions. To probe the contribution of long noncoding RNAs (lncRNAs) to this process, we examined >1 billion RNA-seq reads of polyadenylated and nonpolyadenylated RNA

  15. Long noncoding RNAs as a novel component of the Myc transcriptional network

    NARCIS (Netherlands)

    Winkle, Melanie; van den Berg, Anke; Tayari, Masoumeh; Sietzema, Jantine; Terpstra, Martijn; Kortman, Gertrud; de Jong, Debora; Visser, Lydia; Diepstra, Arjan; Kok, Klaas; Kluiver, Joost

    Myc is a well-known transcription factor with important roles in cell cycle, apoptosis, and cellular transformation. Long noncoding RNAs (lncRNAs) have recently emerged as an important class of regulatory RNAs. Here, we show that lncRNAs are a main component of the Myc-regulated transcriptional

  16. Uncovering the roles of long non-coding RNAs in cancer stem cells

    Directory of Open Access Journals (Sweden)

    Xiaoxing Huang


    Full Text Available Abstract Cancer has been a major public health problem that has threatened human life worldwide throughout history. The main causes that contribute to the poor prognosis of cancer are metastasis and recurrence. Cancer stem cells are a group of tumor cells that possess self-renewal and differentiation ability, which is a vital cause of cancer metastasis and recurrence. Long non-coding RNAs refer to a class of RNAs that are longer than 200 nt and have no potential to code proteins, some of which can be specifically expressed in different tissues and different tumors. Long non-coding RNAs have great biological significance in the occurrence and progression of cancers. However, how long non-coding RNAs interact with cancer stem cells and then affect cancer metastasis and recurrence is not yet clear. Therefore, this review aims to summarize recent studies that focus on how long non-coding RNAs impact tumor occurrence and progression by affecting cancer stem cell self-renewal and differentiation in liver cancer, prostate cancer, breast cancer, and glioma.

  17. Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes

    NARCIS (Netherlands)

    Heesch, S. van; Iterson, M. van; Jacobi, J.; Boymans, S.; Essers, P.B.; Bruijn, E. de; Hao, W.; Macinnes, A.W.; Cuppen, E.; Simonis, M.


    BACKGROUND: Long noncoding RNAs (lncRNAs) form an abundant class of transcripts, but the function of the majority of them remains elusive. While it has been shown that some lncRNAs are bound by ribosomes, it has also been convincingly demonstrated that these transcripts do not code for proteins. To

  18. Progressive changes in non-coding RNA profile in leucocytes with age (United States)

    Muñoz-Culla, Maider; Irizar, Haritz; Gorostidi, Ana; Alberro, Ainhoa; Osorio-Querejeta, Iñaki; Ruiz-Martínez, Javier; Olascoaga, Javier; de Munain, Adolfo López; Otaegui, David


    It has been observed that immune cell deterioration occurs in the elderly, as well as a chronic low-grade inflammation called inflammaging. These cellular changes must be driven by numerous changes in gene expression and in fact, both protein-coding and non-coding RNA expression alterations have been observed in peripheral blood mononuclear cells from elder people. In the present work we have studied the expression of small non-coding RNA (microRNA and small nucleolar RNA -snoRNA-) from healthy individuals from 24 to 79 years old. We have observed that the expression of 69 non-coding RNAs (56 microRNAs and 13 snoRNAs) changes progressively with chronological age. According to our results, the age range from 47 to 54 is critical given that it is the period when the expression trend (increasing or decreasing) of age-related small non-coding RNAs is more pronounced. Furthermore, age-related miRNAs regulate genes that are involved in immune, cell cycle and cancer-related processes, which had already been associated to human aging. Therefore, human aging could be studied as a result of progressive molecular changes, and different age ranges should be analysed to cover the whole aging process. PMID:28448962

  19. Evidence for widespread positive and negative selection in coding and conserved noncoding regions of Capsella grandiflora. (United States)

    Williamson, Robert J; Josephs, Emily B; Platts, Adrian E; Hazzouri, Khaled M; Haudry, Annabelle; Blanchette, Mathieu; Wright, Stephen I


    The extent that both positive and negative selection vary across different portions of plant genomes remains poorly understood. Here, we sequence whole genomes of 13 Capsella grandiflora individuals and quantify the amount of selection across the genome. Using an estimate of the distribution of fitness effects, we show that selection is strong in coding regions, but weak in most noncoding regions, with the exception of 5' and 3' untranslated regions (UTRs). However, estimates of selection on noncoding regions conserved across the Brassicaceae family show strong signals of selection. Additionally, we see reductions in neutral diversity around functional substitutions in both coding and conserved noncoding regions, indicating recent selective sweeps at these sites. Finally, using expression data from leaf tissue we show that genes that are more highly expressed experience stronger negative selection but comparable levels of positive selection to lowly expressed genes. Overall, we observe widespread positive and negative selection in coding and regulatory regions, but our results also suggest that both positive and negative selection on plant noncoding sequence are considerably rarer than in animal genomes.

  20. Long non-coding RNAs: Mechanism of action and functional utility

    Directory of Open Access Journals (Sweden)

    Shakil Ahmad Bhat


    Full Text Available Recent RNA sequencing studies have revealed that most of the human genome is transcribed, but very little of the total transcriptomes has the ability to encode proteins. Long non-coding RNAs (lncRNAs are non-coding transcripts longer than 200 nucleotides. Members of the non-coding genome include microRNA (miRNA, small regulatory RNAs and other short RNAs. Most of long non-coding RNA (lncRNAs are poorly annotated. Recent recognition about lncRNAs highlights their effects in many biological and pathological processes. LncRNAs are dysfunctional in a variety of human diseases varying from cancerous to non-cancerous diseases. Characterization of these lncRNA genes and their modes of action may allow their use for diagnosis, monitoring of progression and targeted therapies in various diseases. In this review, we summarize the functional perspectives as well as the mechanism of action of lncRNAs. Keywords: LncRNA, X-chromosome inactivation, Genome imprinting, Transcription regulation, Cancer, Immunity

  1. Discrepancies in reporting the CAG repeat lengths for Huntington's disease

    DEFF Research Database (Denmark)

    Quarrell, Oliver W; Handley, Olivia; O'Donovan, Kirsty


    results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft......Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original...... European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation...

  2. Removable Type Expansion Bolt Innovative Design (United States)

    Wang, Feng-Lan; Zhang, Bo; Gao, Bo; Liu, Yan-Xin; Gao, Bo


    Expansion bolt is a kind of the most common things in our daily life. Currently, there are many kinds of expansion bolts in the market. However, they have some shortcomings that mainly contain underuse and unremovement but our innovation of design makes up for these shortcomings very well. Principle of working follows this: expansion tube is fixed outside of bolt, steel balls and expansion covers are fixed inside. Meanwhile, the steel balls have 120° with each other. When using it ,expansion cover is moved in the direction of its internal part. So the front part of expansion bolt cover is increasingly becoming big and steel halls is moved outside. Only in this way can it be fixed that steel balls make expansion tube expand. When removing them, expansion bolt is moved outside. So the front part of expansion bolt cover is gradually becoming small and steel balls moves inside, after expansion tube shrinks, we can detach them.

  3. Chromosomal rearrangements occurred repeatedly and ...

    African Journals Online (AJOL)

    Furthermore, molecular and/or chromosomal data indicate that Paroedura is a monophyletic genus, in which chromosome rearrangements occurred repeatedly and independently during the specific diversification. Moreover both P. bastardi and P. gracilis in current definitions are paraphyletic assemblages of several ...

  4. Sequencing Games with Repeated Players

    NARCIS (Netherlands)

    Estevez Fernandez, M.A.; Borm, P.; Calleja, P.; Hamers, H.


    Two classes of one machine sequencing situations are considered in which each job corresponds to exactly one player but a player may have more than one job to be processed, so called RP(repeated player) sequencing situations. In max-RP sequencing situations it is assumed that each player's cost

  5. Pentapeptide Repeat Proteins and Cyanobacteria

    Energy Technology Data Exchange (ETDEWEB)

    Buchko, Garry W.


    Cyanobacteria are unique in many ways and one unusual feature is the presence of a suite of proteins that contain at least one domain with a minimum of eight tandem repeated five-residues (Rfr) of the general consensus sequence A[N/D]LXX. The function of such pentapeptide repeat proteins (PRPs) are still unknown, however, their prevalence in cyanobacteria suggests that they may play some role in the unique biological activities of cyanobacteria. As part of an inter-disciplinary Membrane Biology Grand Challenge at the Environmental Molecular Sciences Laboratory (Pacific Northwest National Laboratory) and Washington University in St. Louis, the genome of Cyanothece 51142 was sequenced and its molecular biology studied with relation to circadian rhythms. The genome of Cyanothece encodes for 35 proteins that contain at least one PRP domain. These proteins range in size from 105 (Cce_3102) to 930 (Cce_2929) kDa with the PRP domains ranging in predicted size from 12 (Cce_1545) to 62 (cce_3979) tandem pentapeptide repeats. Transcriptomic studies with 29 out of the 35 genes showed that at least three of the PRPs in Cyanothece 51142 (cce_0029, cce_3083, and cce_3272) oscillated with repeated periods of light and dark, further supporting a biological function for PRPs. Using X-ray diffraction crystallography, the structure for two pentapeptide repeat proteins from Cyanothece 51142 were determined, cce_1272 (aka Rfr32) and cce_4529 (aka Rfr23). Analysis of their molecular structures suggests that all PRP may share the same structural motif, a novel type of right-handed quadrilateral β-helix, or Rfr-fold, reminiscent of a square tower with four distinct faces. Each pentapeptide repeat occupies one face of the Rfr-fold with four consecutive pentapeptide repeats completing a coil that, in turn, stack upon each other to form “protein skyscrapers”. Details of the structural features of the Rfr-fold are reviewed here together with a discussion for the possible role of end

  6. A single-surface electrochemical biosensor for the detection of DNA triplet repeat expansion

    Czech Academy of Sciences Publication Activity Database

    Fojta, Miroslav; Horáková Brázdilová, Petra; Cahová, Kateřina; Pečinka, Petr


    Roč. 18, č. 2 (2006), s. 141-151 ISSN 1040-0397 R&D Projects: GA MPO(CZ) 1H-PK/42; GA AV ČR(CZ) IAA4004402 Institutional research plan: CEZ:AV0Z50040507 Keywords : DNA hybridization * electrochemical biosensor * enzyme-linked assay Subject RIV: BO - Biophysics Impact factor: 2.444, year: 2006

  7. TALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats. (United States)

    Mosbach, Valentine; Poggi, Lucie; Viterbo, David; Charpentier, Marine; Richard, Guy-Franck


    Trinucleotide repeat expansions involving CTG/CAG triplets are responsible for several neurodegenerative disorders, including myotonic dystrophy and Huntington's disease. Because expansions trigger the disease, contracting repeat length could be a possible approach to gene therapy for these disorders. Here, we show that a TALEN-induced double-strand break was very efficient at contracting expanded CTG repeats in yeast. We show that RAD51, POL32, and DNL4 are dispensable for double-strand break repair within CTG repeats, the only required genes being RAD50, SAE2, and RAD52. Resection was totally abolished in the absence of RAD50 on both sides of the break, whereas it was reduced in a sae2Δ mutant on the side of the break containing the longest repeat tract, suggesting that secondary structures at double-strand break ends must be removed by the Mre11-Rad50 complex and Sae2. Following the TALEN double-strand break, single-strand annealing occurred between both sides of the repeat tract, leading to repeat contraction. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. TALEN-Induced Double-Strand Break Repair of CTG Trinucleotide Repeats

    Directory of Open Access Journals (Sweden)

    Valentine Mosbach


    Full Text Available Trinucleotide repeat expansions involving CTG/CAG triplets are responsible for several neurodegenerative disorders, including myotonic dystrophy and Huntington’s disease. Because expansions trigger the disease, contracting repeat length could be a possible approach to gene therapy for these disorders. Here, we show that a TALEN-induced double-strand break was very efficient at contracting expanded CTG repeats in yeast. We show that RAD51, POL32, and DNL4 are dispensable for double-strand break repair within CTG repeats, the only required genes being RAD50, SAE2, and RAD52. Resection was totally abolished in the absence of RAD50 on both sides of the break, whereas it was reduced in a sae2Δ mutant on the side of the break containing the longest repeat tract, suggesting that secondary structures at double-strand break ends must be removed by the Mre11-Rad50 complex and Sae2. Following the TALEN double-strand break, single-strand annealing occurred between both sides of the repeat tract, leading to repeat contraction.

  9. Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction. (United States)

    Kaikkonen, Minna U; Halonen, Paavo; Liu, Oscar Hsin-Fu; Turunen, Tiia A; Pajula, Juho; Moreau, Pierre; Selvarajan, Ilakya; Tuomainen, Tomi; Aavik, Einari; Tavi, Pasi; Ylä-Herttuala, Seppo


    Microarrays and RNA sequencing are widely used to profile transcriptome remodeling during myocardial ischemia. However, the steady-state RNA analysis lacks in sensitivity to detect all noncoding RNA species and does not provide separation between transcriptional and post-transcriptional regulations. Here, we provide the first comprehensive analysis of nascent RNA profiles of mRNAs, primary micro-RNAs, long noncoding RNAs, and enhancer RNAs in a large animal model of acute infarction. Acute infarction was induced by cardiac catheterization of domestic swine. Nuclei isolated from healthy, border zone, and ischemic regions of the affected heart were subjected to global run-on sequencing. Global run-on sequencing analysis indicated that half of affected genes are regulated at the level of transcriptional pausing. A gradient of induction of inflammatory mediators and repression of peroxisome proliferator-activated receptor signaling and oxidative phosphorylation was detected when moving from healthy toward infarcted area. In addition, we interrogated the transcriptional regulation of primary micro-RNAs and provide evidence that several arrhythmia-related target genes exhibit repression at post-transcriptional level. We identified 450 long noncoding RNAs differently regulated by ischemia, including novel conserved long noncoding RNAs expressed in antisense orientation to myocardial transcription factors GATA-binding protein 4, GATA-binding protein 6, and Krüppel-like factor 6. Finally, characterization of enhancers exhibiting differential expression of enhancer RNAs pointed a central role for Krüppel-like factor, MEF2C, ETS, NFY, ATF, E2F2, and NRF1 transcription factors in determining transcriptional responses to ischemia. Global run-on sequencing allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel noncoding RNAs regulated by oxygen deprivation. These findings highlight potential new targets for diagnosis and

  10. Noncoding RNA in the transcriptional landscape of human neural progenitor cell differentiation (United States)

    Hecht, Patrick M.; Ballesteros-Yanez, Inmaculada; Grepo, Nicole; Knowles, James A.; Campbell, Daniel B.


    Increasing evidence suggests that noncoding RNAs play key roles in cellular processes, particularly in the brain. The present study used RNA sequencing to identify the transcriptional landscape of two human neural progenitor cell lines, SK-N-SH and ReNcell CX, as they differentiate into human cortical projection neurons. Protein coding genes were found to account for 54.8 and 57.0% of expressed genes, respectively, and alignment of RNA sequencing reads revealed that only 25.5–28.1% mapped to exonic regions of the genome. Differential expression analysis in the two cell lines identified altered gene expression in both protein coding and noncoding RNAs as they undergo neural differentiation with 222 differentially expressed genes observed in SK-N-SH cells and 19 differentially expressed genes in ReNcell CX. Interestingly, genes showing differential expression in SK-N-SH cells are enriched in genes implicated in autism spectrum disorder, but not in gene sets related to cancer or Alzheimer's disease. Weighted gene co-expression network analysis (WGCNA) was used to detect modules of co-expressed protein coding and noncoding RNAs in SK-N-SH cells and found four modules to be associated with neural differentiation. These modules contain varying levels of noncoding RNAs ranging from 10.7 to 49.7% with gene ontology suggesting roles in numerous cellular processes important for differentiation. These results indicate that noncoding RNAs are highly expressed in human neural progenitor cells and likely hold key regulatory roles in gene networks underlying neural differentiation and neurodevelopmental disorders. PMID:26557050

  11. Hygroscopic expansion kinetics of dental resin-composites. (United States)

    Alrahlah, A; Silikas, N; Watts, D C


    To evaluate the extent and rate of hygroscopic expansion of resin composites at 37°C. Eight resin composites were examined: 1 micro-hybrid (Bright Light(®)), 5 nano-hybrids (Experimental Vertise™; Nanoceram-Bright(®); Tetric EvoCeram(®); Grandio(®) SO; Ceram X™ duo) and 2 flowables (X-tra base; Venus(®) Diamond Flow). Five disks (15 mm×2 mm) of each material were prepared. The mean change in specimen diameter was recorded by a custom-built non-contact laser micrometer. Specimens were initially measured dry and then at fixed time intervals, over 150 days, after storage in distilled water at 37±1°C. Data were re-expressed in volumetric terms and analysed by repeated measures ANOVA, one-way ANOVA and Tukey's post hoc test (α=0.05). The volumetric hygroscopic expansion ranged from 0.58 to 2.26 and can be considered in three bands. First, Experimental Vertise had the highest expansion (pGrandio So, Nanoceram-Bright and X-tra base, with no significant difference between them. For the size (2mm thickness) and shape of specimen measured, equilibrium was attained in all cases by 60 days. Within this set of resin-composites the equilibrium expansion varied by almost 400% of the lowest material. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  12. Low-Normal FMR1 CGG Repeat Length: Phenotypic Associations

    Directory of Open Access Journals (Sweden)

    Marsha eMailick


    Full Text Available This population-based study investigates genotype-phenotype correlations of low-normal CGG repeats in the fragile X mental retardation 1 (FMR1 gene. FMR1 plays an important role in brain development and function, and encodes FMRP (fragile X mental retardation protein, an RNA-binding protein that regulates protein synthesis impacting activity-dependent synaptic development and plasticity. Most past research has focused on CGG premutation expansions (41 to 200 CGG repeats and on fragile X syndrome (200+ CGG repeats, with considerably less attention on the other end of the spectrum of CGG repeats. Using existing data, older adults with 23 or fewer CGG repeats (2 SDs below the mean were compared with age-peers who have normal numbers of CGGs (24-40 with respect to cognition, mental health, cancer, and having children with disabilities. Men (n = 341 with an allele in the low-normal range and women (n = 46 with two low-normal alleles had significantly more difficulty with their memory and ability to solve day to day problems. Women with both FMR1 alleles in the low-normal category had significantly elevated odds of feeling that they need to drink more to get the same effect as in the past. These women also had two and one-half times the odds of having had breast cancer and four times the odds of uterine cancer. Men and women with low-normal CGGs had higher odds of having a child with a disability, either a developmental disability or a mental health condition. These findings are in line with the hypothesis that there is a need for tight neuronal homeostatic control mechanisms for optimal cognitive and behavioral functioning, and more generally that low numbers as well as high numbers of CGG repeats may be problematic for health.

  13. Non-radioactive detection of trinucleotide repeat size variability. (United States)

    Tomé, Stéphanie; Nicole, Annie; Gomes-Pereira, Mario; Gourdon, Genevieve


    Many human diseases are associated with the abnormal expansion of unstable trinucleotide repeat sequences. The mechanisms of trinucleotide repeat size mutation have not been fully dissected, and their understanding must be grounded on the detailed analysis of repeat size distributions in human tissues and animal models. Small-pool PCR (SP-PCR) is a robust, highly sensitive and efficient PCR-based approach to assess the levels of repeat size variation, providing both quantitative and qualitative data. The method relies on the amplification of a very low number of DNA molecules, through sucessive dilution of a stock genomic DNA solution. Radioactive Southern blot hybridization is sensitive enough to detect SP-PCR products derived from single template molecules, separated by agarose gel electrophoresis and transferred onto DNA membranes. We describe a variation of the detection method that uses digoxigenin-labelled locked nucleic acid probes. This protocol keeps the sensitivity of the original method, while eliminating the health risks associated with the manipulation of radiolabelled probes, and the burden associated with their regulation, manipulation and waste disposal.

  14. French Expansion in North America. (United States)

    Jaenen, Cornelius J.


    Explores the French colonization in North America. Presents background information on New France, focusing on the French in Canada. Covers topics, such as how the French became interested in North American expansion, the French in Louisiana, colonial economics, and the reasons for the collapse of New France. Includes a bibliography. (CMK)

  15. Regulation of gas infrastructure expansion

    NARCIS (Netherlands)

    De Joode, J.


    The topic of this dissertation is the regulation of gas infrastructure expansion in the European Union (EU). While the gas market has been liberalised, the gas infrastructure has largely remained in the regulated domain. However, not necessarily all gas infrastructure facilities – such as gas

  16. On Fourier re-expansions


    Liflyand, E.


    We study an extension to Fourier transforms of the old problem on absolute convergence of the re-expansion in the sine (cosine) Fourier series of an absolutely convergent cosine (sine) Fourier series. The results are obtained by revealing certain relations between the Fourier transforms and their Hilbert transforms.

  17. Multiscale expansions in discrete world

    Indian Academy of Sciences (India)

    Multiscale expansions in discrete world. ÖMER ÜNSAL, FILIZ TASCAN. ∗ and MEHMET NACI ÖZER. Eskisehir Osmangazi University, Art-Science Faculty, Department of Mathematics and Computer. Sciences, Eskisehir-Türkiye. ∗. Corresponding author. E-mail: MS received 12 April 2013; accepted 16 ...

  18. Multiscale expansions in discrete world

    Indian Academy of Sciences (India)

    ... multiscale expansions discretely. The power of this manageable method is confirmed by applying it to two selected nonlinear Schrödinger evolution equations. This approach can also be applied to other nonlinear discrete evolution equations. All the computations have been made with Maple computer packet program.

  19. Multiscale expansions in discrete world

    Indian Academy of Sciences (India)

    This approach can also be applied to other nonlinear discrete evolution equations. All the computations have been made with Maple computer packet program. Keywords. Multiscale expansion; discrete evolution equation; modified nonlinear Schrödinger equation; third-order nonlinear Schrödinger equation; KdV equation.

  20. Discovery of Highly Divergent Repeat Landscapes in Snake Genomes Using High-Throughput Sequencing (United States)

    Castoe, Todd A.; Hall, Kathryn T.; Guibotsy Mboulas, Marcel L.; Gu, Wanjun; de Koning, A.P. Jason; Fox, Samuel E.; Poole, Alexander W.; Vemulapalli, Vijetha; Daza, Juan M.; Mockler, Todd; Smith, Eric N.; Feschotte, Cédric; Pollock, David D.


    We conducted a comprehensive assessment of genomic repeat content in two snake genomes, the venomous copperhead (Agkistrodon contortrix) and the Burmese python (Python molurus bivittatus). These two genomes are both relatively small (∼1.4 Gb) but have surprisingly extensive differences in the abundance and expansion histories of their repeat elements. In the python, the readily identifiable repeat element content is low (21%), similar to bird genomes, whereas that of the copperhead is higher (45%), similar to mammalian genomes. The copperhead's greater repeat content arises from the recent expansion of many different microsatellites and transposable element (TE) families, and the copperhead had 23-fold greater levels of TE-related transcripts than the python. This suggests the possibility that greater TE activity in the copperhead is ongoing. Expansion of CR1 LINEs in the copperhead genome has resulted in TE-mediated microsatellite expansion (“microsatellite seeding”) at a scale several orders of magnitude greater than previously observed in vertebrates. Snakes also appear to be prone to horizontal transfer of TEs, particularly in the copperhead lineage. The reason that the copperhead has such a small genome in the face of so much recent expansion of repeat elements remains an open question, although selective pressure related to extreme metabolic performance is an obvious candidate. TE activity can affect gene regulation as well as rates of recombination and gene duplication, and it is therefore possible that TE activity played a role in the evolution of major adaptations in snakes; some evidence suggests this may include the evolution of venom repertoires. PMID:21572095

  1. Correlation between the CAG repeat size and electrophysiological findings in patients with spinal and bulbar muscular atrophy. (United States)

    Kim, Hyunjin; Lim, Young-Min; Lee, Eun-Jae; Oh, Yeo Jin; Kim, Kwang-Kuk


    Spinal and bulbar muscular atrophy (SBMA) is caused by the expansion of a CAG repeat in the androgen receptor gene. The relationship between the CAG repeat size and electrophysiological findings is not completely understood. We retrospectively analyzed 62 SBMA patients to assess the correlation between their CAG repeat size and electrophysiological findings. In multiple regression analysis including age at examination and disease duration, we identified a negative correlation between the CAG repeat size and the compound muscle action potential (CMAP) amplitude. No significant correlation was found between the CAG repeat size and sensory nerve action potential (SNAP) amplitude. Contrary to previous reports of motor- and sensory-dominant phenotypes correlating with CAG repeat sizes, the CAG repeat size was negatively correlated only with CMAP amplitude, and not with SNAP amplitude. Muscle Nerve 57: 683-686, 2018. © 2017 Wiley Periodicals, Inc.

  2. Base excision repair of chemotherapeutically-induced alkylated DNA damage predominantly causes contractions of expanded GAA repeats associated with Friedreich's ataxia.

    Directory of Open Access Journals (Sweden)

    Yanhao Lai

    Full Text Available Expansion of GAA·TTC repeats within the first intron of the frataxin gene is the cause of Friedreich's ataxia (FRDA, an autosomal recessive neurodegenerative disorder. However, no effective treatment for the disease has been developed as yet. In this study, we explored a possibility of shortening expanded GAA repeats associated with FRDA through chemotherapeutically-induced DNA base lesions and subsequent base excision repair (BER. We provide the first evidence that alkylated DNA damage induced by temozolomide, a chemotherapeutic DNA damaging agent can induce massive GAA repeat contractions/deletions, but only limited expansions in FRDA patient lymphoblasts. We showed that temozolomide-induced GAA repeat instability was mediated by BER. Further characterization of BER of an abasic site in the context of (GAA20 repeats indicates that the lesion mainly resulted in a large deletion of 8 repeats along with small expansions. This was because temozolomide-induced single-stranded breaks initially led to DNA slippage and the formation of a small GAA repeat loop in the upstream region of the damaged strand and a small TTC loop on the template strand. This allowed limited pol β DNA synthesis and the formation of a short 5'-GAA repeat flap that was cleaved by FEN1, thereby leading to small repeat expansions. At a later stage of BER, the small template loop expanded into a large template loop that resulted in the formation of a long 5'-GAA repeat flap. Pol β then performed limited DNA synthesis to bypass the loop, and FEN1 removed the long repeat flap ultimately causing a large repeat deletion. Our study indicates that chemotherapeutically-induced alkylated DNA damage can induce large contractions/deletions of expanded GAA repeats through BER in FRDA patient cells. This further suggests the potential of developing chemotherapeutic alkylating agents to shorten expanded GAA repeats for treatment of FRDA.

  3. Enhancing Motivation through Repeated Listening


    Brown, R. A.


    Listening in a foreign language is difficult. Previous research has identified a number of strategies that can result in increased comprehension. One such is repeated listening. The present article describes a study in which 98 Japanese college students of English as a foreign language viewed five videos, rating their comprehension of each video after an initial viewing and again after a second viewing. Self-reported comprehension was found to be significantly better after the second viewing....

  4. Learning in repeated visual search


    Hout, Michael C.; Goldinger, Stephen D.


    Visual search (e.g., finding a specific object in an array of other objects) is performed most effectively when people are able to ignore distracting nontargets. In repeated search, however, incidental learning of object identities may facilitate performance. In three experiments, with over 1,100 participants, we examined the extent to which search could be facilitated by object memory and by memory for spatial layouts. Participants searched for new targets (real-world, nameable objects) embe...

  5. Preventing repeat pregnancy in adolescents. (United States)

    Milne, Dona; Glasier, Anna


    Teenage pregnancy is on a decline, but there are wide inequalities in those who are still becoming pregnant at an early age. Teenage pregnancy remains a public health concern. Numbers of repeat pregnancy in adolescence are small but contribute to poor health outcomes for young women and their children. A number of studies have demonstrated the impact that low levels of educational attainment, lack of aspiration, low socioeconomic status, dislike of school, lack of family connectedness and poor parental monitoring can have on early sexual activity and, in some cases, pregnancy among adolescents. Risks for repeat pregnancy in adolescence would appear to be linked to whether the pregnancy was intended or not, and what incentives or motivations, if any, existed to prevent subsequent early pregnancies. There would appear to be two options available to those who wish to reduce the negative health outcomes associated with repeat pregnancy in adolescence. First, to increase the life choices available to young women, which improve their social and economic circumstances. Secondly, to develop a clear understanding of pregnancy intentions within this group to ensure the provision of appropriate services which deliver the best possible outcomes for them and their child.

  6. Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy

    NARCIS (Netherlands)

    Bailey, CK; Andriola, IFM; Kampinga, HH; Merry, DE


    Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is

  7. Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Helen Budworth


    Full Text Available Huntington's Disease (HD is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.

  8. Genic non-coding microsatellites in the rice genome: characterization, marker design and use in assessing genetic and evolutionary relationships among domesticated groups

    Directory of Open Access Journals (Sweden)

    Singh Nagendra


    Full Text Available Abstract Background Completely sequenced plant genomes provide scope for designing a large number of microsatellite markers, which are useful in various aspects of crop breeding and genetic analysis. With the objective of developing genic but non-coding microsatellite (GNMS markers for the rice (Oryza sativa L. genome, we characterized the frequency and relative distribution of microsatellite repeat-motifs in 18,935 predicted protein coding genes including 14,308 putative promoter sequences. Results We identified 19,555 perfect GNMS repeats with densities ranging from 306.7/Mb in chromosome 1 to 450/Mb in chromosome 12 with an average of 357.5 GNMS per Mb. The average microsatellite density was maximum in the 5' untranslated regions (UTRs followed by those in introns, promoters, 3'UTRs and minimum in the coding sequences (CDS. Primers were designed for 17,966 (92% GNMS repeats, including 4,288 (94% hypervariable class I types, which were bin-mapped on the rice genome. The GNMS markers were most polymorphic in the intronic region (73.3% followed by markers in the promoter region (53.3% and least in the CDS (26.6%. The robust polymerase chain reaction (PCR amplification efficiency and high polymorphic potential of GNMS markers over genic coding and random genomic microsatellite markers suggest their immediate use in efficient genotyping applications in rice. A set of these markers could assess genetic diversity and establish phylogenetic relationships among domesticated rice cultivar groups. We also demonstrated the usefulness of orthologous and paralogous conserved non-coding microsatellite (CNMS markers, identified in the putative rice promoter sequences, for comparative physical mapping and understanding of evolutionary and gene regulatory complexities among rice and other members of the grass family. The divergence between long-grained aromatics and subspecies japonica was estimated to be more recent (0.004 Mya compared to short

  9. Population dynamics of a meiotic/mitotic expansion model for the fragile X syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Ashley, A.E.; Sherman, S.L. [Emory Univ. School of Medicine, Atlanta, GA (United States)


    A model to explain the mutational process and population dynamics of the fragile X syndrome is presented. The mutational mechanism was assumed to be a multi-pathway, multistep process. Expansion of CGG repeats was based on an underlying biological process and was assumed to occur at two time points: meiosis and early embryonic development (mitosis). Meiotic expansion was assumed to occur equally in oogenesis and spermatogenesis, while mitotic expansion was restricted to somatic, or constitutional, alleles of maternal origin. Testable hypotheses were predicted by this meiotic/mitotic model. First, parental origin of mutation is predicted to be associated with the risk of a woman to have a full-mutation child. Second, {open_quotes}contractions{close_quotes} seen in premutation male transmissions are predicted not to be true contractions in repeat size, but a consequence of the lack of mitotic expansion in paternally derived alleles. Third, a portion of full-mutation males should have full-mutation alleles in their sperm, due to the lack of complete selection against the full-mutation female. Fourth, a specific premutation-allele frequency distribution is predicted and differs from that based on models assuming only meiotic expansion. Last, it is predicted that {approximately}65 generations are required to achieve equilibrium, but this depends greatly on the expansion probabilities. 42 refs., 4 figs., 4 tabs.

  10. Micrografts: the "super" expansion graft. (United States)

    Mardovin, W; Miller, S F; Eppinger, M; Finley, R K


    A novel technique for producing micronized skin grafts that was introduced in a paper presented at the 1990 ABA meeting was evaluated to quantify maximum expansion. Twenty Sprague-Dawley rats were divided into two groups representing 10:1 and 25:1 expanded micrograft ratios, respectively. Grafted sites in both groups were shown to heal better than those of the control group, and both grafted groups showed comparable healing at day 10.


    Directory of Open Access Journals (Sweden)

    Gabriel BURLACU,


    Full Text Available Axial lenticular compensators are made to take over the longitudinal heat expansion, shock , vibration and noise, made elastic connections for piping systems. In order to have a long life for installations it is necessary that all elements, including lenticular compensators, have a good reliability. This desire can be did by technology of manufactoring and assembly of compensators, the material for lenses and by maintenance.of compensator

  12. An integrative approach to predicting the functional effects of small indels in non-coding regions of the human genome. (United States)

    Ferlaino, Michael; Rogers, Mark F; Shihab, Hashem A; Mort, Matthew; Cooper, David N; Gaunt, Tom R; Campbell, Colin


    Small insertions and deletions (indels) have a significant influence in human disease and, in terms of frequency, they are second only to single nucleotide variants as pathogenic mutations. As the majority of mutations associated with complex traits are located outside the exome, it is crucial to investigate the potential pathogenic impact of indels in non-coding regions of the human genome. We present FATHMM-indel, an integrative approach to predict the functional effect, pathogenic or neutral, of indels in non-coding regions of the human genome. Our method exploits various genomic annotations in addition to sequence data. When validated on benchmark data, FATHMM-indel significantly outperforms CADD and GAVIN, state of the art models in assessing the pathogenic impact of non-coding variants. FATHMM-indel is available via a web server at FATHMM-indel can accurately predict the functional impact and prioritise small indels throughout the whole non-coding genome.

  13. ATNX2 is not a regulatory gene in Italian ALS patients with C9ORF72 GGGGCC expansion (United States)

    Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario; Caponnetto, Claudia; Lunetta, Christian; Traynor, Bryan J.; Johnson, Janel O.; Nalls, Mike A.; Calvo, Andrea; Moglia, Cristina; Borghero, Giuseppe; Trojsi, Francesca; La Bella, Vincenzo; Volanti, Paolo; Simone, Isabella; Salvi, Fabrizio; Logullo, Francesco O.; Riva, Nilo; Carrera, Paola; Giannini, Fabio; Mandrioli, Jessica; Tanel, Raffaella; Capasso, Margherita; Tremolizzo, Lucio; Battistini, Stefania; Murru, Maria Rita; Origone, Paola; Zollino, Marcella; Penco, Silvana; Mazzini, Letizia; D’Alfonso, Sandra; Restagno, Gabriella; Brunetti, Maura; Barberis, Marco; Conforti, Francesca L.


    There are indications that both familial ALS and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this paper was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium (ITALSGEN), a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p=0.137; Sardinian cases, p=0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p=0.005; Sardinian cases, p=0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients. PMID:26733254

  14. A Power Series Expansion and Its Applications (United States)

    Chen, Hongwei


    Using the power series solution of a differential equation and the computation of a parametric integral, two elementary proofs are given for the power series expansion of (arcsin x)[squared], as well as some applications of this expansion.

  15. Simplifying Bridge Expansion Joint Design and Maintenance (United States)


    This report presents a study focused on identifying the most durable expansion joints for the South : Carolina Department of Transportation. This is performed by proposing a degradation model for the : expansion joints and updating it based on bridge...

  16. Improving repeatability by improving quality

    Energy Technology Data Exchange (ETDEWEB)

    Ronen, Shuki; Ackers, Mark; Schlumberger, Geco-Prakla; Brink, Mundy


    Time lapse (4-D) seismic is a promising tool for reservoir characterization and monitoring. The method is apparently simple: to acquire data repeatedly over the same reservoir, process and interpret the data sets, then changes between the data sets indicate changes in the reservoir. A problem with time lapse seismic data is that reservoirs are a relatively small part of the earth and important reservoir changes may cause very small differences to the time lapse data. The challenge is to acquire and process economical time lapse data such that reservoir changes can be detected above the noise of varying acquisition and environment. 7 refs., 9 figs.

  17. Coordinated hybrid automatic repeat request

    KAUST Repository

    Makki, Behrooz


    We develop a coordinated hybrid automatic repeat request (HARQ) approach. With the proposed scheme, if a user message is correctly decoded in the first HARQ rounds, its spectrum is allocated to other users, to improve the network outage probability and the users\\' fairness. The results, which are obtained for single- and multiple-antenna setups, demonstrate the efficiency of the proposed approach in different conditions. For instance, with a maximum of M retransmissions and single transmit/receive antennas, the diversity gain of a user increases from M to (J+1)(M-1)+1 where J is the number of users helping that user.

  18. Accumulate Repeat Accumulate Coded Modulation (United States)

    Abbasfar, Aliazam; Divsalar, Dariush; Yao, Kung


    In this paper we propose an innovative coded modulation scheme called 'Accumulate Repeat Accumulate Coded Modulation' (ARA coded modulation). This class of codes can be viewed as serial turbo-like codes, or as a subclass of Low Density Parity Check (LDPC) codes that are combined with high level modulation. Thus at the decoder belief propagation can be used for iterative decoding of ARA coded modulation on a graph, provided a demapper transforms the received in-phase and quadrature samples to reliability of the bits.

  19. Non-Coding RNAs are Differentially Expressed by Nocardia brasiliensis in Vitro and in Experimental Actinomycetoma. (United States)

    Cruz-Rabadán, Josué S; Miranda-Ríos, Juan; Espín-Ocampo, Guadalupe; Méndez-Tovar, Luis J; Maya-Pineda, Héctor Rubén; Hernández-Hernández, Francisca


    Nocardia spp. are common soil-inhabiting bacteria that frequently infect humans through traumatic injuries or inhalation routes and cause infections, such as actinomycetoma and nocardiosis, respectively. Nocardia brasiliensis is the main aetiological agent of actinomycetoma in various countries. Many bacterial non-coding RNAs are regulators of genes associated with virulence factors. The aim of this work was to identify non-coding RNAs (ncRNAs) expressed during infection conditions and in free-living form ( in vitro ) in Nocardia brasiliensis . The N. brasiliensis transcriptome (predominately brasiliensis infection compared with the in vitro conditions. The results of this work suggest a possible role for these transcripts in the regulation of virulence genes in actinomycetoma pathogenesis.

  20. Laminar and Temporal Expression Dynamics of Coding and Noncoding RNAs in the Mouse Neocortex

    Directory of Open Access Journals (Sweden)

    Sofia Fertuzinhos


    Full Text Available The hallmark of the cerebral neocortex is its organization into six layers, each containing a characteristic set of cell types and synaptic connections. The transcriptional events involved in laminar development and function still remain elusive. Here, we employed deep sequencing of mRNA and small RNA species to gain insights into transcriptional differences among layers and their temporal dynamics during postnatal development of the mouse primary somatosensory neocortex. We identify a number of coding and noncoding transcripts with specific spatiotemporal expression and splicing patterns. We also identify signature trajectories and gene coexpression networks associated with distinct biological processes and transcriptional overlap between these processes. Finally, we provide data that allow the study of potential miRNA and mRNA interactions. Overall, this study provides an integrated view of the laminar and temporal expression dynamics of coding and noncoding transcripts in the mouse neocortex and a resource for studies of neurodevelopment and transcriptome.

  1. Long noncoding RNAs: Undeciphered cellular codes encrypting keys of colorectal cancer pathogenesis (United States)

    Kim, Taewan; Croce, Carlo M.


    Long noncoding RNAs are non-protein coding transcripts longer than 200 nucleotides in length. By the advance in genetic and bioinformatic technologies, the new genomic landscape including noncoding transcripts has been revealed. Despite their non-capacity to be translated into proteins, lncRNAs have a versatile functions through various mechanisms interacting with other cellular molecules including DNA, protein, and RNA. Recent research interest and endeavor have identified the functional role of lncRNAs in various diseases including cancer. Colorectal cancer (CRC) is not only one of the most frequent cancer but also one of the cancer types with remarkable achievements in lncRNA research. Of the numerous notable lncRNAs identified and characterized in CRC, we will focus on key lncRNAs with the high potential as CRC-specific biomarkers in this review. PMID:29306015

  2. Non-Coding RNAs are Differentially Expressed by Nocardia brasiliensis in Vitro and in Experimental Actinomycetoma (United States)

    Cruz-Rabadán, Josué S.; Miranda-Ríos, Juan; Espín-Ocampo, Guadalupe; Méndez-Tovar, Luis J.; Maya-Pineda, Héctor Rubén; Hernández-Hernández, Francisca


    Introduction: Nocardia spp. are common soil-inhabiting bacteria that frequently infect humans through traumatic injuries or inhalation routes and cause infections, such as actinomycetoma and nocardiosis, respectively. Nocardia brasiliensis is the main aetiological agent of actinomycetoma in various countries. Many bacterial non-coding RNAs are regulators of genes associated with virulence factors. Objective: The aim of this work was to identify non-coding RNAs (ncRNAs) expressed during infection conditions and in free-living form (in vitro) in Nocardia brasiliensis. Methods and Result: The N. brasiliensis transcriptome (predominately brasiliensis infection compared with the in vitro conditions. Conclusion: The results of this work suggest a possible role for these transcripts in the regulation of virulence genes in actinomycetoma pathogenesis. PMID:28839491

  3. Mammalian hibernation and regulation of lipid metabolism: a focus on non-coding RNAs. (United States)

    Lang-Ouellette, D; Richard, T G; Morin, P


    Numerous species will confront severe environmental conditions by undergoing significant metabolic rate reduction. Mammalian hibernation is one such natural model of hypometabolism. Hibernators experience considerable physiological, metabolic, and molecular changes to survive the harsh challenges associated with winter. Whether as fuel source or as key signaling molecules, lipids are of primary importance for a successful bout of hibernation and their careful regulation throughout this process is essential. In recent years, a plethora of non-coding RNAs has emerged as potential regulators of targets implicated in lipid metabolism in diverse models. In this review, we introduce the general characteristics associated with mammalian hibernation, present the importance of lipid metabolism prior to and during hibernation, as well as discuss the potential relevance of non-coding RNAs such as miRNAs and lncRNAs during this process.

  4. Telomeric noncoding RNA TERRA is induced by telomere shortening to nucleate telomerase molecules at short telomeres. (United States)

    Cusanelli, Emilio; Romero, Carmina Angelica Perez; Chartrand, Pascal


    Elongation of a short telomere depends on the action of multiple telomerase molecules, which are visible as telomerase RNA foci or clusters associated with telomeres in yeast and mammalian cells. How several telomerase molecules act on a single short telomere is unknown. Herein, we report that the telomeric noncoding RNA TERRA is involved in the nucleation of telomerase molecules into clusters prior to their recruitment at a short telomere. We find that telomere shortening induces TERRA expression, leading to the accumulation of TERRA molecules into a nuclear focus. Simultaneous time-lapse imaging of telomerase RNA and TERRA reveals spontaneous events of telomerase nucleation on TERRA foci in early S phase, generating TERRA-telomerase clusters. This cluster is subsequently recruited to the short telomere from which TERRA transcripts originate during S phase. We propose that telomere shortening induces noncoding RNA expression to coordinate the recruitment and activity of telomerase molecules at short telomeres. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. New neurons in aging brains: molecular control by small non-coding RNAs

    Directory of Open Access Journals (Sweden)

    Marijn eSchouten


    Full Text Available Adult neurogenesis is a process that continues in the adult and also aging brain. It generates functional neurons from neural stem cells present in specific brain regions. This phenomenon is largely confined to two main regions: the subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus, in the hippocampus. With age, the hippocampus and particularly the dentate gyrus are affected. For instance, adult neurogenesis is decreased with aging, in both the number of proliferating cells as well as their neuronal differentiation, while in parallel an age-associated decline in cognitive performance is often seen. Surprisingly, the synaptogenic potential of adult-born neurons appears unaffected by aging. Therefore, although proliferation, differentiation, survival and synaptogenesis of adult-born new neurons in the dentate gyrus are closely related to each other, they appear differentially regulated with aging. In this review we discuss the crucial role of a novel class of recently discovered regulators of gene expression, i.e. the small non-coding RNAs, in the development of adult neurogenesis from neural stem cells to functionally integrated neurons. In particular, a subgroup of the small non-coding RNAs, the microRNAs, fine-tune many events during adult neurogenesis progression. Moreover, multiple small non-coding RNAs are differentially expressed in the aged hippocampus. This makes small non-coding RNAs appealing candidates to orchestrate, and possibly correct or prevent, the functional alterations in adult neurogenesis and cognition associated with aging. Finally, we briefly summarize observations that link changes in circulating levels of steroid hormones with alterations in adult neurogenesis and subsequent vulnerability to psychopathology in advanced age, and discuss a possible role of microRNAs in stress-associated alterations in adult neurogenesis during aging.

  6. Identification and characterization of long intergenic noncoding RNAs in bovine mammary glands. (United States)

    Tong, Chao; Chen, Qiaoling; Zhao, Lili; Ma, Junfei; Ibeagha-Awemu, Eveline M; Zhao, Xin


    Mammary glands of dairy cattle produce milk for the newborn offspring and for human consumption. Long intergenic noncoding RNAs (lincRNAs) play various functions in eukaryotic cells. However, types and roles of lincRNAs in bovine mammary glands are still poorly understood. Using computational methods, 886 unknown intergenic transcripts (UITs) were identified from five RNA-seq datasets from bovine mammary glands. Their non-coding potentials were predicted by using the combination of four software programs (CPAT, CNCI, CPC and hmmscan), with 184 lincRNAs identified. By comparison to the NONCODE2016 database and a domestic-animal long noncoding RNA database (ALDB), 112 novel lincRNAs were revealed in bovine mammary glands. Many lincRNAs were found to be located in quantitative trait loci (QTL). In particular, 36 lincRNAs were found in 172 milk related QTLs, whereas one lincRNA was within clinical mastitis QTL region. In addition, targeted genes for 10 lincRNAs with the highest fragments per kilobase of transcript per million fragments mapped (FPKM) were predicted by LncTar for forecasting potential biological functions of these lincRNAs. Further analyses indicate involvement of lincRNAs in several biological functions and different pathways. Our study has provided a panoramic view of lincRNAs in bovine mammary glands and suggested their involvement in many biological functions including susceptibility to clinical mastitis as well as milk quality and production. This integrative annotation of mammary gland lincRNAs broadens and deepens our understanding of bovine mammary gland biology.

  7. Transcriptional dynamics reveal critical roles for non-coding RNAs in the immediate-early response.

    Directory of Open Access Journals (Sweden)

    Stuart Aitken


    Full Text Available The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset.

  8. Hominoid-specific de novo protein-coding genes originating from long non-coding RNAs.

    Directory of Open Access Journals (Sweden)

    Chen Xie


    Full Text Available Tinkering with pre-existing genes has long been known as a major way to create new genes. Recently, however, motherless protein-coding genes have been found to have emerged de novo from ancestral non-coding DNAs. How these genes originated is not well addressed to date. Here we identified 24 hominoid-specific de novo protein-coding genes with precise origination timing in vertebrate phylogeny. Strand-specific RNA-Seq analyses were performed in five rhesus macaque tissues (liver, prefrontal cortex, skeletal muscle, adipose, and testis, which were then integrated with public transcriptome data from human, chimpanzee, and rhesus macaque. On the basis of comparing the RNA expression profiles in the three species, we found that most of the hominoid-specific de novo protein-coding genes encoded polyadenylated non-coding RNAs in rhesus macaque or chimpanzee with a similar transcript structure and correlated tissue expression profile. According to the rule of parsimony, the majority of these hominoid-specific de novo protein-coding genes appear to have acquired a regulated transcript structure and expression profile before acquiring coding potential. Interestingly, although the expression profile was largely correlated, the coding genes in human often showed higher transcriptional abundance than their non-coding counterparts in rhesus macaque. The major findings we report in this manuscript are robust and insensitive to the parameters used in the identification and analysis of de novo genes. Our results suggest that at least a portion of long non-coding RNAs, especially those with active and regulated transcription, may serve as a birth pool for protein-coding genes, which are then further optimized at the transcriptional level.

  9. The role of non-coding RNAs in cytoplasmic male sterility in flowering plants

    Czech Academy of Sciences Publication Activity Database

    Štorchová, Helena


    Roč. 18, č. 11 (2017), č. článku 2429. E-ISSN 1422-0067 R&D Projects: GA ČR GA16-09220S Institutional support: RVO:61389030 Keywords : Cytoplasmic male sterility * Gene expression * Global transcriptome * Non-coding RNA * Pollen development Subject RIV: EF - Botanics OBOR OECD: Plant sciences, botany Impact factor: 3.226, year: 2016

  10. Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression


    Zhai, Hui-yuan; Sui, Ming-hua; Yu, Xiao; Qu, Zhen; Hu, Jin-chen; Sun, Hai-qing; Zheng, Hai-tao; Zhou, Kai; Jiang, Li-xin


    Background Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. Material/Methods qRT-PCR was used to analyze the expression...

  11. Variation in conserved non-coding sequences on chromosome 5q andsusceptibility to asthma and atopy

    Energy Technology Data Exchange (ETDEWEB)

    Donfack, Joseph; Schneider, Daniel H.; Tan, Zheng; Kurz,Thorsten; Dubchak, Inna; Frazer, Kelly A.; Ober, Carole


    Background: Evolutionarily conserved sequences likely havebiological function. Methods: To determine whether variation in conservedsequences in non-coding DNA contributes to risk for human disease, westudied six conserved non-coding elements in the Th2 cytokine cluster onhuman chromosome 5q31 in a large Hutterite pedigree and in samples ofoutbred European American and African American asthma cases and controls.Results: Among six conserved non-coding elements (>100 bp,>70percent identity; human-mouse comparison), we identified one singlenucleotide polymorphism (SNP) in each of two conserved elements and sixSNPs in the flanking regions of three conserved elements. We genotypedour samples for four of these SNPs and an additional three SNPs each inthe IL13 and IL4 genes. While there was only modest evidence forassociation with single SNPs in the Hutterite and European Americansamples (P<0.05), there were highly significant associations inEuropean Americans between asthma and haplotypes comprised of SNPs in theIL4 gene (P<0.001), including a SNP in a conserved non-codingelement. Furthermore, variation in the IL13 gene was strongly associatedwith total IgE (P = 0.00022) and allergic sensitization to mold allergens(P = 0.00076) in the Hutterites, and more modestly associated withsensitization to molds in the European Americans and African Americans (P<0.01). Conclusion: These results indicate that there is overalllittle variation in the conserved non-coding elements on 5q31, butvariation in IL4 and IL13, including possibly one SNP in a conservedelement, influence asthma and atopic phenotypes in diversepopulations.

  12. The validity of certain homogenization expansions

    International Nuclear Information System (INIS)

    Williams, M.


    Asymptotic expansions are formally developed for the transport problem in a cellular medium (full-space) and also for non-cellular media in domains with boundaries. The expansions are asymptotic with respect to the mean free path length and cell dimension. It is proved in this paper that the expansion in the full-space case is valid. (author)

  13. Peptide specific expansion of CD8(+) T cells by recombinant plate bound MHC/peptide complexes

    DEFF Research Database (Denmark)

    Schmidt, Esben G W; Buus, Soren; Thorn, Mette


    Development of methods for efficient in vitro stimulation and expansion of peptide specific CD8(+) T cells is compelling not only with respect to adoptive T cell therapy but also regarding analysis of T cell responses and search for new immunogenic peptides. In the present study, a new approach...... cells (NA-PBMCs) with PB-MHC/CMVp resulted in significant expansion of CMVp specific CD8(+) T cells, which was comparable to that achieved by CMVp pulsed mature dendritic cells (DCs). By repeated exposure of NA-PBMCs to PB-MHC/CMVp more than 60% CMVp specific CD8(+) T cells, representing a 240-fold...... expansion, were reached after only two stimulations. Although stimulation with PB-MHC/CMVp clearly demonstrated efficient peptide specific expansion of CD8(+) T cells, there was a tendency to proliferative exhaustion of the cells after 3-4 stimulations. Thus, it will be of interest to examine the effect...

  14. Definite behavioral variant of frontotemporal dementia with C9ORF72 expansions despite positive Alzheimer's disease cerebrospinal fluid biomarkers. (United States)

    Wallon, David; Rovelet-Lecrux, Anne; Deramecourt, Vincent; Pariente, Jeremie; Auriacombe, Sophie; Le Ber, Isabelle; Schraen, Suzanna; Pasquier, Florence; Campion, Dominique; Hannequin, Didier


    Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer's disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the dementia diagnostic algorithm.

  15. Methods for Using Small Non-Coding RNAs to Improve Recombinant Protein Expression in Mammalian Cells

    Directory of Open Access Journals (Sweden)

    Sarah Inwood


    Full Text Available The ability to produce recombinant proteins by utilizing different “cell factories” revolutionized the biotherapeutic and pharmaceutical industry. Chinese hamster ovary (CHO cells are the dominant industrial producer, especially for antibodies. Human embryonic kidney cells (HEK, while not being as widely used as CHO cells, are used where CHO cells are unable to meet the needs for expression, such as growth factors. Therefore, improving recombinant protein expression from mammalian cells is a priority, and continuing effort is being devoted to this topic. Non-coding RNAs are RNA segments that are not translated into a protein and often have a regulatory role. Since their discovery, major progress has been made towards understanding their functions. Non-coding RNA has been investigated extensively in relation to disease, especially cancer, and recently they have also been used as a method for engineering cells to improve their protein expression capability. In this review, we provide information about methods used to identify non-coding RNAs with the potential of improving recombinant protein expression in mammalian cell lines.

  16. Long non-coding RNAs-towards precision medicine in diabetic kidney disease? (United States)

    Panchapakesan, Usha; Pollock, Carol


    Diabetic kidney disease (DKD) is escalating and is the major cause of end stage kidney failure. There is increasing evidence to support the role of epigenetic factors and metabolic memory in linking the environmental and genetic causes of this disease. Although our understanding of this disease has improved, there has been no significant efficacious therapeutic translation in the last decade. Current sequencing technology has allowed interrogation of the human transcriptome. It is evident that although approximately 80% of the genome is transcribed, only 1-2% is read and coded into protein. The remaining non-coding RNA, historically assumed to be 'junk', is now known to have key roles in regulating gene function and orchestrate how and when coding genes are expressed. This largest subset of non-coding RNAs called long non-coding RNAs (LNCRNAs) drives epigenetic changes and has functional relevance best characterized in cancers and cardiovascular disease. This understanding, coupled with the availability and affordability of RNA sequencing, has shifted our therapeutic strategies towards genomic therapy in DKD. The role of LNCRNAs with respect to DKD is only just emerging. In this review we summarize the role of LNCRNAs in DKD and the existing antisense oligonucleotide therapy that may provide precise and targeted medicine to treat DKD in this postgenomic era. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  17. Long noncoding RNAs in hepatitis B virus-related hepatocellular carcinoma. (United States)

    Yu, Ting-Ting; Xu, Xi-Ming; Hu, Yi; Deng, Jun-Jian; Ge, Wei; Han, Na-Na; Zhang, Mei-Xia


    To study the expression of long noncoding RNAs (lncRNAs) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The lncRNA profiles between HBV-related HCC tissues and corresponding normal liver tissues were generated using microarray analysis. Datasets were analyzed using multiple algorithms to depict alterations in gene expression on the basis of gene ontology (GO), pathway analysis, and lncRNA levels. The microarray revealed that 1772 lncRNAs and 2508 mRNAs were differently expressed. The pathway analysis demonstrated that the cell cycle, cytokine-cytokine receptor interaction, chemokine signaling pathway, and phosphoinositide 3-kinase-protein kinase B signaling pathway may play important roles in HCC. Several GO terms, such as cell cycle, DNA replication, immune response, and signal transduction, were enriched in gene lists, suggesting a potential correlation with HBV-related HCC. The upregulated large intergenic noncoding RNA ULK4P2 was physically combined with enhancer of zeste homolog 2. Therefore, the lncRNAs may participate in regulating HBV-related HCC. lncRNAs play important roles in HCC, future studies should verify whether large intergenic noncoding ULK4P2 functions by combining with enhancer of zeste homolog 2 in HCC.

  18. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. (United States)

    Ounzain, Samir; Pezzuto, Iole; Micheletti, Rudi; Burdet, Frédéric; Sheta, Razan; Nemir, Mohamed; Gonzales, Christine; Sarre, Alexandre; Alexanian, Michael; Blow, Matthew J; May, Dalit; Johnson, Rory; Dauvillier, Jérôme; Pennacchio, Len A; Pedrazzini, Thierry


    The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs. Copyright © 2014. Published by Elsevier Ltd.

  19. CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis. (United States)

    Ounzain, Samir; Micheletti, Rudi; Arnan, Carme; Plaisance, Isabelle; Cecchi, Dario; Schroen, Blanche; Reverter, Ferran; Alexanian, Michael; Gonzales, Christine; Ng, Shi Yan; Bussotti, Giovanni; Pezzuto, Iole; Notredame, Cedric; Heymans, Stephane; Guigó, Roderic; Johnson, Rory; Pedrazzini, Thierry


    Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. The Role of Noncoding RNAs in Neurodevelopmental Disorders: The Case of Rett Syndrome. (United States)

    Obiols-Guardia, Aida; Guil, Sònia


    Current technologies have demonstrated that only a small fraction of our genes encode for protein products. The vast majority of the human transcriptome corresponds to noncoding RNA (ncRNA) of different size, localization, and expression profile. Despite the fact that a biological function remains yet to be determined for most ncRNAs, growing evidence points to their crucial regulatory roles at all stages in gene expression regulation, including transcriptional and posttranscriptional control, so that proper cell homeostasis seems to depend largely on a variety of ncRNA-mediated regulatory networks. This is particularly relevant in the human brain, which displays the richest repertoire of ncRNA species, and where several different ncRNA molecules are known to be involved in crucial steps for brain development and maturation. Rett syndrome is a neurodevelopmental disorder characterized by loss of function mutations in the X-linked gene encoding for methyl-CpG-binding protein 2 (MeCP2). MECP2 deficiency impacts globally on gene expression programs, mainly through its role as a transcriptional repressor, and growing data also points to an important dysregulation of the noncoding transcriptome in the disease. Here, we review the current knowledge on ncRNA alterations in Rett and explore links with other pathologies that might indicate the potential use of particular noncoding transcripts as therapeutical targets, tools, or disease biomarkers.

  1. Psychiatric symptoms and CAG expansion in Huntington`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Weber, M.W.; Schmid, W.; Spiegel, R. [Univ. of Zuerich (Switzerland)


    The mutation responsible for Huntington`s disease (HD) is an elongated CAG repeat in the coding region of the IT15 gene. A PCR-based test with high sensitivity and accuracy is now available to identify asymptomatic gene carriers and patients. An inverse correlation between CAG copy number and age at disease onset has been found in a large number of affected individuals. The influence of the CAG repeat expansion on other phenotypic manifestations, especially specific psychiatric symptoms has not been studied intensively. In order to elucidate this situation we investigated the relation between CAG copy number and distinct psychiatric phenotypes found in 79 HD-patients. None of the four differentiated categories (personality change, psychosis, depression, and nonspecific alterations) showed significant differences in respect to size of the CAG expansion. In addition, no influence of individual sex on psychiatric presentation could be found. On the other hand in patients with personality changes maternal transmission was significantly more frequent compared with all other groups. Therefore we suggest that clinical severity of psychiatric features in HD is not directly dependent on the size of the dynamic mutation involved. The complex pathogenetic mechanisms leading to psychiatric alterations are still unknown and thus genotyping does not provide information about expected psychiatric symptoms in HD gene carriers. 40 refs., 1 fig., 2 tabs.

  2. Unusual Structures Are Present in DNA Fragments Containing Super-Long Huntingtin CAG Repeats (United States)

    Duzdevich, Daniel; Li, Jinliang; Whang, Jhoon; Takahashi, Hirohide; Takeyasu, Kunio; Dryden, David T. F.; Morton, A. Jennifer; Edwardson, J. Michael


    Background In the R6/2 mouse model of Huntington's disease (HD), expansion of the CAG trinucleotide repeat length beyond about 300 repeats induces a novel phenotype associated with a reduction in transcription of the transgene. Methodology/Principal Findings We analysed the structure of polymerase chain reaction (PCR)-generated DNA containing up to 585 CAG repeats using atomic force microscopy (AFM). As the number of CAG repeats increased, an increasing proportion of the DNA molecules exhibited unusual structural features, including convolutions and multiple protrusions. At least some of these features are hairpin loops, as judged by cross-sectional analysis and sensitivity to cleavage by mung bean nuclease. Single-molecule force measurements showed that the convoluted DNA was very resistant to untangling. In vitro replication by PCR was markedly reduced, and TseI restriction enzyme digestion was also hindered by the abnormal DNA structures. However, significantly, the DNA gained sensitivity to cleavage by the Type III restriction-modification enzyme, EcoP15I. Conclusions/Significance “Super-long” CAG repeats are found in a number of neurological diseases and may also appear through CAG repeat instability. We suggest that unusual DNA structures associated with super-long CAG repeats decrease transcriptional efficiency in vitro. We also raise the possibility that if these structures occur in vivo, they may play a role in the aetiology of CAG repeat diseases such as HD. PMID:21347256

  3. Unusual structures are present in DNA fragments containing super-long Huntingtin CAG repeats.

    Directory of Open Access Journals (Sweden)

    Daniel Duzdevich


    Full Text Available In the R6/2 mouse model of Huntington's disease (HD, expansion of the CAG trinucleotide repeat length beyond about 300 repeats induces a novel phenotype associated with a reduction in transcription of the transgene.We analysed the structure of polymerase chain reaction (PCR-generated DNA containing up to 585 CAG repeats using atomic force microscopy (AFM. As the number of CAG repeats increased, an increasing proportion of the DNA molecules exhibited unusual structural features, including convolutions and multiple protrusions. At least some of these features are hairpin loops, as judged by cross-sectional analysis and sensitivity to cleavage by mung bean nuclease. Single-molecule force measurements showed that the convoluted DNA was very resistant to untangling. In vitro replication by PCR was markedly reduced, and TseI restriction enzyme digestion was also hindered by the abnormal DNA structures. However, significantly, the DNA gained sensitivity to cleavage by the Type III restriction-modification enzyme, EcoP15I."Super-long" CAG repeats are found in a number of neurological diseases and may also appear through CAG repeat instability. We suggest that unusual DNA structures associated with super-long CAG repeats decrease transcriptional efficiency in vitro. We also raise the possibility that if these structures occur in vivo, they may play a role in the aetiology of CAG repeat diseases such as HD.

  4. Strain expansion-reduction approach (United States)

    Baqersad, Javad; Bharadwaj, Kedar


    Validating numerical models are one of the main aspects of engineering design. However, correlating million degrees of freedom of numerical models to the few degrees of freedom of test models is challenging. Reduction/expansion approaches have been traditionally used to match these degrees of freedom. However, the conventional reduction/expansion approaches are only limited to displacement, velocity or acceleration data. While in many cases only strain data are accessible (e.g. when a structure is monitored using strain-gages), the conventional approaches are not capable of expanding strain data. To bridge this gap, the current paper outlines a reduction/expansion technique to reduce/expand strain data. In the proposed approach, strain mode shapes of a structure are extracted using the finite element method or the digital image correlation technique. The strain mode shapes are used to generate a transformation matrix that can expand the limited set of measurement data. The proposed approach can be used to correlate experimental and analytical strain data. Furthermore, the proposed technique can be used to expand real-time operating data for structural health monitoring (SHM). In order to verify the accuracy of the approach, the proposed technique was used to expand the limited set of real-time operating data in a numerical model of a cantilever beam subjected to various types of excitations. The proposed technique was also applied to expand real-time operating data measured using a few strain gages mounted to an aluminum beam. It was shown that the proposed approach can effectively expand the strain data at limited locations to accurately predict the strain at locations where no sensors were placed.

  5. CDC Vital Signs: Preventing Repeat Teen Births (United States)

    ... MB] Read the MMWR Science Clips Preventing Repeat Teen Births Recommend on Facebook Tweet Share Compartir On ... live birth before age 20. Problem Too many teens, ages 15–19, have repeat births. Nearly 1 ...

  6. Australian coal industry continues expansion

    International Nuclear Information System (INIS)

    Edwards, G.E.


    Recent saleable Australian black coal production figures are given along with trends in development of new operations and new technology aiming to provide a sound basis for the continuing expansion of the Australian coal industry. Export prices from 1982 to 1991 to Japan (Australia's major export market) are provided, together with Australian dollar return to exporters at the exchange rate prevailing at the start of each contract year. An increased demand for steaming coal is expected, thus maintaining Australia's position as the world's larger exporter. 4 tabs

  7. Contribution of thermal expansion and

    Directory of Open Access Journals (Sweden)



    Full Text Available A theoretical model is developed to describe the experimental results obtained for the isobaric thermal conductivity of rare gas solids (RGS. The isobaric thermal conductivity of RGS has been analysed within Debye approximation with regard to the effect of thermal expansion. The suggested model takes into consideration the fact that thermal conductivity is determined by U-processes while above the phonon mobility edge it is determined by "diffusive" modes migrating randomly from site to site. The mobility edge ω0 is determined from the condition that the phonon mean-free path restricted by the U-processes cannot be smaller than half of the phonon wavelength.

  8. Low-thermal expansion infrared glass ceramics (United States)

    Lam, Philip


    L2 Tech, Inc. is in development of an innovative infrared-transparent glass ceramic material with low-thermal expansion (nano-crystals in a residual glass phase. The major crystalline phase is zirconium tungstate (ZrW2O8) which has Negative Thermal Expansion (NTE). The glass phase is the infrared-transparent germanate glass which has positive thermal expansion (PTE). Then glass ceramic material has a balanced thermal expansion of near zero. The crystal structure is cubic and the thermal expansion of the glass ceramic is isotropic or equal in all directions.

  9. Shrub expansion in tundra ecosystems: dynamics, impacts and research priorities

    International Nuclear Information System (INIS)

    Myers-Smith, Isla H; Forbes, Bruce C; Wilmking, Martin; Hallinger, Martin; Lantz, Trevor; Blok, Daan; Sass-Klaassen, Ute; Tape, Ken D; Macias-Fauria, Marc; Lévesque, Esther; Boudreau, Stéphane; Ropars, Pascale; Hermanutz, Luise; Trant, Andrew; Collier, Laura Siegwart; Weijers, Stef; Rozema, Jelte; Rayback, Shelly A; Schmidt, Niels Martin; Schaepman-Strub, Gabriela


    Recent research using repeat photography, long-term ecological monitoring and dendrochronology has documented shrub expansion in arctic, high-latitude and alpine tundra ecosystems. Here, we (1) synthesize these findings, (2) present a conceptual framework that identifies mechanisms and constraints on shrub increase, (3) explore causes, feedbacks and implications of the increased shrub cover in tundra ecosystems, and (4) address potential lines of investigation for future research. Satellite observations from around the circumpolar Arctic, showing increased productivity, measured as changes in ‘greenness’, have coincided with a general rise in high-latitude air temperatures and have been partly attributed to increases in shrub cover. Studies indicate that warming temperatures, changes in snow cover, altered disturbance regimes as a result of permafrost thaw, tundra fires, and anthropogenic activities or changes in herbivory intensity are all contributing to observed changes in shrub abundance. A large-scale increase in shrub cover will change the structure of tundra ecosystems and alter energy fluxes, regional climate, soil–atmosphere exchange of water, carbon and nutrients, and ecological interactions between species. In order to project future rates of shrub expansion and understand the feedbacks to ecosystem and climate processes, future research should investigate the species or trait-specific responses of shrubs to climate change including: (1) the temperature sensitivity of shrub growth, (2) factors controlling the recruitment of new individuals, and (3) the relative influence of the positive and negative feedbacks involved in shrub expansion.

  10. Topological characteristics of helical repeat proteins

    NARCIS (Netherlands)

    Groves, M R; Barford, D

    The recent elucidation of protein structures based upon repeating amino acid motifs, including the armadillo motif, the HEAT motif and tetratricopeptide repeats, reveals that they belong to the class of helical repeat proteins. These proteins share the common property of being assembled from tandem

  11. Simple sequence repeats in mycobacterial genomes

    Indian Academy of Sciences (India)


    J. Biosci. 32(1), January 2007. The list of microsatellite rich as well as poor regions in the five mycobacterial genomes. Local GC%. Repeat rich(+)/. Repeat poor(-). Total ORFs. Number of ... Simple sequence repeats in mycobacterial genomes. VATTIPALLY .... heat shock protein (grpE) (15839737), heat shock protein (dnaJ) ...

  12. Repeated Reading. What Works Clearinghouse Intervention Report (United States)

    What Works Clearinghouse, 2014


    "Repeated reading" is an academic practice that aims to increase oral reading fluency. "Repeated reading" can be used with students who have developed initial word reading skills but demonstrate inadequate reading fluency for their grade level. During "repeated reading," a student sits in a quiet location with a…

  13. A dual-mode single-molecule fluorescence assay for the detection of expanded CGG repeats in Fragile X syndrome. (United States)

    Cannon, Brian; Pan, Cynthia; Chen, Liangjing; Hadd, Andrew G; Russell, Rick


    Fragile X syndrome is the leading cause of inherited mental impairment and is associated with expansions of CGG repeats within the FMR1 gene. To detect expanded CGG repeats, we developed a dual-mode single-molecule fluorescence assay that allows acquisition of two parallel, independent measures of repeat number based on (1) the number of Cy3-labeled probes bound to the repeat region and (2) the physical length of the electric field-linearized repeat region, obtained from the relative position of a single Cy5 dye near the end of the repeat region. Using target strands derived from cell-line DNA with defined numbers of CGG repeats, we show that this assay can rapidly and simultaneously measure the repeats of a collection of individual sample strands within a single field of view. With a low occurrence of false positives, the assay differentiated normal CGG repeat lengths (CGG( N ), N = 23) and expanded CGG repeat lengths (CGG( N ), N = 118), representing a premutation disease state. Further, mixtures of these DNAs gave results that correlated with their relative populations. This strategy may be useful for identifying heterozygosity or for screening collections of individuals, and it is readily adaptable for screening other repeat disorders.

  14. Digital storage of repeated signals

    International Nuclear Information System (INIS)

    Prozorov, S.P.


    An independent digital storage system designed for repeated signal discrimination from background noises is described. The signal averaging is performed off-line in the real time mode by means of multiple selection of the investigated signal and integration in each point. Digital values are added in a simple summator and the result is recorded the storage device with the volume of 1024X20 bit from where it can be output on an oscillograph, a plotter or transmitted to a compUter for subsequent processing. The described storage is reliable and simple device on one base of which the systems for the nuclear magnetic resonapce signal acquisition in different experiments are developed

  15. Learning in repeated visual search. (United States)

    Hout, Michael C; Goldinger, Stephen D


    Visual search (e.g., finding a specific object in an array of other objects) is performed most effectively when people are able to ignore distracting nontargets. In repeated search, however, incidental learning of object identities may facilitate performance. In three experiments, with over 1,100 participants, we examined the extent to which search could be facilitated by object memory and by memory for spatial layouts. Participants searched for new targets (real-world, nameable objects) embedded among repeated distractors. To make the task more challenging, some participants performed search for multiple targets, increasing demands on visual working memory (WM). Following search, memory for search distractors was assessed using a surprise two-alternative forced choice recognition memory test with semantically matched foils. Search performance was facilitated by distractor object learning and by spatial memory; it was most robust when object identity was consistently tied to spatial locations and weakest (or absent) when object identities were inconsistent across trials. Incidental memory for distractors was better among participants who searched under high WM load, relative to low WM load. These results were observed when visual search included exhaustive-search trials (Experiment 1) or when all trials were self-terminating (Experiment 2). In Experiment 3, stimulus exposure was equated across WM load groups by presenting objects in a single-object stream; recognition accuracy was similar to that in Experiments 1 and 2. Together, the results suggest that people incidentally generate memory for nontarget objects encountered during search and that such memory can facilitate search performance.

  16. Quality control during repeated fryings

    Directory of Open Access Journals (Sweden)

    Cuesta, C.


    Full Text Available Most of the debate ¡s about how the slow or frequent turnover of fresh fat affects the deterioration, of fat used in frying. Then, the modification of different oils used in repeated fryings of potatoes without or with turnover of fresh oil, under similar frying conditions, was evaluated by two criteria: by measuring the total polar component isolated by column chromatography and by the evaluation of the specific compounds related to thermoxidative and hydrolytic alteration by High Performance Size Exclusion Chromatography (HPSEC. The results indicate that with frequent turnover of fresh oil, the critical level of 25% of polar material is rarely reached, and there are fewer problems with fat deterioration because the frying tended to increase the level of polar material and thermoxidative compounds (polymers and dimers of triglycerides and oxidized triglycerides in the fryer oil during the first fryings, followed by minor changes and a tendency to reach a near-steady state in successive fryings. However, in repeated frying of potatoes using a null turnover the alteration rate was higher being linear the relationship found between polar material or the different thermoxidative compounds and the number of fryings. On the other hand chemical reactions produced during deep-fat frying can be minimized by using proper oils. In addition the increased level of consumers awareness toward fat composition and its impact on human health could had an impact on the selection of fats for snacks and for industry. In this way monoenic fats are the most adequate from a nutritional point of view and for its oxidative stability during frying.

  17. Imagination as expansion of experience. (United States)

    Zittoun, Tania; Cerchia, Frédéric


    This paper proposes a developmental view on imagination: from this perspective, imagination can be seen as triggered by some disrupting event, which generates a disjunction from the person's unfolding experience of the "real" world, and as unfolding as a loop, which eventually comes back to the actual experience. Examining recent and classical theorization of imagination in psychology, the paper opposes a deficitary view of imagination to an expansive notion of imagination. The paper explores Piaget, Vygotsky, Harris and Pelaprat & Cole consider: 1) What does provoke a "rupture" or disjunction? 2) What are the psychological processes involved in the imaginary loop? 3) What nourishes such processes? 4) What are the consequences of such imaginary loop, or what does it enable doing? The paper proposes to adopt an expansive view of imagination, as Vygotsky proposed-a perspective that has been under-explored empirically since his seminal work. To stimulate such sociocultural psychology of imagination, two empirical examples are provided, one showing how children make sense of metaphor in an experimental setting, the other showing a young person using a novel met at school as symbolic resource.

  18. Nonperturbative path integral expansion II

    International Nuclear Information System (INIS)

    Kaiser, H.J.


    The Feynman path integral representation of the 2-point function for a self-interacting Bose field is investigated using an expansion ('Path Integral Expansion', PIE) of the exponential of the kinetic term of the Lagrangian. This leads to a series - illustrated by a graph scheme - involving successively a coupling of more and more points of the lattice space commonly employed in the evaluation of path integrals. The values of the individual PIE graphs depend of course on the lattice constant. Two methods - Pade approximation and Borel-type extrapolation - are proposed to extract information about the continuum limit from a finite-order PIE. A more flexible PIE is possible by expanding besides the kinetic term a suitably chosen part of the interaction term too. In particular, if the co-expanded part is a mass term the calculation becomes only slightly more complicated than in the original formulation and the appearance of the graph scheme is unchanged. A significant reduction of the number of graphs and an improvement of the convergence of the PIE can be achieved by performing certain sums over an infinity of graph elements. (author)

  19. Evolutionary expansion of the Monogenea. (United States)

    Kearn, G C


    The evolutionary expansion of the monogeneans has taken place in parallel with the diversification of the fish-like vertebrates. In this article the main trends in monogenean evolution are traced from a hypothetical skin-parasitic ancestor on early vertebrates. Special consideration is given to the following topics: early divergence between skin feeders and blood feeders; diversification and specialization of the haptor for attachment to skin; transfer from host to host, viviparity and the success of the gyrodactylids; predation on skin parasites and camouflage; colonization of the buccal and branchial cavities; diversification and specialization of the haptor for attachment to the gills; phoresy in gill parasites; the development of endoparasitism and the origin of the cestodes; the success of dactylogyroidean gill parasites; the uniqueness of the polyopisthocotyleans; ovoviviparity and the colonization of the tetrapods. Host specificity has been the guiding force of coevolution between monogeneans and their vertebrate hosts, but the establishment of monogeneans on unrelated hosts sharing the same environment (host-switching) may have been underestimated. Host-switching has provided significant opportunities for evolutionary change of direction and is probably responsible for the establishment of monogeneans on cephalopod molluscs, on the hippopotamus and possibly on chelonians. There are indications that host-switching may be more common in monogeneans that spread by direct transfer of adults/juveniles from host to host. A limitation on the further expansion of monogeneans is the need for water for the dispersal of the infective larva (oncomiracidium).

  20. Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation


    Fei-Ran Shen; Hao Kuang; Feng-Xia Hu; Hui Wu; Qing-Zhen Huang; Fei-Xiang Liang; Kai-Ming Qiao; Jia Li; Jing Wang; Yao Liu; Lei Zhang; Min He; Ying Zhang; Wen-Liang Zuo; Ji-Rong Sun


    Materials with zero thermal expansion (ZTE) or precisely tailored thermal expansion are in urgent demand of modern industries. However, the overwhelming majority of materials show positive thermal expansion. To develop ZTE or negative thermal expansion (NTE) materials as compensators has become an important challenge. Here, we present the evidence for the realization of ultra-low thermal expansion in Mn–Co–Ge–In particles. The bulk with the Ni2In-type hexagonal structure undergoes giant NTE o...

  1. The leucine-rich repeat structure. (United States)

    Bella, J; Hindle, K L; McEwan, P A; Lovell, S C


    The leucine-rich repeat is a widespread structural motif of 20-30 amino acids with a characteristic repetitive sequence pattern rich in leucines. Leucine-rich repeat domains are built from tandems of two or more repeats and form curved solenoid structures that are particularly suitable for protein-protein interactions. Thousands of protein sequences containing leucine-rich repeats have been identified by automatic annotation methods. Three-dimensional structures of leucine-rich repeat domains determined to date reveal a degree of structural variability that translates into the considerable functional versatility of this protein superfamily. As the essential structural principles become well established, the leucine-rich repeat architecture is emerging as an attractive framework for structural prediction and protein engineering. This review presents an update of the current understanding of leucine-rich repeat structure at the primary, secondary, tertiary and quaternary levels and discusses specific examples from recently determined three-dimensional structures.

  2. On the Equisummability of Hermite and Fourier Expansions

    Indian Academy of Sciences (India)

    We prove an equisummability result for the Fourier expansions and Hermite expansions as well as special Hermite expansions. We also prove the uniform boundedness of the Bochner-Riesz means associated to the Hermite expansions for polyradial functions.

  3. Operational experience in the Langley expansion tube with various test gases (United States)

    Miller, C. G.


    A resume' of operating experiences with the Langley Expansion Tube is presented. The driver gas was unheated helium at a nominal pressure of 5000 psi and the majority of the data presented are for air and carbon dioxide test gases. The primary purpose of these data is to illustrate the effects of various parameters on quasi-steady test flow duration, as well as free stream and post-normal shock flow conditions. The discussion shows that the Langley Expansion Tube is an operational facility capable of producing good quality, highly repeatable, quasi-steady flow for test times sufficient to establish flow about blunt axisymmetric and two-dimensional models.

  4. Relationship Development in Greenfield Expansions

    DEFF Research Database (Denmark)

    Drogendijk, Rian; Andersson, Ulf


    This paper investigates conceptually how new Greenfield subsidiaries develop relationships over time. We focus our analysis on the earliest start-up stage of new Greenfield subsidiaries, and on the dynamics of relationships development with five different groups of actors within the MNC...... and the local environment of the new Greenfield. We argue that relationship strength, or the intensity of interaction and resource exchange, depends on the new Greenfield''s degree of dependence or interdependence within these relationships and develop propositions based on institutional theory, resource...... dependency theory and network approaches. In the concluding sections we suggest directions for future work to enhance understanding of the dynamics of relationship management in new Greenfield expansions....

  5. Image Compression by Gabor Expansion

    Directory of Open Access Journals (Sweden)

    J. Chmurny


    Full Text Available Transform-based coding methods are popular in data compression. Inthe paper, an easily implemented method is proposed for the weightingfactors of the Gabor decomposition. The method is based on theleast-mean- squares error (LMSE approach. The solution of the LMSEproblem shows that the weighting factors can be extracted by simplemultiplication between a matrix and the vector of data. If the setGabor functions are chosen to be independent of the test images, thismatrix is constant. Images are reconstructed by multiplying the matrixof Gabor functions and the vector of weighting factors. The choise ofGabor functions in the decomposition allows that the resultingdecomposition has a pyramidal structure. In the paper is proposedsimple codec system for pyramidal Gabor expansion for imagecompression.

  6. Repeat Associated Non-AUG Translation (RAN Translation Dependent on Sequence Downstream of the ATXN2 CAG Repeat.

    Directory of Open Access Journals (Sweden)

    Daniel R Scoles

    Full Text Available Spinocerebellar ataxia type 2 (SCA2 is a progressive autosomal dominant disorder caused by the expansion of a CAG tract in the ATXN2 gene. The SCA2 disease phenotype is characterized by cerebellar atrophy, gait ataxia, and slow saccades. ATXN2 mutation causes gains of toxic and normal functions of the ATXN2 gene product, ataxin-2, and abnormally slow Purkinje cell firing frequency. Previously we investigated features of ATXN2 controlling expression and noted expression differences for ATXN2 constructs with varying CAG lengths, suggestive of repeat associated non-AUG translation (RAN translation. To determine whether RAN translation occurs for ATXN2 we assembled various ATXN2 constructs with ATXN2 tagged by luciferase, HA or FLAG tags, driven by the CMV promoter or the ATXN2 promoter. Luciferase expression from ATXN2-luciferase constructs lacking the ATXN2 start codon was weak vs AUG translation, regardless of promoter type, and did not increase with longer CAG repeat lengths. RAN translation was detected on western blots by the anti-polyglutamine antibody 1C2 for constructs driven by the CMV promoter but not the ATXN2 promoter, and was weaker than AUG translation. Strong RAN translation was also observed when driving the ATXN2 sequence with the CMV promoter with ATXN2 sequence downstream of the CAG repeat truncated to 18 bp in the polyglutamine frame but not in the polyserine or polyalanine frames. Our data demonstrate that ATXN2 RAN translation is weak compared to AUG translation and is dependent on ATXN2 sequences flanking the CAG repeat.

  7. Pressurized electrolysis stack with thermal expansion capability (United States)

    Bourgeois, Richard Scott


    The present techniques provide systems and methods for mounting an electrolyzer stack in an outer shell so as to allow for differential thermal expansion of the electrolyzer stack and shell. Generally, an electrolyzer stack may be formed from a material with a high coefficient of thermal expansion, while the shell may be formed from a material having a lower coefficient of thermal expansion. The differences between the coefficients of thermal expansion may lead to damage to the electrolyzer stack as the shell may restrain the thermal expansion of the electrolyzer stack. To allow for the differences in thermal expansion, the electrolyzer stack may be mounted within the shell leaving a space between the electrolyzer stack and shell. The space between the electrolyzer stack and the shell may be filled with a non-conductive fluid to further equalize pressure inside and outside of the electrolyzer stack.

  8. A critical examination of expansion tunnel performance (United States)

    Miller, C. G.


    An experimental study of the performance of the expansion tunnel for various test gases and range of quiescent acceleration section and nozzle pressure, nozzle geometric area ratio, and nozzle axial station has been performed. Flow diagnostics used to examine expansion tunnel flow characteristics were time histories and profiles of pitot pressure and axial component of flow velocity. The purpose of this study was to determine experimentally what limitations might restrict predicted operational flexibility and the advantages and disadvantages of this mode of operation as compared to the expansion tube. Results are presented which demonstrate the expansion tunnel offers several advantages over the expansion tube, but the severity of the disadvantages of the tunnel makes the expansion tube mode of operation the more desirable for performing hypersonic-hypervelocity aerothermodynamic studies of proposed entry configurations.

  9. Repeats and EST analysis for new organisms

    Directory of Open Access Journals (Sweden)

    Jonassen Inge


    Full Text Available Abstract Background Repeat masking is an important step in the EST analysis pipeline. For new species, genomic knowledge is scarce and good repeat libraries are typically unavailable. In these cases it is common practice to mask against known repeats from other species (i.e., model organisms. There are few studies that investigate the effectiveness of this approach, or attempt to evaluate the different methods for identifying and masking repeats. Results Using zebrafish and medaka as example organisms, we show that accurate repeat masking is an important factor for obtaining a high quality clustering. Furthermore, we show that masking with standard repeat libraries based on curated genomic information from other species has little or no positive effect on the quality of the resulting EST clustering. Library based repeat masking which often constitutes a computational bottleneck in the EST analysis pipeline can therefore be reduced to species specific repeat libraries, or perhaps eliminated entirely. In contrast, substantially improved results can be achived by applying a repeat library derived from a partial reference clustering (e.g., from mapping sequences against a partially sequenced genome. Conclusion Of the methods explored, we find that the best EST clustering is achieved after masking with repeat libraries that are species specific. In the absence of such libraries, library-less masking gives results superior to the current practice of using cross-species, genome-based libraries.

  10. ncRNA-class Web Tool: Non-coding RNA feature extraction and pre-miRNA classification web tool

    KAUST Repository

    Kleftogiannis, Dimitrios A.


    Until recently, it was commonly accepted that most genetic information is transacted by proteins. Recent evidence suggests that the majority of the genomes of mammals and other complex organisms are in fact transcribed into non-coding RNAs (ncRNAs), many of which are alternatively spliced and/or processed into smaller products. Non coding RNA genes analysis requires the calculation of several sequential, thermodynamical and structural features. Many independent tools have already been developed for the efficient calculation of such features but to the best of our knowledge there does not exist any integrative approach for this task. The most significant amount of existing work is related to the miRNA class of non-coding RNAs. MicroRNAs (miRNAs) are small non-coding RNAs that play a significant role in gene regulation and their prediction is a challenging bioinformatics problem. Non-coding RNA feature extraction and pre-miRNA classification Web Tool (ncRNA-class Web Tool) is a publicly available web tool ( ) which provides a user friendly and efficient environment for the effective calculation of a set of 58 sequential, thermodynamical and structural features of non-coding RNAs, plus a tool for the accurate prediction of miRNAs. © 2012 IFIP International Federation for Information Processing.

  11. IW-Scoring: an Integrative Weighted Scoring framework for annotating and prioritizing genetic variations in the noncoding genome. (United States)

    Wang, Jun; Dayem Ullah, Abu Z; Chelala, Claude


    The vast majority of germline and somatic variations occur in the noncoding part of the genome, only a small fraction of which are believed to be functional. From the tens of thousands of noncoding variations detectable in each genome, identifying and prioritizing driver candidates with putative functional significance is challenging. To address this, we implemented IW-Scoring, a new Integrative Weighted Scoring model to annotate and prioritise functionally relevant noncoding variations. We evaluate 11 scoring methods, and apply an unsupervised spectral approach for subsequent selective integration into two linear weighted functional scoring schemas for known and novel variations. IW-Scoring produces stable high-quality performance as the best predictors for three independent data sets. We demonstrate the robustness of IW-Scoring in identifying recurrent functional mutations in the TERT promoter, as well as disease SNPs in proximity to consensus motifs and with gene regulatory effects. Using follicular lymphoma as a paradigmatic cancer model, we apply IW-Scoring to locate 11 recurrently mutated noncoding regions in 14 follicular lymphoma genomes, and validate 9 of these regions in an extension cohort, including the promoter and enhancer regions of PAX5. Overall, IW-Scoring demonstrates greater versatility in identifying trait- and disease-associated noncoding variants. Scores from IW-Scoring as well as other methods are freely available from © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

  12. Thermal and hygroscopic expansion characteristics of bamboo


    Huang, Puxi; Chang, Wen-shao; Ansell, Martin P.; Bowen, Chris R.; Chew, John Y. M.; Adamak, Vana i


    The expansion and contraction of bamboo caused by temperature and moisture variations must be evaluated\\ud if bamboo is to be utilised as a building material. However, detailed expansion data, especially data in the ascent and\\ud descent processes of temperature and moisture are unexplored. The aim of this study is to investigate the expansion\\ud characteristics of Phyllostachys edulis (Moso bamboo) in ascent and descent processes of temperature and moisture.\\ud The measurement of linear ther...

  13. Thermal expansion in small metallic particles

    International Nuclear Information System (INIS)

    Ivanov, A.S.


    An anomalously low thermal expansion observable in small particles is attributed to extending effect of the shell. It is shown that the coefficient of thermal expansion of the oxide-film-coated aluminium particles calculated using elastic constants and coefficients of thermal expansion of massive materials agres well with those measured experimentally. The linear dilatation of the shell, its stress to rupture and the values of the structural tension are estimated vs the temperature

  14. Simulation program for multiple expansion Stirling machines

    International Nuclear Information System (INIS)

    Walker, G.; Weiss, M.; Fauvel, R.; Reader, G.; Bingham, E.R.


    Multiple expansion Stirling machines have been a topic of interest at the University of Calgary for some years. Recently a second-order computer simulation program with integral graphics package for Stirling cryocoolers with up to four stages of expansion were developed and made available to the Stirling community. Adaptation of the program to multiple expansion Stirling power systems is anticipated. This paper briefly introduces the program and presents a specimen result

  15. The Tandem Repeats Enabling Reversible Switching between the Two Phases of β-Lactamase Substrate Spectrum


    Yi, Hyojeong; Song, Han; Hwang, Junghyun; Kim, Karan; Nierman, William C.; Kim, Heenam Stanley


    Expansion or shrinkage of existing tandem repeats (TRs) associated with various biological processes has been actively studied in both prokaryotic and eukaryotic genomes, while their origin and biological implications remain mostly unknown. Here we describe various duplications (de novo TRs) that occurred in the coding region of a β-lactamase gene, where a conserved structure called the omega loop is encoded. These duplications that occurred under selection using ceftazidime conferred substra...

  16. Targeted deletion of the 9p21 noncoding coronary artery disease risk interval in mice

    Energy Technology Data Exchange (ETDEWEB)

    Visel, Axel; Zhu, Yiwen; May, Dalit; Afzal, Veena; Gong, Elaine; Attanasio, Catia; Blow, Matthew J.; Cohen, Jonathan C.; Rubin, Edward M.; Pennacchio, Len A.


    Sequence polymorphisms in a 58kb interval on chromosome 9p21 confer a markedly increased risk for coronary artery disease (CAD), the leading cause of death worldwide 1,2. The variants have a substantial impact on the epidemiology of CAD and other life?threatening vascular conditions since nearly a quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein?coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70kb noncoding interval on mouse chromosome 4 affects cardiac expression of neighboring genes, as well as proliferation properties of vascular cells. Chr4delta70kb/delta70kb mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the noncoding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4delta70kb/delta70kb mice, indicating that distant-acting gene regulatory functions are located in the noncoding CAD risk interval. Allelespecific expression of Cdkn2b transcripts in heterozygous mice revealed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4delta70kb/delta70kb aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval plays a pivotal role in regulation of cardiac Cdkn2a/b expression and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.

  17. CONDOR: a database resource of developmentally associated conserved non-coding elements

    Directory of Open Access Journals (Sweden)

    Smith Sarah


    Full Text Available Abstract Background Comparative genomics is currently one of the most popular approaches to study the regulatory architecture of vertebrate genomes. Fish-mammal genomic comparisons have proved powerful in identifying conserved non-coding elements likely to be distal cis-regulatory modules such as enhancers, silencers or insulators that control the expression of genes involved in the regulation of early development. The scientific community is showing increasing interest in characterizing the function, evolution and language of these sequences. Despite this, there remains little in the way of user-friendly access to a large dataset of such elements in conjunction with the analysis and the visualization tools needed to study them. Description Here we present CONDOR (COnserved Non-coDing Orthologous Regions available at: In an interactive and intuitive way the website displays data on > 6800 non-coding elements associated with over 120 early developmental genes and conserved across vertebrates. The database regularly incorporates results of ongoing in vivo zebrafish enhancer assays of the CNEs carried out in-house, which currently number ~100. Included and highlighted within this set are elements derived from duplication events both at the origin of vertebrates and more recently in the teleost lineage, thus providing valuable data for studying the divergence of regulatory roles between paralogs. CONDOR therefore provides a number of tools and facilities to allow scientists to progress in their own studies on the function and evolution of developmental cis-regulation. Conclusion By providing access to data with an approachable graphics interface, the CONDOR database presents a rich resource for further studies into the regulation and evolution of genes involved in early development.

  18. Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT (United States)

    Tomaselli, Pedro J.; Rossor, Alexander M.; Horga, Alejandro; Jaunmuktane, Zane; Carr, Aisling; Saveri, Paola; Piscosquito, Giuseppe; Pareyson, Davide; Laura, Matilde; Blake, Julian C.; Poh, Roy; Polke, James; Houlden, Henry


    Objective: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1). Methods: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected. Results: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population. Conclusions: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions. PMID:28283593

  19. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. (United States)

    Michalik, Katharina M; You, Xintian; Manavski, Yosif; Doddaballapur, Anuradha; Zörnig, Martin; Braun, Thomas; John, David; Ponomareva, Yuliya; Chen, Wei; Uchida, Shizuka; Boon, Reinier A; Dimmeler, Stefanie


    The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown. Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Endothelial cells of different origin express relative high levels of the conserved long noncoding RNAs MALAT1, taurine upregulated gene 1 (TUG1), maternally expressed 3 (MEG3), linc00657, and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by small interfering RNAs or GapmeRs induced a promigratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by vascular endothelial growth factor, MALAT1 small interfering RNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hindlimb ischemia. Gene expression profiling followed by confirmatory quantitative reverse transcriptase-polymerase chain reaction demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators. Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.

  20. Identification of maize long non-coding RNAs responsive to drought stress.

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    Full Text Available Long non-coding RNAs (lncRNAs represent a class of riboregulators that either directly act in long form or are processed to shorter miRNAs and siRNAs. Emerging evidence shows that lncRNAs participate in stress responsive regulation. In this study, to identify the putative maize lncRNAs responsive to drought stress, 8449 drought responsive transcripts were first uploaded to the Coding Potential Calculator website for classification as protein coding or non-coding RNAs, and 1724 RNAs were identified as potential non-coding RNAs. A Perl script was written to screen these 1724 ncRNAs and 664 transcripts were ultimately identified as drought-responsive lncRNAs. Of these 664 transcripts, 126 drought-responsive lncRNAs were highly similar to known maize lncRNAs; the remaining 538 transcripts were considered as novel lncRNAs. Among the 664 lncRNAs identified as drought responsive, 567 were upregulated and 97 were downregulated in drought-stressed leaves of maize. 8 lncRNAs were identified as miRNA precursor lncRNAs, 62 were classified as both shRNA and siRNA precursors, and 279 were classified as siRNA precursors. The remaining 315 lncRNAs were classified as other lncRNAs that are likely to function as longer molecules. Among these 315 lncRNAs, 10 are identified as antisense lncRNAs and 7 could pair with 17 CDS sequences with near-perfect matches. Finally, RT-qPCR results confirmed that all selected lncRNAs could respond to drought stress. These findings extend the current view on lncRNAs as ubiquitous regulators under stress conditions.

  1. The promise of enhancer-associated long noncoding RNAs in cardiac regeneration. (United States)

    Ounzain, Samir; Pedrazzini, Thierry


    Heart failure is a worldwide epidemic and represents a major cause of morbidity and mortality. Current clinical therapies for heart disease prolong survival by protecting the viable muscle, but they are unable to replenish lost cardiomyocytes to restore function. Over the last decade, the notion of promoting cardiac regeneration has engendered considerable research interest. New strategies envisage the transfer of stem cells into the damaged myocardium, the mobilization of cardiac precursor cells, the promotion of cardiomyocyte proliferation in situ and direct reprogramming of non-cardiac cells into electromechanically coupled cardiomyocytes. The molecular and cellular mechanisms underpinning these different regenerative avenues are under the control of integrated transcriptional programs, which are ultimately dependent on epigenomic reprogramming and reorganization of the genome nuclear architecture. Today, it is becoming evident that regulatory noncoding RNAs play fundamental roles in all these aspects of gene regulatory network activity. In particular, thousands of long noncoding RNAs are dynamically expressed across the entire genome during lineage-specific commitment, specialization, and differentiation, as well as during the response to environmental cues. Here, we review this emerging landscape, focusing particularly on a unique class of lncRNA emerging from enhancer sequences, the enhancer-associated lncRNAs, in the context of cardiac regeneration. We propose that characterizing and manipulating these enhancer-associated transcripts could provide a novel approach to awaken the dormant regenerative potential of the adult mammalian heart. Ultimately, this could lead to targeted noncoding RNA-based enhancer therapies to improve effectiveness of current regenerative strategies and provide new avenues for repair. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Involvement of Host Non-Coding RNAs in the Pathogenesis of the Influenza Virus

    Directory of Open Access Journals (Sweden)

    Yanmei Ma


    Full Text Available Non-coding RNAs (ncRNAs are a new type of regulators that play important roles in various cellular processes, including cell growth, differentiation, survival, and apoptosis. ncRNAs, including small non-coding RNAs (e.g., microRNAs, small interfering RNAs and long non-coding RNAs (lncRNAs, are pervasively transcribed in human and mammalian cells. Recently, it has been recognized that these ncRNAs are critically implicated in the virus–host interaction as key regulators of transcription or post-transcription during viral infection. Influenza A virus (IAV is still a major threat to human health. Hundreds of ncRNAs are differentially expressed in response to infection with IAV, such as infection by pandemic H1N1 and highly pathogenic avian strains. There is increasing evidence demonstrating functional involvement of these regulatory microRNAs, vault RNAs (vtRNAs and lncRNAs in pathogenesis of influenza virus, including a variety of host immune responses. For example, it has been shown that ncRNAs regulate activation of pattern recognition receptor (PRR-associated signaling and transcription factors (nuclear factor κ-light-chain-enhancer of activated B cells, NF-κB, as well as production of interferons (IFNs and cytokines, and expression of critical IFN-stimulated genes (ISGs. The vital functions of IAV-regulated ncRNAs either to against defend viral invasion or to promote progeny viron production are summarized in this review. In addition, we also highlight the potentials of ncRNAs as therapeutic targets and diagnostic biomarkers.

  3. Involvement of Host Non-Coding RNAs in the Pathogenesis of the Influenza Virus. (United States)

    Ma, Yanmei; Ouyang, Jing; Wei, Jingyun; Maarouf, Mohamed; Chen, Ji-Long


    Non-coding RNAs (ncRNAs) are a new type of regulators that play important roles in various cellular processes, including cell growth, differentiation, survival, and apoptosis. ncRNAs, including small non-coding RNAs (e.g., microRNAs, small interfering RNAs) and long non-coding RNAs (lncRNAs), are pervasively transcribed in human and mammalian cells. Recently, it has been recognized that these ncRNAs are critically implicated in the virus-host interaction as key regulators of transcription or post-transcription during viral infection. Influenza A virus (IAV) is still a major threat to human health. Hundreds of ncRNAs are differentially expressed in response to infection with IAV, such as infection by pandemic H1N1 and highly pathogenic avian strains. There is increasing evidence demonstrating functional involvement of these regulatory microRNAs, vault RNAs (vtRNAs) and lncRNAs in pathogenesis of influenza virus, including a variety of host immune responses. For example, it has been shown that ncRNAs regulate activation of pattern recognition receptor (PRR)-associated signaling and transcription factors (nuclear factor κ-light-chain-enhancer of activated B cells, NF-κB), as well as production of interferons (IFNs) and cytokines, and expression of critical IFN-stimulated genes (ISGs). The vital functions of IAV-regulated ncRNAs either to against defend viral invasion or to promote progeny viron production are summarized in this review. In addition, we also highlight the potentials of ncRNAs as therapeutic targets and diagnostic biomarkers.

  4. Trichodesmium genome maintains abundant, widespread noncoding DNA in situ, despite oligotrophic lifestyle

    Energy Technology Data Exchange (ETDEWEB)

    Walworth, Nathan G.; Pfreundt, Ulrike; Nelson, William C.; Mincer, Tracy; Heidelberg, John F.; Fu, Feixue; Waterbury, John B.; Glavina del Rio, T.; Goodwin, Lynne A.; Kyrpides, Nikos; Land, Miriam L.; Woyke, Tanja; Hutchins, David A.; Hess, Wolfgang R.; Webb, Eric A.


    Understanding the evolution of the free-living, cyanobacterial, diazotroph Trichodesmium is of great importance due to its critical role in oceanic biogeochemistry and primary production. Unlike the other >150 available genomes of free-living cyanobacteria, only 63.8% of the Trichodesmium erythraeum (strain IMS101) genome is predicted to encode protein, which is 20-25% less than the average for other cyanobacteria and non-pathogenic, free-living bacteria. We use distinctive isolates and metagenomic data to show that low coding density observed in IMS101 is a common feature of the Trichodesmium genus both in culture and in situ. Transcriptome analysis indicates that 86% of the non-coding space is expressed, although the function of these transcripts is unclear. The density of noncoding, possible regulatory elements predicted in Trichodesmium, when normalized per intergenic kilobase, was comparable and two fold higher than that found in the gene dense genomes of the sympatric cyanobacterial genera Synechococcus and Prochlorococcus, respectively. Conserved Trichodesmium ncRNA secondary structures were predicted between most culture and metagenomic sequences lending support to the structural conservation. Conservation of these intergenic regions in spatiotemporally separated Trichodesmium populations suggests possible genus-wide selection for their maintenance. These large intergenic spacers may have developed during intervals of strong genetic drift caused by periodic blooms of a subset of genotypes, which may have reduced effective population size. Our data suggest that transposition of selfish DNA, low effective population size, and high fidelity replication allowed the unusual ‘inflation’ of noncoding sequence observed in Trichodesmium despite its oligotrophic lifestyle.

  5. Quantification of non-coding RNA target localization diversity and its application in cancers. (United States)

    Cheng, Lixin; Leung, Kwong-Sak


    Subcellular localization is pivotal for RNAs and proteins to implement biological functions. The localization diversity of protein interactions has been studied as a crucial feature of proteins, considering the protein-protein interactions take place in various subcellular locations. Nevertheless, the localization diversity of non-coding RNA (ncRNA) target proteins has not been systematically studied, especially its characteristics in cancers. In this study, we provide a new algorithm, non-coding RNA target localization coefficient (ncTALENT), to quantify the target localization diversity of ncRNAs based on the ncRNA-protein interaction and protein subcellular localization data. ncTALENT can be used to calculate the target localization coefficient of ncRNAs and measure how diversely their targets are distributed among the subcellular locations in various scenarios. We focus our study on long non-coding RNAs (lncRNAs), and our observations reveal that the target localization diversity is a primary characteristic of lncRNAs in different biotypes. Moreover, we found that lncRNAs in multiple cancers, differentially expressed cancer lncRNAs, and lncRNAs with multiple cancer target proteins are prone to have high target localization diversity. Furthermore, the analysis of gastric cancer helps us to obtain a better understanding that the target localization diversity of lncRNAs is an important feature closely related to clinical prognosis. Overall, we systematically studied the target localization diversity of the lncRNAs and uncovered its association with cancer. © The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  6. Reducing Hepatocyte Injury and Necrosis in Response to Paracetamol Using Noncoding RNAs (United States)

    Szkolnicka, Dagmara; Lucendo-Villarin, Baltasar; Moore, Joanna K.; Simpson, Kenneth J.; Forbes, Stuart J.


    The liver performs multiple functions within the human body. It is composed of numerous cell types, which play important roles in organ physiology. Our study centers on the major metabolic cell type of the liver, the hepatocyte, and its susceptibility to damage during drug overdose. In these studies, hepatocytes were generated from a renewable and genetically defined resource. In vitro-derived hepatocytes were extensively profiled and exposed to varying levels of paracetamol and plasma isolated from liver-failure patients, with a view to identifying noncoding microRNAs that could reduce drug- or serum-induced hepatotoxicity. We identified a novel anti-microRNA, which reduced paracetamol-induced hepatotoxicity and glutathione depletion. Additionally, we identified a prosurvival role for anti-microRNA-324 following exposure to plasma collected from liver failure patients. We believe that these studies represent an important advance for the field, demonstrating the power of stem cell-derived systems to model human biology “in a dish” and identify novel noncoding microRNAs, which could be translated to the clinic in the future. Significance The liver performs vital functions within the human body and is composed of numerous cell types. The major metabolic cell type of the liver, the hepatocyte, is susceptible to damage during drug overdose. In these studies, hepatocytes were generated from a renewable resource and exposed to varying levels of paracetamol, with a view to identifying interventions that could reduce or attenuate drug-induced liver toxicity. A novel noncoding RNA that reduced paracetamol-induced hepatocyte toxicity was identified. These findings may represent an important advance for the field. PMID:27057006

  7. Adiabatic supernova expansion into the circumstellar medium

    International Nuclear Information System (INIS)

    Band, D.L.; Liang, E.P.


    We perform one dimensional numerical simulations with a Lagrangian hydrodynamics code of the adiabatic expansion of a supernova into the surrounding medium. The early expansion follows Chevalier's analytic self-similar solution until the reverse shock reaches the ejecta core. We follow the expansion as it evolves towards the adiabatic blast wave phase. Some memory of the earlier phases of expansion is retained in the interior even when the outer regions expand as a blast wave. We find the results are sensitive to the initial configuration of the ejecta and to the placement of gridpoints. 6 refs., 2 figs

  8. Thermal expansion of L-ascorbic acid (United States)

    Nicolaï, B.; Barrio, M.; Tamarit, J.-Ll.; Céolin, R.; Rietveld, I. B.


    The specific volume of vitamin C has been investigated by X-ray powder diffraction as a function of temperature from 110 K up to complete degradation around 440 K. Its thermal expansion is relatively small in comparison with other organic compounds with an expansivity α v of 1.2(3) × 10-4 K-1. The structure consists of strongly bound molecules in the ac plane through a dense network of hydrogen bonds. The thermal expansion is anisotropic. Along the b axis, the expansion has most leeway and is about 10 times larger than in the other directions.

  9. Structure and thermal expansion of liquid bismuth

    Directory of Open Access Journals (Sweden)

    Mudry S.


    Full Text Available Experimental structural data for liquid Bi were used for estimation of the main structure parameters as well as the thermal expansion coefficient both in supercooled and superheated temperature ranges. It was shown that the equilibrium melt had a positive thermal expansion coefficient within a temperature range upon melting and a negative one at higher temperatures. The former was related to structure changes upon melting, whereas the latter with topologic disordering upon further heating. It was found that the superheated melt had a negative thermal expansion coefficient. The results obtained from structural data were compared with the thermal expansion coefficient calculated from the data of density for liquid Bi.

  10. Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Paola eSpadaro


    Full Text Available Non-coding RNAs have emerged as critical regulators of transcription, epigenetic processes, and gene silencing, which make them ideal candidates for insight into molecular evolution and a better understanding of the molecular pathways of neuropsychiatric disease. Here we provide an overview of the current state of knowledge regarding various classes of ncRNAs and their role in neural plasticity and cognitive function, and highlight the potential contribution they may make to the development of a variety of neuropsychiatric disorders, including schizophrenia, addiction and fear-related anxiety disorders.

  11. Highly conserved non-coding sequences are associated with vertebrate development.

    Directory of Open Access Journals (Sweden)

    Adam Woolfe


    Full Text Available In addition to protein coding sequence, the human genome contains a significant amount of regulatory DNA, the identification of which is proving somewhat recalcitrant to both in silico and functional methods. An approach that has been used with some success is comparative sequence analysis, whereby equivalent genomic regions from different organisms are compared in order to identify both similarities and differences. In general, similarities in sequence between highly divergent organisms imply functional constraint. We have used a whole-genome comparison between humans and the pufferfish, Fugu rubripes, to identify nearly 1,400 highly conserved non-coding sequences. Given the evolutionary divergence between these species, it is likely that these sequences are found in, and furthermore are essential to, all vertebrates. Most, and possibly all, of these sequences are located in and around genes that act as developmental regulators. Some of these sequences are over 90% identical across more than 500 bases, being more highly conserved than coding sequence between these two species. Despite this, we cannot find any similar sequences in invertebrate genomes. In order to begin to functionally test this set of sequences, we have used a rapid in vivo assay system using zebrafish embryos that allows tissue-specific enhancer activity to be identified. Functional data is presented for highly conserved non-coding sequences associated with four unrelated developmental regulators (SOX21, PAX6, HLXB9, and SHH, in order to demonstrate the suitability of this screen to a wide range of genes and expression patterns. Of 25 sequence elements tested around these four genes, 23 show significant enhancer activity in one or more tissues. We have identified a set of non-coding sequences that are highly conserved throughout vertebrates. They are found in clusters across the human genome, principally around genes that are implicated in the regulation of development

  12. Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy


    Long, Jianyin; Badal, Shawn S.; Ye, Zengchun; Wang, Yin; Ayanga, Bernard A.; Galvan, Daniel L.; Green, Nathanael H.; Chang, Benny H.; Overbeek, Paul A.; Danesh, Farhad R.


    The regulatory roles of long noncoding RNAs (lncRNAs) in transcriptional coactivators are still largely unknown. Here, we have shown that the peroxisome proliferator–activated receptor γ (PPARγ) coactivator α (PGC-1α, encoded by Ppargc1a) is functionally regulated by the lncRNA taurine-upregulated gene 1 (Tug1). Further, we have described a role for Tug1 in the regulation of mitochondrial function in podocytes. Using a murine model of diabetic nephropathy (DN), we performed an unbiased RNA-se...

  13. Evaluation of Agency Non-Code Layered Pressure Vessels (LPVs) . Volume 2; Appendices (United States)

    Prosser, William H.


    In coordination with the Office of Safety and Mission Assurance and the respective Center Pressure System Managers (PSMs), the NASA Engineering and Safety Center (NESC) was requested to formulate a consensus draft proposal for the development of additional testing and analysis methods to establish the technical validity, and any limitation thereof, for the continued safe operation of facility non-code layered pressure vessels. The PSMs from each NASA Center were asked to participate as part of the assessment team by providing, collecting, and reviewing data regarding current operations of these vessels. This document contains the appendices to the main report.

  14. Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging. (United States)

    Grammatikakis, Ioannis; Panda, Amaresh C; Abdelmohsen, Kotb; Gorospe, Myriam


    During aging, progressive deleterious changes increase the risk of disease and death. Prominent molecular hallmarks of aging are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication. Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes, including age-related diseases like cancer, cardiovascular pathologies, and neurodegenerative disorders. Evidence is emerging that lncRNAs influence the molecular processes that underlie age-associated phenotypes. Here, we review our current understanding of lncRNAs that control the development of aging traits.

  15. In silico discovery and modeling of non-coding RNA structure in viruses. (United States)

    Moss, Walter N; Steitz, Joan A


    This review covers several computational methods for discovering structured non-coding RNAs in viruses and modeling their putative secondary structures. Here we will use examples from two target viruses to highlight these approaches: influenza A virus-a relatively small, segmented RNA virus; and Epstein-Barr virus-a relatively large DNA virus with a complex transcriptome. Each system has unique challenges to overcome and unique characteristics to exploit. From these particular cases, generically useful approaches can be derived for the study of additional viral targets. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Challenges of CRISPR/Cas9 applications for long non-coding RNA genes


    Goyal, Ashish; Myacheva, Ksenia; Gro?, Matthias; Klingenberg, Marcel; Duran?Arqu?, Berta; Diederichs, Sven


    Abstract The CRISPR/Cas9 system provides a revolutionary genome editing tool for all areas of molecular biology. In long non-coding RNA (lncRNA) research, the Cas9 nuclease can delete lncRNA genes or introduce RNA-destabilizing elements into their locus. The nuclease-deficient dCas9 mutant retains its RNA-dependent DNA-binding activity and can modulate gene expression when fused to transcriptional repressor or activator domains. Here, we systematically analyze whether CRISPR approaches are su...

  17. Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer

    Directory of Open Access Journals (Sweden)

    Yiwen Fang


    Full Text Available Long non-coding RNAs (lncRNAs play important roles in cancer. They are involved in chromatin remodeling, as well as transcriptional and post-transcriptional regulation, through a variety of chromatin-based mechanisms and via cross-talk with other RNA species. lncRNAs can function as decoys, scaffolds, and enhancer RNAs. This review summarizes the characteristics of lncRNAs, including their roles, functions, and working mechanisms, describes methods for identifying and annotating lncRNAs, and discusses future opportunities for lncRNA-based therapies using antisense oligonucleotides.

  18. The prognostic potential and carcinogenesis of long non-coding RNA TUG1 in human cholangiocarcinoma


    Xu, Yi; Leng, Kaiming; Li, Zhenglong; Zhang, Fumin; Zhong, Xiangyu; Kang, Pengcheng; Jiang, Xingming; Cui, Yunfu


    Cholangiocarcinoma (CCA) is a fatal disease with increasing worldwide incidence and is characterized by poor prognosis due to its poor response to conventional chemotherapy or radiotherapy. Long non-coding RNAs (lncRNAs) play key roles in multiple human cancers, including CCA. Cancer progression related lncRNA taurine-up-regulated gene 1 (TUG1) was reported to be involved in human carcinomas. However, the impact of TUG1 in CCA is unclear. The aim of this study was to explore the expression pa...

  19. The beginning of the road for non-coding RNAs in normal hematopoiesis and hematologic malignancies

    Directory of Open Access Journals (Sweden)

    Elisabeth eHeuston


    Full Text Available The field of non-coding RNAs (ncRNAs encompasses a wide array of RNA classes that are indispensible for the regulation of cellular activities. However, deregulation of these ncRNAs can also play key roles in malignant transformation and cancer cell behavior. In this article we survey a select group of microRNAs and long ncRNAs that appear critical in the development of acute and chronic leukemias, as well as contribute to their diagnosis, prognosis, and potentially, the treatment of disease.

  20. The 5' region ofXistRNA has the potential to associate with chromatin through the A-repeat. (United States)

    Chigi, Yuta; Sasaki, Hiroyuki; Sado, Takashi


    X inactive-specific transcript ( Xist ) is a long noncoding RNA that plays an essential role in X chromosome inactivation. Although Xist RNA, like common protein-coding mRNAs, is transcribed by RNA polymerase II, spliced and polyadenylated, it is retained in the nucleus and associates with the X chromosome it originates from. It has been assumed that Xist RNA recruits proteins involved in epigenetic modifications and chromatin compaction to the X chromosome. One of the major proteins constituting the nuclear matrix, hnRNP U, has been shown to be required for the association of Xist RNA with the inactive X chromosome (Xi). In this study, we found that the first 950-nt sequence of Xist RNA had the potential to associate with chromatin in a manner independent of hnRNP U. Furthermore, its chromatin association is apparently dependent on the presence of an intact A-repeat sequence, which is one of the repeats in Xist / XIST RNA conserved among many mammalian species, and has been shown to be important for Xist RNA-mediated silencing. Taking this unexpected finding and a previous study demonstrating the effect of Xist RNA lacking the A-repeat on the formation of the silent heterochromatin domain together, we suggest that the A-repeat captures chromatin near the initial loading site of Xist RNA and relocates it into the core of the heterochromatin domain. © 2017 Chigi et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  1. Brain-specific noncoding RNAs are likely to originate in repeats and may play a role in up-regulating genes in cis

    DEFF Research Database (Denmark)

    Francescatto, Margherita; Vitezic, Morana; Heutink, Peter


    . Dysregulation of specific long ncRNAs (lncRNAs) has been shown in neuro-developmental and neuro-degenerative diseases thus highlighting the importance of lncRNAs in brain function. Even though it is known that lncRNAs are expressed in cells at low levels in a tissue-specific manner, bioinformatics analyses...

  2. Supporting data for characterization of non-coding RNAs associated with the Neuronal growth regulator 1 (NEGR1 adhesion protein

    Directory of Open Access Journals (Sweden)

    Prameet Kaur


    Full Text Available Long non-coding RNAs and microRNAs control gene expression to determine central nervous system development and function. Neuronal growth regulator 1 (NEGR1 is a cell adhesion molecule that plays an important role in neurite outgrowth during neuronal development and its precise expression is crucial for correct brain development. The data described here is related to the research article titled “A long non-coding RNA, BC048612 and a microRNA, miR-203 coordinate the gene expression of Neuronal growth regulator 1 (NEGR1 adhesion protein” [1]. This data article contains detailed bioinformatics analysis of genetic signatures at the Negr1 gene locus retrieved from the UCSC genome browser. This approach could be adopted to identify putative regulatory non-coding RNAs in other tissues and diseases.

  3. Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics. (United States)

    Gussow, Ayal B; Copeland, Brett R; Dhindsa, Ryan S; Wang, Quanli; Petrovski, Slavé; Majoros, William H; Allen, Andrew S; Goldstein, David B


    There is broad agreement that genetic mutations occurring outside of the protein-coding regions play a key role in human disease. Despite this consensus, we are not yet capable of discerning which portions of non-coding sequence are important in the context of human disease. Here, we present Orion, an approach that detects regions of the non-coding genome that are depleted of variation, suggesting that the regions are intolerant of mutations and subject to purifying selection in the human lineage. We show that Orion is highly correlated with known intolerant regions as well as regions that harbor putatively pathogenic variation. This approach provides a mechanism to identify pathogenic variation in the human non-coding genome and will have immediate utility in the diagnostic interpretation of patient genomes and in large case control studies using whole-genome sequences.

  4. microRNA-9 targets the long non-coding RNA MALAT1 for degradation in the nucleus

    DEFF Research Database (Denmark)

    Leucci, Eleonora; Patella, Francesca; Waage, Johannes


    microRNAs regulate the expression of over 60% of protein coding genes by targeting their mRNAs to AGO2-containing complexes in the cytoplasm and promoting their translational inhibition and/or degradation. There is little evidence so far for microRNA-mediated regulation of other classes of non......-coding RNAs. Here we report that microRNA-9 (miR-9) regulates the expression of the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT-1), one of the most abundant and conserved long non-coding RNAs. Intriguingly, we find that miR-9 targets AGO2-mediated regulation of MALAT1 in the nucleus. Our...... findings reveal a novel direct regulatory link between two important classes of non-coding RNAs, miRs and lncRNAs, and advance our understanding of microRNA functions....

  5. Lifetimes and heavy quark expansion (United States)

    Lenz, Alexander


    Kolya Uraltsev was one of the inventors of the Heavy Quark Expansion (HQE), that describes inclusive weak decays of hadrons containing heavy quarks and in particular lifetimes. Besides giving a pedagogic introduction to the subject, we review the development and the current status of the HQE, which just recently passed several non-trivial experimental tests with an unprecedented precision. In view of many new experimental results for lifetimes of heavy hadrons, we also update several theory predictions: τ (B+)/τ (Bd) = 1.04+0.05-0.01 ± 0.02 ± 0.01, τ(Bs)/τ(Bd) = 1.001 ±0.002, τ(Λb)/τ(Bd) = 0.935 ±0.054 and \\bar {τ } (Ξ b0)/\\bar {τ } (Ξ b+) = 0.95 ± 0.06. The theoretical precision is currently strongly limited by the unknown size of the non-perturbative matrix elements of four-quark operators, which could be determined with lattice simulations.

  6. Local expansions and accretive mappings

    Directory of Open Access Journals (Sweden)

    W. A. Kirk


    Full Text Available Let X and Y be complete metric spaces with Y metrically convex, let D⊂X be open, fix u0∈X, and let d(u=d(u0,u for all u∈D. Let f:X→2Y be a closed mapping which maps open subsets of D onto open sets in Y, and suppose f is locally expansive on D in the sense that there exists a continuous nonincreasing function c:R+→R+ with ∫+∞c(sds=+∞ such that each point x∈D has a neighborhood N for which dist(f(u,f(v≥c(max{d(u,d(v}d(u,v for all u,v∈N. Then, given y∈Y, it is shown that y∈f(D iff there exists x0∈D such that for x∈X\\D, dist(y,f(x0≤dist(u,f(x. This result is then applied to the study of existence of zeros of (set-valued locally strongly accretive and ϕ-accretive mappings in Banach spaces

  7. Hubble expansion in static spacetime

    International Nuclear Information System (INIS)

    Rossler, Otto E.; Froehlich, Dieter; Movassagh, Ramis; Moore, Anthony


    A recently proposed mechanism for light-path expansion in a static spacetime is based on the moving-lenses paradigm. Since the latter is valid independently of whether space expands or not, a static universe can be used to better see the implications. The moving-lenses paradigm is related to the paradigm of dynamical friction. If this is correct, a Hubble-like law is implicit. It is described quantitatively. A bent in the Hubble-like line is predictably implied. The main underlying assumption is Price's Principle (PI 3 ). If the theory is sound, the greatest remaining problem in cosmology becomes the origin of hydrogen. Since Blandford's jet production mechanism for quasars is too weak, a generalized Hawking radiation hidden in the walls of cosmic voids is invoked. A second prediction is empirical: slow pattern changes in the cosmic microwave background. A third is ultra-high redshifts for Giacconi quasars. Bruno's eternal universe in the spirit of Augustine becomes a bit less outlandish

  8. Primordial vorticity and gradient expansion

    CERN Document Server

    Giovannini, Massimo


    The evolution equations of the vorticities of the electrons, ions and photons in a pre-decoupling plasma are derived, in a fully inhomogeneous geometry, by combining the general relativistic gradient expansion and the drift approximation within the Adler-Misner-Deser decomposition. The vorticity transfer between the different species is discussed in this novel framework and a set of general conservation laws, connecting the vorticities of the three-component plasma with the magnetic field intensity, is derived. After demonstrating that a source of large-scale vorticity resides in the spatial gradients of the geometry and of the electromagnetic sources, the total vorticity is estimated to lowest order in the spatial gradients and by enforcing the validity of the momentum constraint. By acknowledging the current bounds on the tensor to scalar ratio in the (minimal) tensor extension of the $\\Lambda$CDM paradigm the maximal comoving magnetic field induced by the total vorticity turns out to be, at most, of the or...

  9. Negative thermal expansion materials: technological key for control of thermal expansion


    Koshi Takenaka


    Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K−1. Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining pra...

  10. Sequencing illustrates the transcriptional response of Legionella pneumophila during infection and identifies seventy novel small non-coding RNAs.

    LENUS (Irish Health Repository)

    Weissenmayer, Barbara A


    Second generation sequencing has prompted a number of groups to re-interrogate the transcriptomes of several bacterial and archaeal species. One of the central findings has been the identification of complex networks of small non-coding RNAs that play central roles in transcriptional regulation in all growth conditions and for the pathogen\\'s interaction with and survival within host cells. Legionella pneumophila is a gram-negative facultative intracellular human pathogen with a distinct biphasic lifestyle. One of its primary environmental hosts in the free-living amoeba Acanthamoeba castellanii and its infection by L. pneumophila mimics that seen in human macrophages. Here we present analysis of strand specific sequencing of the transcriptional response of L. pneumophila during exponential and post-exponential broth growth and during the replicative and transmissive phase of infection inside A. castellanii. We extend previous microarray based studies as well as uncovering evidence of a complex regulatory architecture underpinned by numerous non-coding RNAs. Over seventy new non-coding RNAs could be identified; many of them appear to be strain specific and in configurations not previously reported. We discover a family of non-coding RNAs preferentially expressed during infection conditions and identify a second copy of 6S RNA in L. pneumophila. We show that the newly discovered putative 6S RNA as well as a number of other non-coding RNAs show evidence for antisense transcription. The nature and extent of the non-coding RNAs and their expression patterns suggests that these may well play central roles in the regulation of Legionella spp. specific traits and offer clues as to how L. pneumophila adapts to its intracellular niche. The expression profiles outlined in the study have been deposited into Genbank\\'s Gene Expression Omnibus (GEO) database under the series accession GSE27232.

  11. Sequencing illustrates the transcriptional response of Legionella pneumophila during infection and identifies seventy novel small non-coding RNAs.

    Directory of Open Access Journals (Sweden)

    Barbara A Weissenmayer


    Full Text Available Second generation sequencing has prompted a number of groups to re-interrogate the transcriptomes of several bacterial and archaeal species. One of the central findings has been the identification of complex networks of small non-coding RNAs that play central roles in transcriptional regulation in all growth conditions and for the pathogen's interaction with and survival within host cells. Legionella pneumophila is a gram-negative facultative intracellular human pathogen with a distinct biphasic lifestyle. One of its primary environmental hosts in the free-living amoeba Acanthamoeba castellanii and its infection by L. pneumophila mimics that seen in human macrophages. Here we present analysis of strand specific sequencing of the transcriptional response of L. pneumophila during exponential and post-exponential broth growth and during the replicative and transmissive phase of infection inside A. castellanii. We extend previous microarray based studies as well as uncovering evidence of a complex regulatory architecture underpinned by numerous non-coding RNAs. Over seventy new non-coding RNAs could be identified; many of them appear to be strain specific and in configurations not previously reported. We discover a family of non-coding RNAs preferentially expressed during infection conditions and identify a second copy of 6S RNA in L. pneumophila. We show that the newly discovered putative 6S RNA as well as a number of other non-coding RNAs show evidence for antisense transcription. The nature and extent of the non-coding RNAs and their expression patterns suggests that these may well play central roles in the regulation of Legionella spp. specific traits and offer clues as to how L. pneumophila adapts to its intracellular niche. The expression profiles outlined in the study have been deposited into Genbank's Gene Expression Omnibus (GEO database under the series accession GSE27232.

  12. Nras Overexpression Results in Granulocytosis, T-Cell Expansion and Early Lethality in Mice

    DEFF Research Database (Denmark)

    Lassen, Louise Berkhoudt; Gonzalez, Borja Ballarin; Schmitz, Alexander


    NRAS is a proto-oncogene involved in numerous myeloid malignancies. Here, we report on a mouse line bearing a single retroviral long terminal repeat inserted into Nras. This genetic modification resulted in an increased level of wild type Nras mRNA giving the possibility of studying the function ...... the increment in immature myeloid cells detected in these mice. The short latency period indicates that Nras overexpression alone is sufficient to cause dose-dependent granulocytosis and T-cell expansion....

  13. The heavy quark expansion of QCD

    Energy Technology Data Exchange (ETDEWEB)

    Falk, A.F. [Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Physics and Astronomy


    These lectures contain an elementary introduction to heavy quark symmetry and the heavy quark expansion. Applications such as the expansion of heavy meson decay constants and the treatment of inclusive and exclusive semileptonic B decays are included. Heavy hadron production via nonperturbative fragmentation processes is also discussed. 54 refs., 7 figs.

  14. foundations on expansive soils introduction characteristic

    African Journals Online (AJOL)

    FOUNDATIONS ON EXPANSIVE SOILS. Girma Tessema. Ethiopian Building Construction Authority. Ministry of Construction, Addis Ababa. INTRODUCTION. It is a welJ known fact that expansive soils pose considerable problems in civil engineering constructions. Structures built on such soils show movements which are.

  15. Thermal expansion of doped lanthanum gallates

    Indian Academy of Sciences (India)


    Since the components are in intimate mechanical contact, any stress generated due to their thermal expansion mis- match during thermal cycling could lead to catastrophic failure of the cell. The functional materials must have similar thermal expansions to avoid mechanical stresses. Hence it is useful to study the thermal ...

  16. Series expansion of the modified Einstein Procedure (United States)

    Seema Chandrakant Shah-Fairbank


    This study examines calculating total sediment discharge based on the Modified Einstein Procedure (MEP). A new procedure based on the Series Expansion of the Modified Einstein Procedure (SEMEP) has been developed. This procedure contains four main modifications to MEP. First, SEMEP solves the Einstein integrals quickly and accurately based on a series expansion. Next,...

  17. Thermal expansion of doped lanthanum gallates

    Indian Academy of Sciences (India)

    The dependence of average thermal expansion coefficient (av) on the dopant concentration on either or site of the perovskite structure was found to be linear, when the composition at the other site was kept constant. Mg doping on the -site had a greater effect on the average thermal expansion coefficient than Sr ...

  18. The heavy quark expansion of QCD

    International Nuclear Information System (INIS)

    Falk, A.F.


    These lectures contain an elementary introduction to heavy quark symmetry and the heavy quark expansion. Applications such as the expansion of heavy meson decay constants and the treatment of inclusive and exclusive semileptonic B decays are included. Heavy hadron production via nonperturbative fragmentation processes is also discussed. 54 refs., 7 figs

  19. A reduced volumetric expansion factor plot (United States)

    Hendricks, R. C.


    A reduced volumetric expansion factor plot has been constructed for simple fluids which is suitable for engineering computations in heat transfer. Volumetric expansion factors have been found useful in correlating heat transfer data over a wide range of operating conditions including liquids, gases and the near critical region.

  20. Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. (United States)

    Li, Yuehua; Jiang, Baohong; Zhu, Hongbo; Qu, Xiaofei; Zhao, Liqin; Tan, Yeru; Jiang, Yiling; Liao, Mingchu; Wu, Xiaoping


    This study explored the mechanism underlying long non-coding RNA ROR regulating autophagy on Tamoxifen resistance in breast cancer. Cancer tissues and adjacent normal tissues were collected from 74 breast cancer patients. Human breast cancer BT474 cells were assigned into blank, phosphate buffered saline, Tamoxifen, negative control + Tamoxifen, siROR + Tamoxifen, 3-methyladenine + Tamoxifen, and siROR + 3-methyladenine + TA groups. The expression of long non-coding RNA ROR and expressions of multi-drug resistance-associated P-glycoprotein and glutathione S-transferase-π messenger RNA were detected using quantitative real-time polymerase chain reaction. The expressions of light chain 3, Beclin 1, multi-drug resistance-associated P-glycoprotein, and glutathione S-transferase-π protein were determined using western blotting. Cell proliferation, invasion, and migration abilities were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Transwell assay, and scratch test, respectively. The long non-coding RNA ROR expression was higher in the breast cancer tissues than that in the adjacent normal tissues. Compared with the blank group, light chain 3 and Beclin 1 expressions were increased in the siROR + Tamoxifen group but decreased in the 3-methyladenine + Tamoxifen group; these data indicated that downregulated long non-coding RNA ROR promoted autophagy. In comparison with the blank group, multi-drug resistance-associated P-glycoprotein and glutathione S-transferase-π messenger RNA and protein expressions were reduced in the siROR + Tamoxifen group but elevated in the 3-methyladenine + Tamoxifen group, suggesting that downregulated long non-coding RNA ROR suppressed the drug resistance to Tamoxifen and the inhibition of autophagy reversed the effect of long non-coding RNA ROR on drug resistance. Compared with the Tamoxifen, negative control, and siROR + 3-methyladenine + Tamoxifen groups, the cell

  1. Noncoding after All: Biases in Proteomics Data Do Not Explain Observed Absence of lncRNA Translation Products. (United States)

    Verheggen, Kenneth; Volders, Pieter-Jan; Mestdagh, Pieter; Menschaert, Gerben; Van Damme, Petra; Gevaert, Kris; Martens, Lennart; Vandesompele, Jo


    Over the past decade, long noncoding RNAs (lncRNAs) have emerged as novel functional entities of the eukaryotic genome. However, the scientific community remains divided over the amount of true noncoding transcripts among the large number of unannotated transcripts identified by recent large scale and deep RNA-sequencing efforts. Here, we systematically exclude possible technical reasons underlying the absence of lncRNA-encoded proteins in mass spectrometry data sets, strongly suggesting that the large majority of lncRNAs is indeed not translated.

  2. Long Non-Coding RNAs Associated with Metabolic Traits in Human White Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Hui Gao


    Full Text Available Long non-coding RNAs (lncRNAs belong to a recently discovered class of molecules proposed to regulate various cellular processes. Here, we systematically analyzed their expression in human subcutaneous white adipose tissue (WAT and found that a limited set was differentially expressed in obesity and/or the insulin resistant state. Two lncRNAs herein termed adipocyte-specific metabolic related lncRNAs, ASMER-1 and ASMER-2 were enriched in adipocytes and regulated by both obesity and insulin resistance. Knockdown of either ASMER-1 or ASMER-2 by antisense oligonucleotides in in vitro differentiated human adipocytes revealed that both genes regulated adipogenesis, lipid mobilization and adiponectin secretion. The observed effects could be attributed to crosstalk between ASMERs and genes within the master regulatory pathways for adipocyte function including PPARG and INSR. Altogether, our data demonstrate that lncRNAs are modulators of the metabolic and secretory functions in human fat cells and provide an emerging link between WAT and common metabolic conditions. Keywords: White adipose tissue, Adipocytes, Long non-coding RNAs, Metabolic traits, Lipolysis, Adiponectin

  3. Keeping Abreast with long non-coding RNAs in mammary gland development and breast cancer

    Directory of Open Access Journals (Sweden)

    Herah eHansji


    Full Text Available The majority of the human genome is transcribed, even though only 2% of transcripts encode proteins. Non-coding transcripts were originally dismissed as evolutionary junk or transcriptional noise, but with the development of whole genome technologies, these ncRNAs are emerging as molecules with vital roles in regulating gene expression. While shorter ncRNAs have been extensively studied, the functional roles of long non-coding RNAs are still being elucidated. Studies over the last decade show that lncRNAs are emerging as new players in a number of diseases including cancer. Potential roles in both oncogenic and tumour suppressive pathways in cancer have been elucidated, but the biological functions of the majority of lncRNAs remain to be identified. Accumulated data are identifying the molecular mechanisms by which lncRNA mediates both structural and functional roles. LncRNA can regulate gene expression at both transcriptional and post-transcriptional levels, including splicing and regulating mRNA processing, transport and translation. Much current research is aimed at elucidating the function of lncRNAs in breast cancer and mammary gland development, and at identifying the cellular processes influenced by lncRNAs. In this paper we review current knowledge of lncRNAs contributing to these processes and present lncRNA as a new paradigm in breast cancer development.

  4. Control of seed dormancy in Arabidopsis by a cis-acting noncoding antisense transcript. (United States)

    Fedak, Halina; Palusinska, Malgorzata; Krzyczmonik, Katarzyna; Brzezniak, Lien; Yatusevich, Ruslan; Pietras, Zbigniew; Kaczanowski, Szymon; Swiezewski, Szymon


    Seed dormancy is one of the most crucial process transitions in a plant's life cycle. Its timing is tightly controlled by the expression level of the Delay of Germination 1 gene (DOG1). DOG1 is the major quantitative trait locus for seed dormancy in Arabidopsis and has been shown to control dormancy in many other plant species. This is reflected by the evolutionary conservation of the functional short alternatively polyadenylated form of the DOG1 mRNA. Notably, the 3' region of DOG1, including the last exon that is not included in this transcript isoform, shows a high level of conservation at the DNA level, but the encoded polypeptide is poorly conserved. Here, we demonstrate that this region of DOG1 contains a promoter for the transcription of a noncoding antisense RNA, asDOG1, that is 5' capped, polyadenylated, and relatively stable. This promoter is autonomous and asDOG1 has an expression profile that is different from known DOG1 transcripts. Using several approaches we show that asDOG1 strongly suppresses DOG1 expression during seed maturation in cis, but is unable to do so in trans Therefore, the negative regulation of seed dormancy by asDOG1 in cis results in allele-specific suppression of DOG1 expression and promotes germination. Given the evolutionary conservation of the asDOG1 promoter, we propose that this cis-constrained noncoding RNA-mediated mechanism limiting the duration of seed dormancy functions across the Brassicaceae.

  5. Comprehensive reconstruction and visualization of non-coding regulatory networks in human. (United States)

    Bonnici, Vincenzo; Russo, Francesco; Bombieri, Nicola; Pulvirenti, Alfredo; Giugno, Rosalba


    Research attention has been powered to understand the functional roles of non-coding RNAs (ncRNAs). Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established on-line repositories. The interactions involve RNA, DNA, proteins, and diseases. ncRNA-DB is available at It is equipped with three interfaces: web based, command-line, and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape.

  6. The roles of non-coding RNAs in cardiac regenerative medicine

    Directory of Open Access Journals (Sweden)

    Oi Kuan Choong


    Full Text Available The emergence of non-coding RNAs (ncRNAs has challenged the central dogma of molecular biology that dictates that the decryption of genetic information starts from transcription of DNA to RNA, with subsequent translation into a protein. Large numbers of ncRNAs with biological significance have now been identified, suggesting that ncRNAs are important in their own right and their roles extend far beyond what was originally envisaged. ncRNAs do not only regulate gene expression, but are also involved in chromatin architecture and structural conformation. Several studies have pointed out that ncRNAs participate in heart disease; however, the functions of ncRNAs still remain unclear. ncRNAs are involved in cellular fate, differentiation, proliferation and tissue regeneration, hinting at their potential therapeutic applications. Here, we review the current understanding of both the biological functions and molecular mechanisms of ncRNAs in heart disease and describe some of the ncRNAs that have potential heart regeneration effects. Keywords: Non-coding RNAs, Cardiac regeneration, Cardiac fate, Proliferation, Differentiation, Reprograming

  7. Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction. (United States)

    De Filippis, Vincenzo; Acquasaliente, Laura; Pontarollo, Giulia; Peterle, Daniele


    The advent of recombinant DNA technology allowed to site-specifically insert, delete, or mutate almost any amino acid in a given protein, significantly improving our knowledge of protein structure, stability, and function. Nevertheless, a quantitative description of the physical and chemical basis that makes a polypeptide chain to efficiently fold into a stable and functionally active conformation is still elusive. This mainly originates from the fact that nature combined, in a yet unknown manner, different properties (i.e., hydrophobicity, conformational propensity, polarizability, and hydrogen bonding capability) into the 20 standard natural amino acids, thus making difficult, if not impossible, to univocally relate the change in protein stability or function to the alteration of physicochemical properties caused by amino acid exchange(s). In this view, incorporation of noncoded amino acids with tailored side chains, allowing to finely tune the structure at a protein site, would facilitate to dissect the effects of a given mutation in terms of one or a few physicochemical properties, thus much expanding the scope of physical organic chemistry in the study of proteins. In this review, relevant applications from our laboratory will be presented on the use of noncoded amino acids in structure-activity relationships studies of hirudin binding to thrombin. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  8. Genome-wide identification of non-coding RNAs interacted with microRNAs in soybean

    Directory of Open Access Journals (Sweden)

    Chuyu eYe


    Full Text Available A wide range of RNA species interacting with microRNAs (miRNAs form a complex gene regulation network and play vital roles in diverse biological processes. In this study, we performed a genome-wide identification of endogenous target mimics (eTMs for miRNAs and phased-siRNA-producing loci (PHAS in soybean with a focus on those involved in lipid metabolism. The results showed that a large number of eTMs and PHAS genes could be found in soybean. Additionally, we found that lipid metabolism related genes were potentially regulated by 28 miRNAs, and nine of them were potentially further regulated by a number of eTMs with expression evidence. Thirty-three miRNAs were found to trigger production of phasiRNAs from 49 PHAS genes, which were able to target lipid metabolism related genes. Degradome data supported miRNA- and/or phasiRNA-mediated cleavage of genes involved in lipid metabolism. Most eTMs for miRNAs involved in lipid metabolism and phasiRNAs targeting lipid metabolism related genes showed a tissue-specific expression pattern. Our bioinformatical evidences suggested that lipid metabolism in soybean is potentially regulated by a complex non-coding network, including miRNAs, eTMs and phasiRNAs, and the results extended our knowledge on functions of non-coding RNAs.

  9. The regulatory roles of non-coding RNAs in nerve injury and regeneration. (United States)

    Yu, Bin; Zhou, Songlin; Yi, Sheng; Gu, Xiaosong


    Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have attracted much attention since their regulatory roles in diverse cell processes were recognized. Emerging studies demonstrate that many ncRNAs are differentially expressed after injury to the nervous system, significantly affecting nerve regeneration. In this review, we compile the miRNAs and lncRNAs that have been reported to be dysregulated following a variety of central and peripheral nerve injuries, including acquired brain injury, spinal cord injury, and peripheral nerve injury. We also list investigations on how these miRNAs and lncRNAs exert the regulatory actions in neurodegenerative and neuroregenerative processes through different mechanisms involving their interaction with target coding genes. We believe that comprehension of the expression profiles and the possible functions of ncRNAs during the processes of nerve injury and regeneration will help understand the molecular mechanisms responsible for post-nerve-injury changes, and may contribute to the potential use of ncRNAs as a diagnostic marker and therapeutic target for nerve injury. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Genomic context analysis reveals dense interaction network between vertebrate ultraconserved non-coding elements. (United States)

    Dimitrieva, Slavica; Bucher, Philipp


    Genomic context analysis, also known as phylogenetic profiling, is widely used to infer functional interactions between proteins but rarely applied to non-coding cis-regulatory DNA elements. We were wondering whether this approach could provide insights about utlraconserved non-coding elements (UCNEs). These elements are organized as large clusters, so-called gene regulatory blocks (GRBs) around key developmental genes. Their molecular functions and the reasons for their high degree of conservation remain enigmatic. In a special setting of genomic context analysis, we analyzed the fate of GRBs after a whole-genome duplication event in five fish genomes. We found that in most cases all UCNEs were retained together as a single block, whereas the corresponding target genes were often retained in two copies, one completely devoid of UCNEs. This 'winner-takes-all' pattern suggests that UCNEs of a GRB function in a highly cooperative manner. We propose that the multitude of interactions between UCNEs is the reason for their extreme sequence conservation. Supplementary data are available at Bioinformatics online and at

  11. Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature. (United States)

    Davanian, Haleh; Balasiddaiah, Anangi; Heymann, Robert; Sundström, Magnus; Redenström, Poppy; Silfverberg, Mikael; Brodin, David; Sällberg, Matti; Lindskog, Sven; Kruger Weiner, Carina; Chen, Margaret


    Ameloblastoma of the jaws remains the top difficult to treat odontogenic tumour and has a high recurrence rate. New evidence suggests that non-coding RNAs (ncRNAs) play a critical role in tumourgenesis and prognosis of cancer. However, ameloblastoma ncRNA expression data is lacking. Here we present the first report of ameloblastoma ncRNA signatures. A total of 95 ameloblastoma cases and a global array transcriptome technology covering > 285.000 full-length transcripts were used in this two-step analysis. The analysis first identified in a test cohort 31 upregulated ameloblastoma-associated ncRNAs accompanied by signalling pathways of cancer, spliceosome, mRNA surveillance and Wnt. Further validation in an independent cohort points out the long non-coding (lncRNAs) and small nucleolar RNA (snoRNAs): LINC340, SNORD116-25, SNORA11, SNORA21, SNORA47 and SNORA65 as a distinct ncRNA signature of ameloblastoma. Importantly, the presence of these ncRNAs was independent of BRAF-V600E and SMO-L412F mutations, histology type or tumour location, but was positively correlated with the tumour size. Taken together, this study shows a systematic investigation of ncRNA expression of ameloblastoma, and illuminates new diagnostic and therapeutic targets for this invasive odontogenic tumour.

  12. The Regulatory Effects of Long Noncoding RNA-ANCR on Dental Tissue-Derived Stem Cells

    Directory of Open Access Journals (Sweden)

    Qian Jia


    Full Text Available Long noncoding RNAs (lncRNA have been recognized as important regulators in diverse biological processes, such as transcriptional regulation, stem cell proliferation, and differentiation. Previous study has demonstrated that lncRNA-ANCR (antidifferentiation ncRNA plays a key role in regulating the proliferation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs. However, little is known about the role of ANCR in regulating other types of dental tissue-derived stem cells (DTSCs behaviours (including proliferation and multiple-potential of differentiation. In this study, we investigated the regulatory effects of lncRNA-ANCR on the proliferation and differentiation (including osteogenic, adipogenic, and neurogenic differentiation of DTSCs, including dental pulp stem cells (DPSCs, PDLSCs, and stem cells from the apical papilla (SCAP by downregulation of lncRNA-ANCR. We found that downregulation of ANCR exerted little effect on proliferation of DPSCs and SCAP but promoted the osteogenic, adipogenic, and neurogenic differentiation of DTSCs. These data provide an insight into the regulatory effects of long noncoding RNA-ANCR on DTSCs and indicate that ANCR is a very important regulatory factor in stem cell differentiation.

  13. Estradiol-Induced Transcriptional Regulation of Long Non-Coding RNA, HOTAIR. (United States)

    Bhan, Arunoday; Mandal, Subhrangsu S


    HOTAIR (HOX antisense intergenic RNA) is a 2.2 kb long non-coding RNA (lncRNA), transcribed from the antisense strand of homeobox C (HOXC) gene locus in chromosome 12. HOTAIR acts as a scaffolding lncRNA. It interacts and guides various chromatin-modifying complexes such as PRC2 (polycomb-repressive complex 2) and LSD1 (lysine-specific demethylase 1) to the target gene promoters leading to their gene silencing. Various studies have demonstrated that HOTAIR overexpression is associated with breast cancer. Recent studies from our laboratory demonstrate that HOTAIR is required for viability of breast cancer cells and is transcriptionally regulated by estradiol (E2) in vitro and in vivo. This chapter describes protocols for analysis of the HOTAIR promoter, cloning, transfection and dual luciferase assays, knockdown of protein synthesis by antisense oligonucleotides, and chromatin immunoprecipitation (ChIP) assay. These protocols are useful for studying the estrogen-mediated transcriptional regulation of lncRNA HOTAIR, as well as other protein coding genes and non-coding RNAs.

  14. The interplay of long non-coding RNAs and MYC in cancer

    Directory of Open Access Journals (Sweden)

    Michael J. Hamilton


    Full Text Available Long non-coding RNAs (lncRNAs are a class of RNA molecules that are changing how researchers view eukaryotic gene regulation. Once considered to be non-functional products of low-level aberrant transcription from non-coding regions of the genome, lncRNAs are now viewed as important epigenetic regulators and several lncRNAs have now been demonstrated to be critical players in the development and/or maintenance of cancer. Similarly, the emerging variety of interactions between lncRNAs and MYC, a well-known oncogenic transcription factor linked to most types of cancer, have caught the attention of many biomedical researchers. Investigations exploring the dynamic interactions between lncRNAs and MYC, referred to as the lncRNA-MYC network, have proven to be especially complex. Genome-wide studies have shown that MYC transcriptionally regulates many lncRNA genes. Conversely, recent reports identified lncRNAs that regulate MYC expression both at the transcriptional and post-transcriptional levels. These findings are of particular interest because they suggest roles of lncRNAs as regulators of MYC oncogenic functions and the possibility that targeting lncRNAs could represent a novel avenue to cancer treatment. Here, we briefly review the current understanding of how lncRNAs regulate chromatin structure and gene transcription, and then focus on the new developments in the emerging field exploring the lncRNA-MYC network in cancer.

  15. BlastR—fast and accurate database searches for non-coding RNAs (United States)

    Bussotti, Giovanni; Raineri, Emanuele; Erb, Ionas; Zytnicki, Matthias; Wilm, Andreas; Beaudoing, Emmanuel; Bucher, Philipp; Notredame, Cedric


    We present and validate BlastR, a method for efficiently and accurately searching non-coding RNAs. Our approach relies on the comparison of di-nucleotides using BlosumR, a new log-odd substitution matrix. In order to use BlosumR for comparison, we recoded RNA sequences into protein-like sequences. We then showed that BlosumR can be used along with the BlastP algorithm in order to search non-coding RNA sequences. Using Rfam as a gold standard, we benchmarked this approach and show BlastR to be more sensitive than BlastN. We also show that BlastR is both faster and more sensitive than BlastP used with a single nucleotide log-odd substitution matrix. BlastR, when used in combination with WU-BlastP, is about 5% more accurate than WU-BlastN and about 50 times slower. The approach shown here is equally effective when combined with the NCBI-Blast package. The software is an open source freeware available from PMID:21624887

  16. Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection

    Energy Technology Data Exchange (ETDEWEB)

    Meseda, Clement A. [Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States); Srinivasan, Kumar [Division of Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States); Wise, Jasen [Qiagen, Frederick, MD (United States); Catalano, Jennifer [Center for Tobacco Products, Food and Drug Administration, Bethesda, MD (United States); Yamada, Kenneth M. [National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Dhawan, Subhash, E-mail: [Division of Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States)


    Highlights: • Heme oxygenase-1 (HO-1) induction inhibited vaccinia virus infection of macrophages. • Reduced infectivity inversely correlated with increased expression of non-coding RNAs. • The regulation of HO-1 and ncRNAs suggests a novel host defense response against vaccinia virus infection. - Abstract: Small nuclear RNAs (snRNAs) are <200 nucleotide non-coding uridylate-rich RNAs. Although the functions of many snRNAs remain undetermined, a population of snRNAs is produced during the early phase of infection of cells by vaccinia virus. In the present study, we demonstrate a direct correlation between expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), suppression of selective snRNA expression, and inhibition of vaccinia virus infection of macrophages. Hemin induced HO-1 expression, completely reversed virus-induced host snRNA expression, and suppressed vaccinia virus infection. This involvement of specific virus-induced snRNAs and associated gene clusters suggests a novel HO-1-dependent host-defense pathway in poxvirus infection.

  17. Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. (United States)

    Han, Yonghua; Liu, Yuchen; Gui, Yaoting; Cai, Zhiming


    Long intergenic non-coding RNAs (lincRNAs) are a class of non-coding RNAs that regulate gene expression via chromatin reprogramming. Taurine Up-regulated Gene 1 (TUG1) is a lincRNA that is associated with chromatin-modifying complexes and plays roles in gene regulation. In this study, we determined the expression patterns of TUG1 and the cell proliferation inhibition and apoptosis induced by silencing TUG1 in urothelial carcinoma of the bladder. The expression levels of TUG1 were determined using Real-Time qPCR in a total of 44 patients with bladder urothelial carcinomas. Bladder urothelial carcinoma T24 and 5637 cells were transfected with TUG1 siRNA or negative control siRNA. Cell proliferation was evaluated using MTT assay. Apoptosis was determined using ELISA assay. TUG1 was up-regulated in bladder urothelial carcinoma compared to paired normal urothelium. High TUG1 expression levels were associated with high grade and stage carcinomas. Cell proliferation inhibition and apoptosis induction were observed in TUG1 siRNA-transfected bladder urothelial carcinoma T24 and 5637 cells. Our data suggest that lincRNA TUG1 is emerging as a novel player in the disease state of bladder urothelial carcinoma. TUG1 may have potential roles as a biomarker and/or a therapeutic target in bladder urothelial carcinoma. Copyright © 2012 Wiley Periodicals, Inc.

  18. Principles of Long Noncoding RNA Evolution Derived from Direct Comparison of Transcriptomes in 17 Species

    Directory of Open Access Journals (Sweden)

    Hadas Hezroni


    Full Text Available The inability to predict long noncoding RNAs from genomic sequence has impeded the use of comparative genomics for studying their biology. Here, we develop methods that use RNA sequencing (RNA-seq data to annotate the transcriptomes of 16 vertebrates and the echinoid sea urchin, uncovering thousands of previously unannotated genes, most of which produce long intervening noncoding RNAs (lincRNAs. Although in each species, >70% of lincRNAs cannot be traced to homologs in species that diverged >50 million years ago, thousands of human lincRNAs have homologs with similar expression patterns in other species. These homologs share short, 5′-biased patches of sequence conservation nested in exonic architectures that have been extensively rewired, in part by transposable element exonization. Thus, over a thousand human lincRNAs are likely to have conserved functions in mammals, and hundreds beyond mammals, but those functions require only short patches of specific sequences and can tolerate major changes in gene architecture.

  19. Noncoding RNAs that associate with YB-1 alter proliferation in prostate cancer cells. (United States)

    Liu, Teresa T; Arango-Argoty, Gustavo; Li, Zhihua; Lin, Yuefeng; Kim, Sang Woo; Dueck, Anne; Ozsolak, Fatih; Monaghan, A Paula; Meister, Gunter; DeFranco, Donald B; John, Bino


    The highly conserved, multifunctional YB-1 is a powerful breast cancer prognostic indicator. We report on a pervasive role for YB-1 in which it associates with thousands of nonpolyadenylated short RNAs (shyRNAs) that are further processed into small RNAs (smyRNAs). Many of these RNAs have previously been identified as functional noncoding RNAs ( We identified a novel, abundant, 3'-modified short RNA antisense to Dicer1 (Shad1) that colocalizes with YB-1 to P-bodies and stress granules. The expression of Shad1 was shown to correlate with that of YB-1 and whose inhibition leads to an increase in cell proliferation. Additionally, Shad1 influences the expression of additional prognostic markers of cancer progression such as DLX2 and IGFBP2. We propose that the examination of these noncoding RNAs could lead to better understanding of prostate cancer progression. © 2015 Liu et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  20. 3′ terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing (United States)


    Background Post-transcriptional 3′ end processing is a key component of RNA regulation. The abundant and essential RNA subunit of RNase MRP has been proposed to function in three distinct cellular compartments and therefore may utilize this mode of regulation. Here we employ 3′ RACE coupled with high-throughput sequencing to characterize the 3′ terminal sequences of human MRP RNA and other noncoding RNAs that form RNP complexes. Results The 3′ terminal sequence of MRP RNA from HEK293T cells has a distinctive distribution of genomically encoded termini (including an assortment of U residues) with a portion of these selectively tagged by oligo(A) tails. This profile contrasts with the relatively homogenous 3′ terminus of an in vitro transcribed MRP RNA control and the differing 3′ terminal profiles of U3 snoRNA, RNase P RNA, and telomerase RNA (hTR). Conclusions 3′ RACE coupled with deep sequencing provides a valuable framework for the functional characterization of 3′ terminal sequences of noncoding RNAs. PMID:24053768

  1. 3' terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing. (United States)

    Goldfarb, Katherine C; Cech, Thomas R


    Post-transcriptional 3' end processing is a key component of RNA regulation. The abundant and essential RNA subunit of RNase MRP has been proposed to function in three distinct cellular compartments and therefore may utilize this mode of regulation. Here we employ 3' RACE coupled with high-throughput sequencing to characterize the 3' terminal sequences of human MRP RNA and other noncoding RNAs that form RNP complexes. The 3' terminal sequence of MRP RNA from HEK293T cells has a distinctive distribution of genomically encoded termini (including an assortment of U residues) with a portion of these selectively tagged by oligo(A) tails. This profile contrasts with the relatively homogenous 3' terminus of an in vitro transcribed MRP RNA control and the differing 3' terminal profiles of U3 snoRNA, RNase P RNA, and telomerase RNA (hTR). 3' RACE coupled with deep sequencing provides a valuable framework for the functional characterization of 3' terminal sequences of noncoding RNAs.

  2. Two seemingly homologous noncoding RNAs act hierarchically to activate glmS mRNA translation.

    Directory of Open Access Journals (Sweden)

    Johannes H Urban


    Full Text Available Small noncoding RNAs (sRNA can function as posttranscriptional activators of gene expression to regulate stress responses and metabolism. We here describe the mechanisms by which two sRNAs, GlmY and GlmZ, activate the Escherichia coli glmS mRNA, coding for an essential enzyme in amino-sugar metabolism. The two sRNAs, although being highly similar in sequence and structure, act in a hierarchical manner. GlmZ, together with the RNA chaperone, Hfq, directly activates glmS mRNA translation by an anti-antisense mechanism. In contrast, GlmY acts upstream of GlmZ and positively regulates glmS by antagonizing GlmZ RNA inactivation. We also report the first example, to our knowledge, of mRNA expression being controlled by the poly(A status of a chromosomally encoded sRNA. We show that in wild-type cells, GlmY RNA is unstable due to 3' end polyadenylation; whereas in an E. coli pcnB mutant defective in RNA polyadenylation, GlmY is stabilized and accumulates, which in turn stabilizes GlmZ and causes GlmS overproduction. Our study reveals hierarchical action of two well-conserved sRNAs in a complex regulatory cascade that controls the glmS mRNA. Similar cascades of noncoding RNA regulators may operate in other organisms.

  3. Expansion of Einstein-Yang-Mills amplitude (United States)

    Fu, Chih-Hao; Du, Yi-Jian; Huang, Rijun; Feng, Bo


    In this paper, we study from various perspectives the expansion of tree level single trace Einstein-Yang-Mills amplitudes into linear combination of color-ordered Yang-Mills amplitudes. By applying the gauge invariance principle, a programable recursive construction is devised to expand EYM amplitude with arbitrary number of gravitons into EYM amplitudes with fewer gravitons. Based on this recursive technique we write down the complete expansion of any single trace EYM amplitude in the basis of color-order Yang-Mills amplitude. As a byproduct, an algorithm for constructing a polynomial form of the BCJ numerator for Yang-Mills amplitudes is also outlined in this paper. In addition, by applying BCFW recursion relation we show how to arrive at the same EYM amplitude expansion from the on-shell perspective. And we examine the EYM expansion using KLT relations and show how to evaluate the expansion coefficients efficiently.

  4. Maxwell superalgebras and Abelian semigroup expansion

    Directory of Open Access Journals (Sweden)

    P.K. Concha


    Full Text Available The Abelian semigroup expansion is a powerful and simple method to derive new Lie algebras from a given one. Recently it was shown that the S-expansion of so(3,2 leads us to the Maxwell algebra M. In this paper we extend this result to superalgebras, by proving that different choices of abelian semigroups S lead to interesting D=4 Maxwell Superalgebras. In particular, the minimal Maxwell superalgebra sM and the N-extended Maxwell superalgebra sM(N recently found by the Maurer–Cartan expansion procedure, are derived alternatively as an S-expansion of osp(4|N. Moreover, we show that new minimal Maxwell superalgebras type sMm+2 and their N-extended generalization can be obtained using the S-expansion procedure.

  5. Flexible concrete link slabs used as expansion joints in bridge decks

    DEFF Research Database (Denmark)

    Lárusson, Lárus Helgi; Fischer, Gregor


    reinforcement serves as a flexible concrete element between the adjacent deck segments. The use of an Engineered Cementitious Composite (ECC) material instead of conventional concrete significantly reduces crack widths under service conditions and prevents deterioration of the link slab in the tension......Deterioration of bridge structures with mechanical expansion joints between simply supported spans can cause repeated maintenance needs and high repair costs. Damage occurs due to accumulation of debris within the expansion joint, corrosion of deck reinforcement, spalling of concrete, leakage...... of water through the expansion joint and subsequent corrosion of girders and girder bearings. Investigations on joint-less superstructures using conventional steel reinforcement in so-called concrete link slabs indicate improved performance and economic feasibility. However, this concept requires...

  6. Giant negative thermal expansion in Fe-doped layered ruthenate ceramics (United States)

    Takenaka, Koshi; Shinoda, Tsubasa; Inoue, Naruhiro; Okamoto, Yoshihiko; Katayama, Naoyuki; Sakai, Yuki; Nishikubo, Takumi; Azuma, Masaki


    The effects of iron doping on the giant negative thermal expansion (NTE) of Ca2RuO4- y ceramics are investigated. Fe-doped ruthenate ceramics exhibit a large NTE even though the crystallographic unit-cell volume shows no NTE. The anisotropic thermal strain of crystal grains consumes open spaces in the sintered body and causes giant bulk volume contraction on heating. This giant NTE is reproducible against repeated thermal cycling, indicating a tough microstructure. The thermal expansion of epoxy resin is fully suppressed below 400 K by the 56 vol % loading of the Fe-doped ruthenate ceramic powder, demonstrating tough microstructures and the capability of thermal expansion compensation of the ruthenate sintered body.

  7. simple sequence repeats (EST-SSR)

    African Journals Online (AJOL)



    Jan 19, 2012 ... 212 primer pairs selected, based on repeat patterns of n≥8 for di-, tri-, tetra- and penta-nucleotide repeat ... Cluster analysis revealed a high genetic similarity among the sugarcane (Saccharum spp.) breeding lines which could reduce the genetic gain in ..... The multiple allele characteristic of SSR com-.

  8. Repeatability & Workability Evaluation of SIGMOD 2009

    KAUST Repository

    Manegold, Stefan


    SIGMOD 2008 was the first database conference that offered to test submitters\\' programs against their data to verify the repeatability of the experiments published [1]. Given the positive feedback concerning the SIGMOD 2008 repeatability initiative, SIGMOD 2009 modified and expanded the initiative with a workability assessment.

  9. (SSR) and inter simple sequence repeat (ISSR)

    African Journals Online (AJOL)

    Finally, they were washed 3 to 4 times with sterile distilled water and inoculated aseptically on Murashige and Skoog (MS) basal medium free hormones. Single nodes resulted from seedlings cultured as explants. Inter simple sequence repeat (ISSR) and simple sequence repeat (SSR) primers used produced different ...

  10. Myotonin protein-kinase [AGC]n trinucleotide repeat in seven nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Novelli, G.; Sineo, L.; Pontieri, E. [Catholic Univ. of Rome (Italy)]|[Univ. of Milan (Italy)]|[Univ. Florence (Italy)] [and others


    Myotonic dystrophy (DM) is due to a genomic instability of a trinucleotide [AGC]n motif, located at the 3{prime} UTR region of a protein-kinase gene (myotonin protein kinase, MT-PK). The [AGC] repeat is meiotically and mitotically unstable, and it is directly related to the manifestations of the disorder. Although a gene dosage effect of the MT-PK has been demonstrated n DM muscle, the mechanism(s) by which the intragenic repeat expansion leads to disease is largely unknown. This non-standard mutational event could reflect an evolutionary mechanism widespread among animal genomes. We have isolated and sequenced the complete 3{prime}UTR region of the MT-PK gene in seven primates (macaque, orangutan, gorilla, chimpanzee, gibbon, owl monkey, saimiri), and examined by comparative sequence nucleotide analysis the [AGC]n intragenic repeat and the surrounding nucleotides. The genomic organization, including the [AGC]n repeat structure, was conserved in all examined species, excluding the gibbon (Hylobates agilis), in which the [AGC]n upstream sequence (GGAA) is replaced by a GA dinucleotide. The number of [AGC]n in the examined species ranged between 7 (gorilla) and 13 repeats (owl monkeys), with a polymorphism informative content (PIC) similar to that observed in humans. These results indicate that the 3{prime}UTR [AGC] repeat within the MT-PK gene is evolutionarily conserved, supporting that this region has important regulatory functions.

  11. DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes (United States)

    Smith, G. K.; Jie, J.; Fox, G. E.; Gao, X.


    DNA triplet repeats, 5'-d(CTG)n and 5'-d(CAG)n, are present in genes which have been implicated in several neurodegenerative disorders. To investigate possible stable structures formed by these repeating sequences, we have examined d(CTG)n, d(CAG)n and d(CTG).d(CAG)n (n = 2 and 3) using NMR and UV optical spectroscopy. These studies reveal that single stranded (CTG)n (n > 2) forms stable, antiparallel helical duplexes, while the single stranded (CAG)n requires at least three repeating units to form a duplex. NMR and UV melting experiments show that the Tm increases in the order of [(CAG)3]2 DNA. However, unique NOE and 1H-31P coupling patterns associated with the repetitive T.T mismatches in the CTG repeats are discerned. These results, in conjunction with recent in vitro studies suggest that longer CTG repeats may form hairpin structures, which can potentially cause interruption in replication, leading to dynamic expansion or deletion of triplet repeats.

  12. UK 2009-2010 repeat station report

    Directory of Open Access Journals (Sweden)

    Thomas J.G. Shanahan


    Full Text Available The British Geological Survey is responsible for conducting the UK geomagnetic repeat station programme. Measurements made at the UK repeat station sites are used in conjunction with the three UK magnetic observatories: Hartland, Eskdalemuir and Lerwick, to produce a regional model of the local field each year. The UK network of repeat stations comprises 41 stations which are occupied at approximately 3-4 year intervals. Practices for conducting repeat station measurements continue to evolve as advances are made in survey instrumentation and as the usage of the data continues to change. Here, a summary of the 2009 and 2010 UK repeat station surveys is presented, highlighting the measurement process and techniques, density of network, reduction process and recent results.

  13. The Population Origins and Expansion of Feral Cats in Australia (United States)

    Yurchenko, Andrey A.; David, Victor A.; Scott, Rachael; Koepfli, Klaus-Peter; Driscoll, Carlos; O’Brien, Stephen J.; Menotti-Raymond, Marilyn


    The historical literature suggests that in Australia, the domestic cat (Felis catus) had a European origin [~200 years before present (ybp)], but it is unclear if cats arrived from across the Asian land bridge contemporaneously with the dingo (4000 ybp), or perhaps immigrated ~40000 ybp in association with Aboriginal settlement from Asia. The origin of cats in Australia is important because the continent has a complex and ancient faunal assemblage that is dominated by endemic rodents and marsupials and lacks the large placental carnivores found on other large continents. Cats are now ubiquitous across the entire Australian continent and have been implicit in the range contraction or extinction of its small to medium sized (cats using 15 short tandem repeat (STR) genomic markers. Their origin appears to come exclusively from European founders. Feral cats in continental Australia exhibit high genetic diversity in comparison with the low diversity found in populations of feral cats living on islands. The genetic structure is consistent with a rapid westerly expansion from eastern Australia and a limited expansion in coastal Western Australia. Australian cats show modest if any population structure and a close genetic alignment with European feral cats as compared to cats from Asia, the Christmas and Cocos (Keeling) Islands (Indian Ocean), and European wildcats (F. silvestris silvestris). PMID:26647063

  14. Hygroscopic Expansion of Aesthetic Restorative Materials: One-Year Report (United States)

    Emamieh, S.; Ghasemi, A.; Torabzadeh, H.


    Objective: To measure the long-term linear hygroscopic expansion (LHE) of several materials using bulked and layered techniques. Materials and Methods: Seven materials were used; Fuji Cap II, Fuji II LC, Photac-Fil Aplicap, Vitremer, Dyract, Tetric and Z100. Ten specimens (6×4 mm) were made for each material using layered and bulked techniques (each group comprises five specimens). The specimens were stored in distilled water at 37°C. The length of each specimen was measured immediately after preparation, 24 hours, one week, one month, three months, six months, nine months and one year. This was used to calculate the percentage change in the length of materials. The mean LHE and standard deviation were calculated. Repeated measure analysis and paired sample t-test were used. Results: The type of material and time had a significant effect on LHE. Fuji Cap II and Fuji II LC exhibited no significant changes after one-year and one month, respectively. However, layered specimens of Photac-Fil Aplicap and Tetric showed constant expansion until six month, whereas bulked specimens reached the constant length at three months. Constant expansion was obtained for layered and bulked specimens of Dyract and Z100 at six month. Layered specimens of Vitremer showed no significant differences except between 24 hours and one year measurements. But in bulked specimens, the results at nine months and one year were significantly different from those obtained at three months and before. Conclusion: Fuji II showed no significant LHE and resin-modified glass ionomer cements (RMGICs) exhibited the highest LHE. Dyract maintained an intermediate LHE in comparison with RMGIC and composite resin. PMID:21998804

  15. Collective pulsatile expansion and swirls in proliferating tumor tissue (United States)

    Yang, Taeseok Daniel; Kim, Hyun; Yoon, Changhyeong; Baek, Seung-Kuk; Lee, Kyoung J.


    Understanding the dynamics of expanding biological tissues is essential to a wide range of phenomena in morphogenesis, wound healing and tumor proliferation. Increasing evidence suggests that many of the relevant phenomena originate from complex collective dynamics, inherently nonlinear, of constituent cells that are physically active. Here, we investigate thin disk layers of proliferating, cohesive, monoclonal tumor cells and report the discovery of macroscopic, periodic, soliton-like mechanical waves with which cells are collectively ratcheting, as in the traveling-wave chemotaxis of dictyostelium discodium amoeba cells. The relevant length-scale of the waves is remarkably large (∼1 mm), compared to the thickness of a mono-layer tissue (∼ 10 μ {{m}}). During the tissue expansion, the waves are found to repeat several times with a quite well defined period of approximately 4 h. Our analyses suggest that the waves are initiated by the leading edge that actively pulls the tissue in the outward direction, while the cells within the bulk tissue do not seem to generate a strong self-propulsion. Subsequently, we demonstrate that a simple mathematical model chain of nonlinear springs that are constantly pulled in the outward direction at the leading edge recapitulates the observed phenomena well. As the areal cell density becomes too high, the tissue expansion stalls and the periodic traveling waves yield to multiple swirling vortices. Cancer cells are known to possess a broad spectrum of migration mechanisms. Yet, our finding has established a new unusual mode of tumor tissue expansion, and it may be equally applicable for many different expanding thin layers of cell tissues.

  16. Fish are sensitive to expansion-contraction color effects.

    Directory of Open Access Journals (Sweden)

    Liliana Albertazzi


    Full Text Available Some visual phenomena reveal the visual system’s tendency to structure the scene according to rules that do not always have a direct correspondence in the external physical world. Color information can affect the perception of other object attributes such as size, generating contextual expansion, and contraction effects. We investigated phenomena of this kind in redtail splitfin fish (Xenotoca eiseni, family Goodeidae. As in previous studies, the fish were trained to discriminate a larger from a smaller grey rectangle in order to locate the exit from the test tank. The fish were then presented with two rectangles of equal size but different colors. Isoluminant colors were employed for each pair to control for luminance contrast from the background. The fish were tested in three different conditions with three color pairs corresponding to the human yellow-blue, red-green, and red-blue. The three color test conditions affected fish responses in significantly different ways. In the blue-yellow condition the fish seemed to experience the expansion-contraction effects as reported by human observers. By contrast, no difference between the choices of the two training groups was observed in the red-green and red-blue conditions. This is the first demonstration of human-like phenomenal chromatic expansion-contraction effects in non-human animals. Notably, the effect of the yellow-blue pair, which is usually the one most pronounced in humans, seems to be robust also under conditions of isoluminance in our model species. Future studies could repeat the experiment using non-isoluminant pairs that better preserve the connotative chromatic dimensions in humans.

  17. Giant negative thermal expansion in magnetic nanocrystals. (United States)

    Zheng, X G; Kubozono, H; Yamada, H; Kato, K; Ishiwata, Y; Xu, C N


    Most solids expand when they are heated, but a property known as negative thermal expansion has been observed in a number of materials, including the oxide ZrW2O8 (ref. 1) and the framework material ZnxCd1-x(CN)2 (refs 2,3). This unusual behaviour can be understood in terms of low-energy phonons, while the colossal values of both positive and negative thermal expansion recently observed in another framework material, Ag3[Co(CN)6], have been explained in terms of the geometric flexibility of its metal-cyanide-metal linkages. Thermal expansion can also be stopped in some magnetic transition metal alloys below their magnetic ordering temperature, a phenomenon known as the Invar effect, and the possibility of exploiting materials with tuneable positive or negative thermal expansion in industrial applications has led to intense interest in both the Invar effect and negative thermal expansion. Here we report the results of thermal expansion experiments on three magnetic nanocrystals-CuO, MnF2 and NiO-and find evidence for negative thermal expansion in both CuO and MnF2 below their magnetic ordering temperatures, but not in NiO. Larger particles of CuO and MnF2 also show prominent magnetostriction (that is, they change shape in response to an applied magnetic field), which results in significantly reduced thermal expansion below their magnetic ordering temperatures; this behaviour is not observed in NiO. We propose that the negative thermal expansion effect in CuO (which is four times larger than that observed in ZrW2O8) and MnF2 is a general property of nanoparticles in which there is strong coupling between magnetism and the crystal lattice.

  18. Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons

    Directory of Open Access Journals (Sweden)

    Chul-Yong Park


    Full Text Available Fragile X syndrome (FXS is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1 gene. Here, we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders.

  19. Some Improved Nonperturbative Bounds for Fermionic Expansions

    Energy Technology Data Exchange (ETDEWEB)

    Lohmann, Martin, E-mail: [Universita di Roma Tre, Dipartimento di Matematica (Italy)


    We reconsider the Gram-Hadamard bound as it is used in constructive quantum field theory and many body physics to prove convergence of Fermionic perturbative expansions. Our approach uses a recursion for the amplitudes of the expansion, discovered in a model problem by Djokic (2013). It explains the standard way to bound the expansion from a new point of view, and for some of the amplitudes provides new bounds, which avoid the use of Fourier transform, and are therefore superior to the standard bounds for models like the cold interacting Fermi gas.

  20. Cosmic growth history and expansion history

    International Nuclear Information System (INIS)

    Linder, Eric V.


    The cosmic expansion history tests the dynamics of the global evolution of the universe and its energy density contents, while the cosmic growth history tests the evolution of the inhomogeneous part of the energy density. Precision comparison of the two histories can distinguish the nature of the physics responsible for the accelerating cosmic expansion: an additional smooth component--dark energy--or a modification of the gravitational field equations. With the aid of a new fitting formula for linear perturbation growth accurate to 0.05%-0.2%, we separate out the growth dependence on the expansion history and introduce a new growth index parameter γ that quantifies the gravitational modification