C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population.

Science.gov (United States)

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

2015-01-01

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.

Noncoding Elements: Evolution and Epigenetic Regulation

KAUST Repository

Seridi, Loqmane

2016-03-09

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

C9ORF72 G4C2-repeat expansion and frontotemporal dementia first reported case in Argentina.

Science.gov (United States)

Fernández Suarez, M; Surace, Ezequiel; Harris, P; Tapajoz, F; Sevlever, G; Allegri, R; Russo, G N

2016-06-01

We present a female patient aged 51 who developed behavioral disorders followed by cognitive impairment over 3 years. Neuropsychological, neuropsychiatric, and radiological features suggested a probable behavioral variant of frontotemporal dementia (bvFTD). A family history of amyotrophic lateral sclerosis and parkinsonism suggested the hexanucleotide repeat expansion G4C2 in C9ORF72 . We set up a two-step genotyping algorithm for the detection of the expansion using fragment-length analysis polymerase chain reaction (PCR) and repeat-primed PCR with fluorescent primers. We confirmed the presence of an expanded G4C2 allele in the patient. This represents the first documented case of bvFTD due to a C9ORF72 expansion in Argentina.

DNA dynamics is likely to be a factor in the genomic nucleotide repeats expansions related to diseases.

Directory of Open Access Journals (Sweden)

Boian S Alexandrov

Full Text Available Trinucleotide repeats sequences (TRS represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results for a novel and notable collective breathing behavior of genomic DNA of tandem TRS, leading to propensity for large local DNA transient openings at physiological temperature. Our Langevin molecular dynamics (LMD and Markov Chain Monte Carlo (MCMC simulations demonstrate that the patterns of openings of various TRSs depend specifically on their length. The collective propensity for DNA strand separation of repeated sequences serves as a precursor for outsized intermediate bubble states independently of the G/C-content. We report that repeats have the potential to interfere with the binding of transcription factors to their consensus sequence by altered DNA breathing dynamics in proximity of the binding sites. These observations might influence ongoing attempts to use LMD and MCMC simulations for TRS-related modeling of genomic DNA functionality in elucidating the common denominators of the dynamic TRS expansion mutation with potential therapeutic applications.

Functional interrogation of non-coding DNA through CRISPR genome editing.

Science.gov (United States)

Canver, Matthew C; Bauer, Daniel E; Orkin, Stuart H

2017-05-15

Methodologies to interrogate non-coding regions have lagged behind coding regions despite comprising the vast majority of the genome. However, the rapid evolution of clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has provided a multitude of novel techniques for laboratory investigation including significant contributions to the toolbox for studying non-coding DNA. CRISPR-mediated loss-of-function strategies rely on direct disruption of the underlying sequence or repression of transcription without modifying the targeted DNA sequence. CRISPR-mediated gain-of-function approaches similarly benefit from methods to alter the targeted sequence through integration of customized sequence into the genome as well as methods to activate transcription. Here we review CRISPR-based loss- and gain-of-function techniques for the interrogation of non-coding DNA. Copyright © 2017 Elsevier Inc. All rights reserved.

Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy.

Science.gov (United States)

Hu, Jiaxin; Rong, Ziye; Gong, Xin; Zhou, Zhengyang; Sharma, Vivek K; Xing, Chao; Watts, Jonathan K; Corey, David R; Mootha, V Vinod

2018-03-15

Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing. We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has ∼2 sense foci and each foci is single RNA molecule. We designed antisense oligonucleotides (ASOs) to target the mutant-repetitive RNA and demonstrated potent inhibition of foci in patient-derived cells. Ex vivo treatment of FECD human corneas effectively inhibits foci and reverses pathological changes in splicing. FECD has the potential to be a model for treating many trinucleotide repeat diseases and targeting the TCF4 expansion with ASOs represents a promising therapeutic strategy to prevent and treat FECD.

Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion.

Science.gov (United States)

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

2014-03-01

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.

Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases

NARCIS (Netherlands)

van Rheenen, Wouter; van Blitterswijk, Marka; Huisman, Mark H. B.; Vlam, Lotte; van Doormaal, Perry T. C.; Seelen, Meinie; Medic, Jelena; Dooijes, Dennis; de Visser, Marianne; van der Kooi, Anneke J.; Raaphorst, Joost; Schelhaas, Helenius J.; van der Pol, W. Ludo; Veldink, Jan H.; van den Berg, Leonard H.

2012-01-01

Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).

A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families.

Science.gov (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

2014-11-01

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.

Validation of a screening tool for the rapid and reliable detection of CGG trinucleotide repeat expansions in FMR1.

Science.gov (United States)

Basehore, Monica J; Marlowe, Natalia M; Jones, Julie R; Behlendorf, Deborah E; Laver, Thomas A; Friez, Michael J

2012-06-01

Most individuals with intellectual disability and/or autism are tested for Fragile X syndrome at some point in their lifetime. Greater than 99% of individuals with Fragile X have an expanded CGG trinucleotide repeat motif in the promoter region of the FMR1 gene, and diagnostic testing involves determining the size of the CGG repeat as well as methylation status when an expansion is present. Using a previously described triplet repeat-primed polymerase chain reaction, we have performed additional validation studies using two cohorts with previous diagnostic testing results available for comparison purposes. The first cohort (n=88) consisted of both males and females and had a high percentage of abnormal samples, while the second cohort (n=624) consisted of only females and was not enriched for expansion mutations. Data from each cohort were completely concordant with the results previously obtained during the course of diagnostic testing. This study further demonstrates the utility of using laboratory-developed triplet repeat-primed FMR1 testing in a clinical setting.

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

Indian Academy of Sciences (India)

Unknown

interact with these noncoding transcripts, we examined the in situ ... reduced RNA-processing activities in the nucleus. (Lakhotia et al. 1999 ... This process was repeated for 10 generations. .... wild-type testes were distributed in the anterior part and along the ..... various nuclear RNA-processing proteins to protect them.

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.

The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.

Science.gov (United States)

Zhang, Ke; Donnelly, Christopher J; Haeusler, Aaron R; Grima, Jonathan C; Machamer, James B; Steinwald, Peter; Daley, Elizabeth L; Miller, Sean J; Cunningham, Kathleen M; Vidensky, Svetlana; Gupta, Saksham; Thomas, Michael A; Hong, Ingie; Chiu, Shu-Ling; Huganir, Richard L; Ostrow, Lyle W; Matunis, Michael J; Wang, Jiou; Sattler, Rita; Lloyd, Thomas E; Rothstein, Jeffrey D

2015-09-03

The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.

Bilateral cross-bite treated by repeated rapid maxillary expansions: a 17-year follow-up case.

Science.gov (United States)

Cozzani, M; Mazzotta, L; Caprioglio, A

2014-07-01

The objective of this paper is to show the clinical results after the repeated application of a Haas expander for rapid maxillary expansion (RME) anchored onto deciduous teeth in a 7-year-old patient that presented bilateral cross-bite, superior crowding and no space for permanent lateral incisors eruption. A first Haas expander was applied to the patient. She was told to activate it once a day, each activation was equal to 0.20 mm. After the first RME, the bilateral cross-bite was solved but still there was not enough space for lateral incisor eruption. A second and then a third Haas expander were applied, with the same activation protocol as the first one, in order to gain space in the anterior region and to achieve proper eruption of the lateral incisors. The patient was then treated with fixed appliances. At debonding the patient presented well aligned arch-forms: space for lateral incisor eruption was gained and superior crowding was solved. Bilateral cross-bite was also corrected. She was seen again 10 years and 17 years after expansions: she showed no relapse and presented a good functional occlusion that had remained stable, and an aesthetically pleasant smile, however she exhibited gingival recessions. Repeated rapid maxillary expansion, anchored onto deciduous teeth, performed in early mixed dentition represents a safe and successful treatment to correct severe bilateral cross- bites and to create space for maxillary incisor eruption.

The Long Non-coding RNA HOTTIP Enhances Pancreatic Cancer Cell Proliferation, Survival and Migration

Science.gov (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...

Expansion of inverted repeat does not decrease substitution rates in Pelargonium plastid genomes.

Science.gov (United States)

Weng, Mao-Lun; Ruhlman, Tracey A; Jansen, Robert K

2017-04-01

For species with minor inverted repeat (IR) boundary changes in the plastid genome (plastome), nucleotide substitution rates were previously shown to be lower in the IR than the single copy regions (SC). However, the impact of large-scale IR expansion/contraction on plastid nucleotide substitution rates among closely related species remains unclear. We included plastomes from 22 Pelargonium species, including eight newly sequenced genomes, and used both pairwise and model-based comparisons to investigate the impact of the IR on sequence evolution in plastids. Ten types of plastome organization with different inversions or IR boundary changes were identified in Pelargonium. Inclusion in the IR was not sufficient to explain the variation of nucleotide substitution rates. Instead, the rate heterogeneity in Pelargonium plastomes was a mixture of locus-specific, lineage-specific and IR-dependent effects. Our study of Pelargonium plastomes that vary in IR length and gene content demonstrates that the evolutionary consequences of retaining these repeats are more complicated than previously suggested. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Systematic analysis of coding and noncoding DNA sequences using methods of statistical linguistics

Science.gov (United States)

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

1995-01-01

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.

Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress.

Science.gov (United States)

Sonobe, Yoshifumi; Ghadge, Ghanashyam; Masaki, Katsuhisa; Sendoel, Ataman; Fuchs, Elaine; Roos, Raymond P

2018-08-01

Expansion of a hexanucleotide repeat (HRE), GGGGCC, in the C9ORF72 gene is recognized as the most common cause of familial amyotrophic lateral sclerosis (FALS), frontotemporal dementia (FTD) and ALS-FTD, as well as 5-10% of sporadic ALS. Despite the location of the HRE in the non-coding region (with respect to the main C9ORF72 gene product), dipeptide repeat proteins (DPRs) that are thought to be toxic are translated from the HRE in all three reading frames from both the sense and antisense transcript. Here, we identified a CUG that has a good Kozak consensus sequence as the translation initiation codon. Mutation of this CTG significantly suppressed polyglycine-alanine (GA) translation. GA was translated when the G 4 C 2 construct was placed as the second cistron in a bicistronic construct. CRISPR/Cas9-induced knockout of a non-canonical translation initiation factor, eIF2A, impaired GA translation. Transfection of G 4 C 2 constructs induced an integrated stress response (ISR), while triggering the ISR led to a continuation of translation of GA with a decline in conventional cap-dependent translation. These in vitro observations were confirmed in chick embryo neural cells. The findings suggest that DPRs translated from an HRE in C9ORF72 aggregate and lead to an ISR that then leads to continuing DPR production and aggregation, thereby creating a continuing pathogenic cycle. Copyright © 2018 Elsevier Inc. All rights reserved.

Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1.

Science.gov (United States)

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

2017-07-11

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.

Hexanucleotide Repeat Expansion in C9ORF72 Is Not Detected in the Treatment-Resistant Schizophrenia Patients of Chinese Han.

Directory of Open Access Journals (Sweden)

Xijia Xu

Full Text Available Hexanucleotide (GGGGCC repeat expansion in C9ORF72 (HRE causes frontotemporal lobar degeneration, frontotemporal dementia-amyotrophic lateral sclerosis, and amyotrophic lateral sclerosis. HRE was also seen in the genomes of patients suffering from several other degenerative diseases. However, whether it is present in the treatment-resistant schizophrenia patients remains unknown. Genotyping 386 patients suffering from treatment-resistant schizophrenia using the method of Repeat-Primed PCR, we reported here that no HRE was detected in the patients of Chinese Han.

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

2012-03-01

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.

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

Indian Academy of Sciences (India)

and SMC3, as all STRs for these genes fall in noncoding region only. ... This indicates that more repeated STRs are at the risk of replication ... patients versus controls. ... ing from a balance between slippage events and point mutations. Proc.

No CAG repeat expansion of polymerase gamma is associated with male infertility in Tamil Nadu, South India

Science.gov (United States)

Poongothai, J.

2013-01-01

Mitochondria contains a single deoxyribonucleic acid (DNA) polymerase, polymerase gamma (POLG) mapped to long arm of chromosome 15 (15q25), responsible for replication and repair of mitochondrial DNA. Exon 1 of the human POLG contains CAG trinucleotide repeat, which codes for polyglutamate. Ten copies of CAG repeat were found to be uniformly high (0.88) in different ethnic groups and considered as the common allele, whereas the mutant alleles (not -10/not -10 CAG repeats) were found to be associated with oligospermia/oligoasthenospermia in male infertility. Recent data suggested the implication of POLG CAG repeat expansion in infertility, but are debated. The aim of our study was to explore whether the not -10/not -10 variant is associated with spermatogenic failure. As few study on Indian population have been conducted so far to support this view, we investigated the distribution of the POLG CAG repeats in 61 infertile men and 60 normozoospermic control Indian men of Tamil Nadu, from the same ethnic background. This analysis interestingly revealed that the homozygous wild type genotype (10/-10) was common in infertile men (77% - 47/61) and in normozoospermic control men (71.7% - 43/60). Our study failed to confirm any influence of the POLG gene polymorphism on the efficiency of the spermatogenesis. PMID:24339545

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

2016-07-01

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.

Mouse Models of C9orf72 Hexanucleotide Repeat Expansion in Amyotrophic Lateral Sclerosis/ Frontotemporal Dementia

Directory of Open Access Journals (Sweden)

Ranjan Batra

2017-07-01

Full Text Available The presence of hexanucleotide repeat expansion (HRE in the first intron of the human C9orf72 gene is the most common genetic cause underlying both familial amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD. Studies aimed at elucidating the pathogenic mechanisms associated of C9orf72 FTD and ALS (C9FTD/ALS have focused on the hypothesis of RNA and protein toxic gain-of-function models, including formation of nuclear RNA foci containing GGGGCC (G4C2 HRE, inclusions containing dipeptide repeat proteins through a non-canonical repeat associated non-ATG (RAN translation mechanism, and on loss-of-function of the C9orf72 protein. Immense effort to elucidate these mechanisms has been put forth and toxic gain-of-function models have especially gained attention. Various mouse models that recapitulate distinct disease-related pathological, functional, and behavioral phenotypes have been generated and characterized. Although these models express the C9orf72 HRE mutation, there are numerous differences among them, including the transgenesis approach to introduce G4C2-repeat DNA, genomic coverage of C9orf72 features in the transgene, G4C2-repeat length after genomic stabilization, spatiotemporal expression profiles of RNA foci and RAN protein aggregates, neuropathological features, and neurodegeneration-related clinical symptoms. This review aims to (1 provide an overview of the key characteristics; (2 provide insights into potential pathological factors contributing to neurotoxicity and clinical phenotypes through systematic comparison of these models.

CRISPR/Cas9-mediated noncoding RNA editing in human cancers.

Science.gov (United States)

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

2018-01-02

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.

The expanding universe of noncoding RNAs.

Science.gov (United States)

Hannon, G J; Rivas, F V; Murchison, E P; Steitz, J A

2006-01-01

The 71st Cold Spring Harbor Symposium on Quantitative Biology celebrated the numerous and expanding roles of regulatory RNAs in systems ranging from bacteria to mammals. It was clearly evident that noncoding RNAs are undergoing a renaissance, with reports of their involvement in nearly every cellular process. Previously known classes of longer noncoding RNAs were shown to function by every possible means-acting catalytically, sensing physiological states through adoption of complex secondary and tertiary structures, or using their primary sequences for recognition of target sites. The many recently discovered classes of small noncoding RNAs, generally less than 35 nucleotides in length, most often exert their effects by guiding regulatory complexes to targets via base-pairing. With the ability to analyze the RNA products of the genome in ever greater depth, it has become clear that the universe of noncoding RNAs may extend far beyond the boundaries we had previously imagined. Thus, as much as the Symposium highlighted exciting progress in the field, it also revealed how much farther we must go to understand fully the biological impact of noncoding RNAs.

Large scale analysis of small repeats via mining of the human genome

NARCIS (Netherlands)

van den Berg, I.; Bosnacki, D.; Hilbers, P.A.J.

2009-01-01

Small repetitive sequences, called tandem repeats, are abundant throughout the human genome, both in coding and in non-coding regions. Their role is still mostly unknown, but at least 20 of those repetitive sequences have been related to neurodegenerative disorders. The mutational process that is

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study

NARCIS (Netherlands)

E. Majounie (Elisa); A. Renton (Alan); K. Mok (Kin); E.G.P. Dopper (Elise); A. Waite (Adrian); S. Rollinson (Sara); A. Chiò (Adriano); G. Restagno (Gabriella); N. Nicolaou (Nayia); J. Simón-Sánchez (Javier); J.C. van Swieten (John); Y. Abramzon (Yevgeniya); J. Johnson (Janel); M. Sendtner (Michael); R. Pamphlett (Roger); R. Orrell (Richard); S. Mead (Simon); K.C. Sidle (Katie); H. Houlden (Henry); J.D. Rohrer (Jonathan Daniel); K.E. Morrison (Karen); H. Pall (Hardev); D. Talbot; O. Ansorge (Olaf); D.G. Hernandez (Dena); S. Arepalli (Sampath); M. Sabatelli (Mario); G. Mora (Gabriele); J.C. Corbo (Joseph); F. Giannini (Fabio); A. Calvo (Andrea); E. Englund (Elisabet); G. Borghero (Giuseppe); O.A.M. Floris; A. Remes (Anne); H. Laaksovirta (Hannu); L. McCluskey (Leo); J.Q. Trojanowski (John); V.M. Deerlin (Vivianna); G.D. Schellenberg (Gerard); M.A. Nalls (Michael); V.E. Drory (Vivian E); C.S. Lu (Chin-Song); T.-H. Yeh (Tu-Hsueh); H. Ishiura (Hiroyuki); Y. Takahashi (Yukari); S. Tsuji (Shoji); I. Le Ber (Isabelle); A. Brice; C. Drepper (Carsten); N. Williams (Nigel); J. Kirby (Janine); P.J. Shaw (Pamela); J. Hardy (John); P.J. Tienari (Pentti); P. Heutink (Peter); H. Morris (Huw); S. Pickering-Brown (Stuart); B.J. Traynor (Bryan)

2012-01-01

textabstractBackground: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

NARCIS (Netherlands)

Majounie, E.; Renton, A.E.; Mok, K.; Dopper, E.G.P.; Waite, A.; Rollinson, S.; Chio, A.; Restagno, G.; Nicolaou, N.; Simon-Sanchez, J.; van Swieten, J.C.; Abramzon, Y.; Johnson, J.O.; Sendtner, M.; Pamphlett, R.; Orrell, R.W.; Mead, S.; Sidle, K.C.; Houlden, H.; Rohrer, J.D.; Morrison, K.E.; Pall, H.; Talbot, K.; Ansorge, O.; Hernandez, D.G.; Arepalli, S.; Sabatelli, M.; Mora, G.; Corbo, M.; Giannini, F.; Calvo, A.; Englund, E.; Borghero, G.; Foris, G.L.; Remes, A.M.; Laaksovirta, H.; McCluskey, L.; Trojanowski, J.Q.; Van Deerlin, V.M.; Schellenberg, G.D.; Nalls, M.A.; Drory, V.E.; Lu, C.S.; Yeh, T.H.; Ishiura, H.; Takahashi, Y.; Tsuji, S.; Le Ber, I.; Brice, A.; Drepper, C.; Williams, N.; Kirby, J.; Shaw, P.; Hardy, J.; Tienari, P.J.; Heutink, P.; Morris, H.R.; Pickering-Brown, S.; Traynor, B.J.

2012-01-01

Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with ALS (El

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

Directory of Open Access Journals (Sweden)

Siyu Han

2016-01-01

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.

Function and Application Areas in Medicine of Non-Coding RNA

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Figen Guzelgul

2009-06-01

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

Non-Coding RNAs in Hodgkin Lymphoma

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Anna Cordeiro

2017-05-01

Full Text Available MicroRNAs (miRNAs, small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL is a B cell origin disease characterized by the presence of only 1% of tumor cells, known as Hodgkin and Reed-Stenberg (HRS cells, which interact with the microenvironment to evade apoptosis. Several studies have reported specific miRNA signatures that can differentiate HL lymph nodes from reactive lymph nodes, identify histologic groups within classical HL, and distinguish HRS cells from germinal center B cells. Moreover, some signatures are associated with survival or response to chemotherapy. Most of the miRNAs in the signatures regulate genes related to apoptosis, cell cycle arrest, or signaling pathways. Here we review findings on miRNAs in HL, as well as on other non-coding RNAs.

Battles and hijacks: Noncoding transcription in plants

KAUST Repository

Ariel, Federico

2015-06-01

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.

Emerging properties and functional consequences of noncoding transcription

DEFF Research Database (Denmark)

Ard, Ryan; Allshire, Robin C; Marquardt, Sebastian

2017-01-01

specific lncRNAs, support grows for the notion that the act of transcription rather than the RNA product itself is functionally important in many cases. Indeed, this alternative mechanism might better explain how low-abundance lncRNAs transcribed from noncoding DNA function in organisms. Here, we highlight......Eukaryotic genomes are rich in transcription units encoding "long noncoding RNAs" (lncRNAs). The purpose of all this transcription is unclear since most lncRNAs are quickly targeted for destruction during synthesis or shortly thereafter. As debates continue over the functional significance of many...... some of the recently emerging features that distinguish coding from noncoding transcription and discuss how these differences might have important implications for the functional consequences of noncoding transcription....

Panning for Long Noncoding RNAs

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Li Yang

2013-02-01

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.

Noncoding sequence classification based on wavelet transform analysis: part I

Science.gov (United States)

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

2017-09-01

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.

Annotating pathogenic non-coding variants in genic regions.

Science.gov (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

2017-08-09

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.

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

2012-01-01

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.

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: jlmartinez@ccia.uned.es [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)

2012-04-15

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.

Identifying noncoding risk variants using disease-relevant gene regulatory networks.

Science.gov (United States)

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

2018-02-16

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.

Hypoxic regulation of the noncoding genome and NEAT1

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Choudhry, Hani

2016-01-01

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

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

OpenAIRE

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

2016-01-01

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 ...

Anlægsbærere for fragilt X-syndrom kan udvise et bredt spektrum af kliniske manifestationer

DEFF Research Database (Denmark)

Jønch, Aia Elise; Grønskov, Karen; Lunding, Jytte

2014-01-01

Fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are three clinically distinct disorders caused by expansions of a CGG repeat sequence in the non-coding part of the FMR1. FXTAS and FXPOI are seen in carriers...

The origins and evolutionary history of human non-coding RNA regulatory networks.

Science.gov (United States)

Sherafatian, Masih; Mowla, Seyed Javad

2017-04-01

The evolutionary history and origin of the regulatory function of animal non-coding RNAs are not well understood. Lack of conservation of long non-coding RNAs and small sizes of microRNAs has been major obstacles in their phylogenetic analysis. In this study, we tried to shed more light on the evolution of ncRNA regulatory networks by changing our phylogenetic strategy to focus on the evolutionary pattern of their protein coding targets. We used available target databases of miRNAs and lncRNAs to find their protein coding targets in human. We were able to recognize evolutionary hallmarks of ncRNA targets by phylostratigraphic analysis. We found the conventional 3'-UTR and lesser known 5'-UTR targets of miRNAs to be enriched at three consecutive phylostrata. Firstly, in eukaryata phylostratum corresponding to the emergence of miRNAs, our study revealed that miRNA targets function primarily in cell cycle processes. Moreover, the same overrepresentation of the targets observed in the next two consecutive phylostrata, opisthokonta and eumetazoa, corresponded to the expansion periods of miRNAs in animals evolution. Coding sequence targets of miRNAs showed a delayed rise at opisthokonta phylostratum, compared to the 3' and 5' UTR targets of miRNAs. LncRNA regulatory network was the latest to evolve at eumetazoa.

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

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Kamila Maliszewska-Olejniczak

2015-07-01

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

Bleomycin Can Cleave an Oncogenic Noncoding RNA.

Science.gov (United States)

Angelbello, Alicia J; Disney, Matthew D

2018-01-04

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.

A genome-wide signature of positive selection in ancient and recent invasive expansions of the honey bee Apis mellifera.

Science.gov (United States)

Zayed, Amro; Whitfield, Charles W

2008-03-04

Apis mellifera originated in Africa and extended its range into Eurasia in two or more ancient expansions. In 1956, honey bees of African origin were introduced into South America, their descendents admixing with previously introduced European bees, giving rise to the highly invasive and economically devastating "Africanized" honey bee. Here we ask whether the honey bee's out-of-Africa expansions, both ancient and recent (invasive), were associated with a genome-wide signature of positive selection, detected by contrasting genetic differentiation estimates (F(ST)) between coding and noncoding SNPs. In native populations, SNPs in protein-coding regions had significantly higher F(ST) estimates than those in noncoding regions, indicating adaptive evolution in the genome driven by positive selection. This signal of selection was associated with the expansion of honey bees from Africa into Western and Northern Europe, perhaps reflecting adaptation to temperate environments. We estimate that positive selection acted on a minimum of 852-1,371 genes or approximately 10% of the bee's coding genome. We also detected positive selection associated with the invasion of African-derived honey bees in the New World. We found that introgression of European-derived alleles into Africanized bees was significantly greater for coding than noncoding regions. Our findings demonstrate that Africanized bees exploited the genetic diversity present from preexisting introductions in an adaptive way. Finally, we found a significant negative correlation between F(ST) estimates and the local GC content surrounding coding SNPs, suggesting that AT-rich genes play an important role in adaptive evolution in the honey bee.

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

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Xiao-Nan Zhao

2016-09-01

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.

Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation.

Science.gov (United States)

Kanekura, Kohsuke; Yagi, Takuya; Cammack, Alexander J; Mahadevan, Jana; Kuroda, Masahiko; Harms, Matthew B; Miller, Timothy M; Urano, Fumihiko

2016-05-01

The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Long Noncoding RNAs in Lung Cancer.

Science.gov (United States)

Roth, Anna; Diederichs, Sven

2016-01-01

Despite great progress in research and treatment options, lung cancer remains the leading cause of cancer-related deaths worldwide. Oncogenic driver mutations in protein-encoding genes were defined and allow for personalized therapies based on genetic diagnoses. Nonetheless, diagnosis of lung cancer mostly occurs at late stages, and chronic treatment is followed by a fast onset of chemoresistance. Hence, there is an urgent need for reliable biomarkers and alternative treatment options. With the era of whole genome and transcriptome sequencing technologies, long noncoding RNAs emerged as a novel class of versatile, functional RNA molecules. Although for most of them the mechanism of action remains to be defined, accumulating evidence confirms their involvement in various aspects of lung tumorigenesis. They are functional on the epigenetic, transcriptional, and posttranscriptional level and are regulators of pathophysiological key pathways including cell growth, apoptosis, and metastasis. Long noncoding RNAs are gaining increasing attention as potential biomarkers and a novel class of druggable molecules. It has become clear that we are only beginning to understand the complexity of tumorigenic processes. The clinical integration of long noncoding RNAs in terms of prognostic and predictive biomarker signatures and additional cancer targets could provide a chance to increase the therapeutic benefit. Here, we review the current knowledge about the expression, regulation, biological function, and clinical relevance of long noncoding RNAs in lung cancer.

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

International Nuclear Information System (INIS)

Miro-Bueno, Jesus

2015-01-01

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

Noncoding DNA in lipofection of HeLa cells-a few insights.

Science.gov (United States)

Symens, Nathalie; Rejman, Joanna; Lucas, Bart; Demeester, Joseph; De Smedt, Stefaan C; Remaut, Katrien

2013-03-04

In cationic carrier-mediated gene delivery, the disproportional relationship between the quantity of delivered DNA and the amount of encoded protein produced is a well-known phenomenon. The numerous intracellular barriers which need to be overcome by pDNA to reach the nucleoplasm play a major role in it. In contrast to what one would expect, a partial replacement of coding pDNA by noncoding DNA does not lead to a decrease in transfection efficiency. The mechanism underlying this observation is still unclear. Therefore, we investigated which constituents of the transfection process might contribute to this phenomenon. Our data reveal that the topology of the noncoding plasmid DNA plays a major role. Noncoding pDNA can be used only in a supercoiled form to replace coding pDNA in Lipofectamine lipoplexes, without a loss in transfection levels. When noncoding pDNA is linearized or partly digested, it diminishes the transfection potential of coding pDNA, as does noncoding salmon DNA. The difference in transfection efficiencies could not be attributed to diverse physicochemical characteristics of the Lipofectamine lipoplexes containing different types of noncoding DNA or to the extent of their internalization. At the level of endosomal release, however, nucleic acid release from the endosomal compartment proceeds faster when lipoplexes contain noncoding salmon DNA. Since the half-life of pDNA in the cytosol hardly exceeds 90 min, it is conceivable that prolonged release of coding pDNA from complexes carrying supercoiled noncoding pDNA may explain its positive effect on transfection, while this depot effect does not exist when noncoding salmon DNA is used.

ChloroSSRdb: a repository of perfect and imperfect chloroplastic simple sequence repeats (cpSSRs) of green plants.

Science.gov (United States)

Kapil, Aditi; Rai, Piyush Kant; Shanker, Asheesh

2014-01-01

Simple sequence repeats (SSRs) are regions in DNA sequence that contain repeating motifs of length 1-6 nucleotides. These repeats are ubiquitously present and are found in both coding and non-coding regions of genome. A total of 534 complete chloroplast genome sequences (as on 18 September 2014) of Viridiplantae are available at NCBI organelle genome resource. It provides opportunity to mine these genomes for the detection of SSRs and store them in the form of a database. In an attempt to properly manage and retrieve chloroplastic SSRs, we designed ChloroSSRdb which is a relational database developed using SQL server 2008 and accessed through ASP.NET. It provides information of all the three types (perfect, imperfect and compound) of SSRs. At present, ChloroSSRdb contains 124 430 mined SSRs, with majority lying in non-coding region. Out of these, PCR primers were designed for 118 249 SSRs. Tetranucleotide repeats (47 079) were found to be the most frequent repeat type, whereas hexanucleotide repeats (6414) being the least abundant. Additionally, in each species statistical analyses were performed to calculate relative frequency, correlation coefficient and chi-square statistics of perfect and imperfect SSRs. In accordance with the growing interest in SSR studies, ChloroSSRdb will prove to be a useful resource in developing genetic markers, phylogenetic analysis, genetic mapping, etc. Moreover, it will serve as a ready reference for mined SSRs in available chloroplast genomes of green plants. Database URL: www.compubio.in/chlorossrdb/ © The Author(s) 2014. Published by Oxford University Press.

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

2014-01-01

The mouse and human brain express a large number of noncoding RNAs (ncRNAs). Some of these are known to participate in neural progenitor cell fate determination, cell differentiation, neuronal and synaptic plasticity and transposable elements derived ncRNAs contribute to somatic variation...

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

Science.gov (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

2017-07-19

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.

Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.

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Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C; Pinto, Ricardo Mouro

2017-02-01

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. Copyright © 2017 by the Genetics Society of America.

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

KAUST Repository

Shimada, Makoto K.; Sanbonmatsu, Ryoko; Yamaguchi-Kabata, Yumi; Yamasaki, Chisato; Suzuki, Yoshiyuki; Chakraborty, Ranajit; Gojobori, Takashi; Imanishi, Tadashi

2016-01-01

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

A PCR-based protocol to accurately size C9orf72 intermediate-length alleles.

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Biasiotto, Giorgio; Archetti, Silvana; Di Lorenzo, Diego; Merola, Francesca; Paiardi, Giulia; Borroni, Barbara; Alberici, Antonella; Padovani, Alessandro; Filosto, Massimiliano; Bonvicini, Cristian; Caimi, Luigi; Zanella, Isabella

2017-04-01

Although large expansions of the non-coding GGGGCC repeat in C9orf72 gene are clearly defined as pathogenic for Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), intermediate-length expansions have also been associated with those and other neurodegenerative diseases. Intermediate-length allele sizing is complicated by intrinsic properties of current PCR-based methodologies, in that somatic mosaicism could be suspected. We designed a protocol that allows the exact sizing of intermediate-length alleles, as well as the identification of large expansions. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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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.

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

KAUST Repository

Viterbo, David; Michoud, Gregoire; Mosbach, Valentine; Dujon, Bernard; Richard, Guy-Franck

2016-01-01

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.

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

KAUST Repository

Viterbo, David

2016-03-16

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.

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

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Valentine Mosbach

2018-02-01

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.

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.

Science.gov (United States)

Lattante, Serena; Millecamps, Stéphanie; Stevanin, Giovanni; Rivaud-Péchoux, Sophie; Moigneu, Carine; Camuzat, Agnès; Da Barroca, Sandra; Mundwiller, Emeline; Couarch, Philippe; Salachas, François; Hannequin, Didier; Meininger, Vincent; Pasquier, Florence; Seilhean, Danielle; Couratier, Philippe; Danel-Brunaud, Véronique; Bonnet, Anne-Marie; Tranchant, Christine; LeGuern, Eric; Brice, Alexis; Le Ber, Isabelle; Kabashi, Edor

2014-09-09

The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. © 2014 American Academy of Neurology.

Non-Coding Transcript Heterogeneity in Mesothelioma: Insights from Asbestos-Exposed Mice.

Science.gov (United States)

Felley-Bosco, Emanuela; Rehrauer, Hubert

2018-04-11

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.

R-loops: targets for nuclease cleavage and repeat instability.

Science.gov (United States)

Freudenreich, Catherine H

2018-01-11

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.

DNA Replication Dynamics of the GGGGCC Repeat of the C9orf72 Gene.

Science.gov (United States)

Thys, Ryan Griffin; Wang, Yuh-Hwa

2015-11-27

DNA has the ability to form a variety of secondary structures in addition to the normal B-form DNA, including hairpins and quadruplexes. These structures are implicated in a number of neurological diseases and cancer. Expansion of a GGGGCC repeat located at C9orf72 is associated with familial amyotrophic lateral sclerosis and frontotemporal dementia. This repeat expands from two to 24 copies in normal individuals to several hundreds or thousands of repeats in individuals with the disease. Biochemical studies have demonstrated that as little as four repeats have the ability to form a stable DNA secondary structure known as a G-quadruplex. Quadruplex structures have the ability to disrupt normal DNA processes such as DNA replication and transcription. Here we examine the role of GGGGCC repeat length and orientation on DNA replication using an SV40 replication system in human cells. Replication through GGGGCC repeats leads to a decrease in overall replication efficiency and an increase in instability in a length-dependent manner. Both repeat expansions and contractions are observed, and replication orientation is found to influence the propensity for expansions or contractions. The presence of replication stress, such as low-dose aphidicolin, diminishes replication efficiency but has no effect on instability. Two-dimensional gel electrophoresis analysis demonstrates a replication stall with as few as 20 GGGGCC repeats. These results suggest that replication of the GGGGCC repeat at C9orf72 is perturbed by the presence of expanded repeats, which has the potential to result in further expansion, leading to disease. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Selective constraint on noncoding regions of hominid genomes.

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Eliot C Bush

2005-12-01

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.

Selective Constraint on Noncoding Regions of Hominid Genomes.

Directory of Open Access Journals (Sweden)

2005-12-01

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.

Molecular mechanisms of muscle atrophy in myotonic dystrophies

OpenAIRE

Timchenko, Lubov

2013-01-01

Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and Zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in p...

Instability of (CTGn•(CAGn trinucleotide repeats and DNA synthesis

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Liu Guoqi

2012-02-01

Full Text Available Abstract Expansion of (CTGn•(CAGn trinucleotide repeat (TNR microsatellite sequences is the cause of more than a dozen human neurodegenerative diseases. (CTGn and (CAGn repeats form imperfectly base paired hairpins that tend to expand in vivo in a length-dependent manner. Yeast, mouse and human models confirm that (CTGn•(CAGn instability increases with repeat number, and implicate both DNA replication and DNA damage response mechanisms in (CTGn•(CAGn TNR expansion and contraction. Mutation and knockdown models that abrogate the expression of individual genes might also mask more subtle, cumulative effects of multiple additional pathways on (CTGn•(CAGn instability in whole animals. The identification of second site genetic modifiers may help to explain the variability of (CTGn•(CAGn TNR instability patterns between tissues and individuals, and offer opportunities for prognosis and treatment.

Alanine repeats influence protein localization in splicing speckles and paraspeckles.

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

2014-12-16

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.

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

DEFF Research Database (Denmark)

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

2011-01-01

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...

Detecting non-coding selective pressure in coding regions

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Blanchette Mathieu

2007-02-01

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.

ATXN2 trinucleotide repeat length correlates with risk of ALS.

Science.gov (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

2017-03-01

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.

Partners in crime: bidirectional transcription in unstable microsatellite disease.

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Batra, Ranjan; Charizanis, Konstantinos; Swanson, Maurice S

2010-04-15

Nearly two decades have passed since the discovery that the expansion of microsatellite trinucleotide repeats is responsible for a prominent class of neurological disorders, including Huntington disease and fragile X syndrome. These hereditary diseases are characterized by genetic anticipation or the intergenerational increase in disease severity accompanied by a decrease in age-of-onset. The revelation that the variable expansion of simple sequence repeats accounted for anticipation spawned a number of pathogenesis models and a flurry of studies designed to reveal the molecular events affected by these expansions. This work led to our current understanding that expansions in protein-coding regions result in extended homopolymeric amino acid tracts, often polyglutamine or polyQ, and deleterious protein gain-of-function effects. In contrast, expansions in noncoding regions cause RNA-mediated toxicity. However, the realization that the transcriptome is considerably more complex than previously imagined, as well as the emerging regulatory importance of antisense RNAs, has blurred this distinction. In this review, we summarize evidence for bidirectional transcription of microsatellite disease genes and discuss recent suggestions that some repeat expansions produce variable levels of both toxic RNAs and proteins that influence cell viability, disease penetrance and pathological severity.

Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations and C9orf72 repeat expansions.

Science.gov (United States)

Lattante, Serena; Le Ber, Isabelle; Galimberti, Daniela; Serpente, Maria; Rivaud-Péchoux, Sophie; Camuzat, Agnès; Clot, Fabienne; Fenoglio, Chiara; Scarpini, Elio; Brice, Alexis; Kabashi, Edor

2014-11-01

TMEM106B was identified as a risk factor for frontotemporal lobar degeneration (FTD) with TAR DNA-binding protein 43 kDa inclusions. It has been reported that variants in this gene are genetic modifiers of the disease and that this association is stronger in patients carrying a GRN mutation or a pathogenic expansion in chromosome 9 open reading frame 72 (C9orf72) gene. Here, we investigated the contribution of TMEM106B polymorphisms in cohorts of FTD and FTD with amyotrophic lateral sclerosis patients from France and Italy. Patients carrying the C9orf72 expansion (n = 145) and patients with GRN mutations (n = 76) were compared with a group of FTD patients (n = 384) negative for mutations and to a group of healthy controls (n = 552). In our cohorts, the presence of the C9orf72 expansion did not correlate with TMEM106B genotypes but the association was very strong in individuals with pathogenic GRN mutations (p = 9.54 × 10(-6)). Our data suggest that TMEM106B genotypes differ in FTD patient cohorts and strengthen the protective role of TMEM106B in GRN carriers. Further studies are needed to determine whether TMEM106B polymorphisms are associated with other genetic causes for FTD, including C9orf72 repeat expansions. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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Stinus Lindgreen

2014-10-01

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.

Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion.

Science.gov (United States)

Oliveira Santos, Miguel; Caldeira, Inês; Gromicho, Marta; Pronto-Laborinho, Ana; de Carvalho, Mamede

2017-10-01

A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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Shakil Ahmad Bhat

2016-10-01

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

Expression of a family of noncoding mitochondrial RNAs distinguishes normal from cancer cells.

Science.gov (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

2009-06-09

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.

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

Science.gov (United States)

Usdin, Karen; Kumari, Daman

2015-01-01

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

Short-lived non-coding transcripts (SLiTs): Clues to regulatory long non-coding RNA.

Science.gov (United States)

Tani, Hidenori

2017-03-22

Whole transcriptome analyses have revealed a large number of novel long non-coding RNAs (lncRNAs). Although the importance of lncRNAs has been documented in previous reports, the biological and physiological functions of lncRNAs remain largely unknown. The role of lncRNAs seems an elusive problem. Here, I propose a clue to the identification of regulatory lncRNAs. The key point is RNA half-life. RNAs with a long half-life (t 1/2 > 4 h) contain a significant proportion of ncRNAs, as well as mRNAs involved in housekeeping functions, whereas RNAs with a short half-life (t 1/2 regulatory ncRNAs and regulatory mRNAs. This novel class of ncRNAs with a short half-life can be categorized as Short-Lived non-coding Transcripts (SLiTs). I consider that SLiTs are likely to be rich in functionally uncharacterized regulatory RNAs. This review describes recent progress in research into SLiTs.

Huntingtin gene repeat size variations affect risk of lifetime depression

DEFF Research Database (Denmark)

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

2017-01-01

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...

The human noncoding genome defined by genetic diversity.

Science.gov (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

2018-03-01

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.

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

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Huang Fengzhen

2017-05-01

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.

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

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Rosanna H. E. Krakowsky

2015-05-01

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.

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

Indian Academy of Sciences (India)

Unknown

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.

The complete chloroplast genome sequence of Mahonia bealei (Berberidaceae) reveals a significant expansion of the inverted repeat and phylogenetic relationship with other angiosperms.

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Ma, Ji; Yang, Bingxian; Zhu, Wei; Sun, Lianli; Tian, Jingkui; Wang, Xumin

2013-10-10

Mahonia bealei (Berberidaceae) is a frequently-used traditional Chinese medicinal plant with efficient anti-inflammatory ability. This plant is one of the sources of berberine, a new cholesterol-lowering drug with anti-diabetic activity. We have sequenced the complete nucleotide sequence of the chloroplast (cp) genome of M. bealei. The complete cp genome of M. bealei is 164,792 bp in length, and has a typical structure with large (LSC 73,052 bp) and small (SSC 18,591 bp) single-copy regions separated by a pair of inverted repeats (IRs 36,501 bp) of large size. The Mahonia cp genome contains 111 unique genes and 39 genes are duplicated in the IR regions. The gene order and content of M. bealei are almost unarranged which is consistent with the hypothesis that large IRs stabilize cp genome and reduce gene loss-and-gain probabilities during evolutionary process. A large IR expansion of over 12 kb has occurred in M. bealei, 15 genes (rps19, rpl22, rps3, rpl16, rpl14, rps8, infA, rpl36, rps11, petD, petB, psbH, psbN, psbT and psbB) have expanded to have an additional copy in the IRs. The IR expansion rearrangement occurred via a double-strand DNA break and subsequence repair, which is different from the ordinary gene conversion mechanism. Repeat analysis identified 39 direct/inverted repeats 30 bp or longer with a sequence identity ≥ 90%. Analysis also revealed 75 simple sequence repeat (SSR) loci and almost all are composed of A or T, contributing to a distinct bias in base composition. Comparison of protein-coding sequences with ESTs reveals 9 putative RNA edits and 5 of them resulted in non-synonymous modifications in rpoC1, rps2, rps19 and ycf1. Phylogenetic analysis using maximum parsimony (MP) and maximum likelihood (ML) was performed on a dataset composed of 65 protein-coding genes from 25 taxa, which yields an identical tree topology as previous plastid-based trees, and provides strong support for the sister relationship between Ranunculaceae and Berberidaceae

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, ...

An expanding universe of noncoding RNAs between the poles of basic science and clinical investigations.

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Weil, Patrick P; Hensel, Kai O; Weber, David; Postberg, Jan

2016-03-01

The Keystone Symposium 'MicroRNAs and Noncoding RNAs in Cancer', Keystone, CO, USA, 7-12 June 2015 Since the discovery of RNAi, great efforts have been undertaken to unleash the potential biomedical applicability of small noncoding RNAs, mainly miRNAs, involving their use as biomarkers for personalized diagnostics or their usability as active agents or therapy targets. The research's focus on the noncoding RNA world is now slowly moving from a phase of basic discoveries into a new phase, where every single molecule out of many hundreds of cataloged noncoding RNAs becomes dissected in order to investigate these molecules' biomedical relevance. In addition, RNA classes neglected before, such as long noncoding RNAs or circular RNAs attract more attention. Numerous timely results and hypotheses were presented at the 2015 Keystone Symposium 'MicroRNAs and Noncoding RNAs in Cancer'.

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

2017-07-05

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.

Gene conversion homogenizes the CMT1A paralogous repeats

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Hurles Matthew E

2001-12-01

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.

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

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Alejandra Sandoval-Bórquez

2015-01-01

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.

The primary structures of two yeast enolase genes. Homology between the 5' noncoding flanking regions of yeast enolase and glyceraldehyde-3-phosphate dehydrogenase genes.

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Holland, M J; Holland, J P; Thill, G P; Jackson, K A

1981-02-10

Segments of yeast genomic DNA containing two enolase structural genes have been isolated by subculture cloning procedures using a cDNA hybridization probe synthesized from purified yeast enolase mRNA. Based on restriction endonuclease and transcriptional maps of these two segments of yeast DNA, each hybrid plasmid contains a region of extensive nucleotide sequence homology which forms hybrids with the cDNA probe. The DNA sequences which flank this homologous region in the two hybrid plasmids are nonhomologous indicating that these sequences are nontandemly repeated in the yeast genome. The complete nucleotide sequence of the coding as well as the flanking noncoding regions of these genes has been determined. The amino acid sequence predicted from one reading frame of both structural genes is extremely similar to that determined for yeast enolase (Chin, C. C. Q., Brewer, J. M., Eckard, E., and Wold, F. (1981) J. Biol. Chem. 256, 1370-1376), confirming that these isolated structural genes encode yeast enolase. The nucleotide sequences of the coding regions of the genes are approximately 95% homologous, and neither gene contains an intervening sequence. Codon utilization in the enolase genes follows the same biased pattern previously described for two yeast glyceraldehyde-3-phosphate dehydrogenase structural genes (Holland, J. P., and Holland, M. J. (1980) J. Biol. Chem. 255, 2596-2605). DNA blotting analysis confirmed that the isolated segments of yeast DNA are colinear with yeast genomic DNA and that there are two nontandemly repeated enolase genes per haploid yeast genome. The noncoding portions of the two enolase genes adjacent to the initiation and termination codons are approximately 70% homologous and contain sequences thought to be involved in the synthesis and processing messenger RNA. Finally there are regions of extensive homology between the two enolase structural genes and two yeast glyceraldehyde-3-phosphate dehydrogenase structural genes within the 5

At the intersection of non-coding transcription, DNA repair, chromatin structure, and cellular senescence

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Ryosuke eOhsawa

2013-07-01

Full Text Available It is well accepted that non-coding RNAs play a critical role in regulating gene expression. Recent paradigm-setting studies are now revealing that non-coding RNAs, other than microRNAs, also play intriguing roles in the maintenance of chromatin structure, in the DNA damage response, and in adult human stem cell aging. In this review, we will discuss the complex inter-dependent relationships among non-coding RNA transcription, maintenance of genomic stability, chromatin structure and adult stem cell senescence. DNA damage-induced non-coding RNAs transcribed in the vicinity of the DNA break regulate recruitment of the DNA damage machinery and DNA repair efficiency. We will discuss the correlation between non-coding RNAs and DNA damage repair efficiency and the potential role of changing chromatin structures around double-strand break sites. On the other hand, induction of non-coding RNA transcription from the repetitive Alu elements occurs during human stem cell aging and hinders efficient DNA repair causing entry into senescence. We will discuss how this fine balance between transcription and genomic instability may be regulated by the dramatic changes to chromatin structure that accompany cellular senescence.

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

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Chris Hewson

2016-10-01

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

Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS

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Vijay Kumar

2017-12-01

Full Text Available The most frequent genetic cause of amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD is intronic hexanucleotide (G4C2 repeat expansions (HRE in the C9orf72 gene. The non-exclusive pathogenic mechanisms by which C9orf72 repeat expansions contribute to these neurological disorders include loss of C9orf72 function and gain-of-function determined by toxic RNA molecules and dipeptides repeats protein toxicity. The expanded repeats are transcribed bidirectionally and forms RNA foci in the central nervous system, and sequester key RNA-binding proteins (RBPs leading to impairment in RNA processing events. Many studies report widespread transcriptome changes in ALS carrying a C9orf72 repeat expansion. Here we review the contribution of RNA foci interaction with RBPs as well as transcriptome changes involved in the pathogenesis of C9orf72- associated FTD/ALS. These informations are essential to elucidate the pathology and therapeutic intervention of ALS and/or FTD.

Non-coding RNAs in the Ovarian Follicle

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Rosalia Battaglia

2017-05-01

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.

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

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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.

Long noncoding RNA in prostate, bladder, and kidney cancer.

Science.gov (United States)

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

2014-06-01

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

Non-coding RNA in Deinococcus radiodurans

International Nuclear Information System (INIS)

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

2006-01-01

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)

Battles and hijacks: Noncoding transcription in plants

KAUST Repository

Ariel, Federico; Romero-Barrios, Natali; Jé gu, Teddy; Benhamed, Moussa; Crespi, Martin

2015-01-01

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

Gene expression and adaptive noncoding changes during human evolution.

Science.gov (United States)

Babbitt, Courtney C; Haygood, Ralph; Nielsen, William J; Wray, Gregory A

2017-06-05

Despite evidence for adaptive changes in both gene expression and non-protein-coding, putatively regulatory regions of the genome during human evolution, the relationship between gene expression and adaptive changes in cis-regulatory regions remains unclear. Here we present new measurements of gene expression in five tissues of humans and chimpanzees, and use them to assess this relationship. We then compare our results with previous studies of adaptive noncoding changes, analyzing correlations at the level of gene ontology groups, in order to gain statistical power to detect correlations. Consistent with previous studies, we find little correlation between gene expression and adaptive noncoding changes at the level of individual genes; however, we do find significant correlations at the level of biological function ontology groups. The types of function include processes regulated by specific transcription factors, responses to genetic or chemical perturbations, and differentiation of cell types within the immune system. Among functional categories co-enriched with both differential expression and noncoding adaptation, prominent themes include cancer, particularly epithelial cancers, and neural development and function.

Characterization of noncoding regulatory DNA in the human genome.

Science.gov (United States)

Elkon, Ran; Agami, Reuven

2017-08-08

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.

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)

2015-01-01

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

Potentials and limitations of histone repeat sequences for phylogenetic reconstruction of Sophophora.

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

1999-11-01

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.

Progressive changes in non-coding RNA profile in leucocytes with age

Science.gov (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

2017-01-01

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

Definite behavioral variant of frontotemporal dementia with C9ORF72 expansions despite positive Alzheimer's disease cerebrospinal fluid biomarkers.

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Wallon, David; Rovelet-Lecrux, Anne; Deramecourt, Vincent; Pariente, Jeremie; Auriacombe, Sophie; Le Ber, Isabelle; Schraen, Suzanna; Pasquier, Florence; Campion, Dominique; Hannequin, Didier

2012-01-01

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.

Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases

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Nayra Soares do Amaral

2016-12-01

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.

Expansion of all multitrace tree level EYM amplitudes

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Du, Yi-Jian; Feng, Bo; Teng, Fei

2017-12-01

In this paper, we investigate the expansion of tree level multitrace Einstein-Yang-Mills (EYM) amplitudes. First, we propose two types of recursive expansions of tree level EYM amplitudes with an arbitrary number of gluons, gravitons and traces by those amplitudes with fewer traces or/and gravitons. Then we give many support evidence, including proofs using the Cachazo-He-Yuan (CHY) formula and Britto-Cachazo-Feng-Witten (BCFW) recursive relation. As a byproduct, two types of generalized BCJ relations for multitrace EYM are further proposed, which will be useful in the BCFW proof. After one applies the recursive expansions repeatedly, any multitrace EYM amplitudes can be given in the Kleiss-Kuijf (KK) basis of tree level color ordered Yang-Mills (YM) amplitudes. Thus the Bern-Carrasco-Johansson (BCJ) numerators, as the expansion coefficients, for all multitrace EYM amplitudes are naturally constructed.

Identification of coding and non-coding mutational hotspots in cancer genomes.

Science.gov (United States)

Piraino, Scott W; Furney, Simon J

2017-01-05

The identification of mutations that play a causal role in tumour development, so called "driver" mutations, is of critical importance for understanding how cancers form and how they might be treated. Several large cancer sequencing projects have identified genes that are recurrently mutated in cancer patients, suggesting a role in tumourigenesis. While the landscape of coding drivers has been extensively studied and many of the most prominent driver genes are well characterised, comparatively less is known about the role of mutations in the non-coding regions of the genome in cancer development. The continuing fall in genome sequencing costs has resulted in a concomitant increase in the number of cancer whole genome sequences being produced, facilitating systematic interrogation of both the coding and non-coding regions of cancer genomes. To examine the mutational landscapes of tumour genomes we have developed a novel method to identify mutational hotspots in tumour genomes using both mutational data and information on evolutionary conservation. We have applied our methodology to over 1300 whole cancer genomes and show that it identifies prominent coding and non-coding regions that are known or highly suspected to play a role in cancer. Importantly, we applied our method to the entire genome, rather than relying on predefined annotations (e.g. promoter regions) and we highlight recurrently mutated regions that may have resulted from increased exposure to mutational processes rather than selection, some of which have been identified previously as targets of selection. Finally, we implicate several pan-cancer and cancer-specific candidate non-coding regions, which could be involved in tumourigenesis. We have developed a framework to identify mutational hotspots in cancer genomes, which is applicable to the entire genome. This framework identifies known and novel coding and non-coding mutional hotspots and can be used to differentiate candidate driver regions from

Noncoding RNA in the Transcriptional Landscape of Human Neural Progenitor Cell Differentiation

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Patrick eHecht

2015-10-01

Full Text Available 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.

Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation.

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Buchman, Vladimir L; Cooper-Knock, Johnathan; Connor-Robson, Natalie; Higginbottom, Adrian; Kirby, Janine; Razinskaya, Olga D; Ninkina, Natalia; Shaw, Pamela J

2013-04-08

Sizing of GGGGCC hexanucleotide repeat expansions within the C9ORF72 locus, which account for approximately 10% of all amyotrophic lateral sclerosis (ALS) cases, is urgently required to answer fundamental questions about mechanisms of pathogenesis in this important genetic variant. Currently employed PCR protocols are limited to discrimination between the presence and absence of a modified allele with more than 30 copies of the repeat, while Southern hybridisation-based methods are confounded by the somatic heterogeneity commonly present in blood samples, which might cause false-negative or ambiguous results. We describe an optimised Southern hybridisation-based protocol that allows confident detection of the presence of a C9ORF72 repeat expansion alongside independent assessment of its heterogeneity and the number of repeat units. The protocol can be used with either a radiolabeled or non-radiolabeled probe. Using this method we have successfully sized the C9ORF72 repeat expansion in lymphoblastoid cells, peripheral blood, and post-mortem central nervous system (CNS) tissue from ALS patients. It was also possible to confidently demonstrate the presence of repeat expansion, although of different magnitude, in both C9ORF72 alleles of the genome of one patient. The suggested protocol has sufficient advantages to warrant adoption as a standard for Southern blot hybridisation analysis of GGGGCC repeat expansions in the C9ORF72 locus.

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

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Oyoshi Takanori

2012-01-01

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.

On the classification of long non-coding RNAs

KAUST Repository

Ma, Lina; Bajic, Vladimir B.; Zhang, Zhang

2013-01-01

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

Non-Coding RNAs in Arabidopsis

DEFF Research Database (Denmark)

van Wonterghem, Miranda

This work evolves around elucidating the mechanisms of micro RNAs (miRNAs) in Arabidopsis thaliana. I identified a new class of nuclear non-coding RNAs derived from protein coding genes. The genes are miRNA targets with extensive gene body methylation. The RNA species are nuclear localized and de...

Purifying selection acts on coding and non-coding sequences of paralogous genes in Arabidopsis thaliana.

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Hoffmann, Robert D; Palmgren, Michael

2016-06-13

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.

Predicting effects of noncoding variants with deep learning-based sequence model.

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Zhou, Jian; Troyanskaya, Olga G

2015-10-01

Identifying functional effects of noncoding variants is a major challenge in human genetics. To predict the noncoding-variant effects de novo from sequence, we developed a deep learning-based algorithmic framework, DeepSEA (http://deepsea.princeton.edu/), that directly learns a regulatory sequence code from large-scale chromatin-profiling data, enabling prediction of chromatin effects of sequence alterations with single-nucleotide sensitivity. We further used this capability to improve prioritization of functional variants including expression quantitative trait loci (eQTLs) and disease-associated variants.

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

2012-01-01

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...

An atlas of over 90.000 conserved noncoding sequences provides insight into crucifer regulatory regions

NARCIS (Netherlands)

Haudry, A.; Platts, A.E.; Vello, E.; Hoen, D.R.; Leclerq, M.; Williamson, R.J.; Forczek, E.; Joly-Lopez, Z.; Steffen, J.G.; Hazzouri, K.M.; Dewar, K.; Stinchcombe, J.R.; Schoen, D.J.; Wang, X.; Schmutz, J.; Town, C.D.; Edger, P.P.; Pires, J.C.; Schumaker, K.S.; Jarvis, D.E.; Mandakova, T.; Lysak, M.; Bergh, van den E.; Schranz, M.E.; Harrison, P.M.

2013-01-01

Despite the central importance of noncoding DNA to gene regulation and evolution, understanding of the extent of selection on plant noncoding DNA remains limited compared to that of other organisms. Here we report sequencing of genomes from three Brassicaceae species (Leavenworthia alabamica,

The role of epigenetics and long noncoding RNA MIAT in neuroendocrine prostate cancer.

Science.gov (United States)

Crea, Francesco; Venalainen, Erik; Ci, Xinpei; Cheng, Hongwei; Pikor, Larissa; Parolia, Abhijit; Xue, Hui; Nur Saidy, Nur Ridzwan; Lin, Dong; Lam, Wan; Collins, Colin; Wang, Yuzhuo

2016-05-01

Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm. NEPC is thought to originate from the transdifferentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/noncoding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drug-resistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, miRNAs) play a key role in NEPC initiation and progression. Long noncoding RNAs represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively upregulated in NEPCs and might interact with Polycomb genes. Our results indicate that long noncoding RNAs can be exploited as new biomarkers and therapeutic targets for NEPC.

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

2017-01-01

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...

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

DEFF Research Database (Denmark)

Lindquist, S. G.; Duno, M.; Batbayli, M.

2013-01-01

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...

Identification of Novel Long Non-coding and Circular RNAs in Human Papillomavirus-Mediated Cervical Cancer

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Hongbo Wang

2017-09-01

Full Text Available Cervical cancer is the third most common cancer worldwide and the fourth leading cause of cancer-associated mortality in women. Accumulating evidence indicates that long non-coding RNAs (lncRNAs and circular RNAs (circRNAs may play key roles in the carcinogenesis of different cancers; however, little is known about the mechanisms of lncRNAs and circRNAs in the progression and metastasis of cervical cancer. In this study, we explored the expression profiles of lncRNAs, circRNAs, miRNAs, and mRNAs in HPV16 (human papillomavirus genotype 16 mediated cervical squamous cell carcinoma and matched adjacent non-tumor (ATN tissues from three patients with high-throughput RNA sequencing (RNA-seq. In total, we identified 19 lncRNAs, 99 circRNAs, 28 miRNAs, and 304 mRNAs that were commonly differentially expressed (DE in different patients. Among the non-coding RNAs, 3 lncRNAs and 44 circRNAs are novel to our knowledge. Functional enrichment analysis showed that DE lncRNAs, miRNAs, and mRNAs were enriched in pathways crucial to cancer as well as other gene ontology (GO terms. Furthermore, the co-expression network and function prediction suggested that all 19 DE lncRNAs could play different roles in the carcinogenesis and development of cervical cancer. The competing endogenous RNA (ceRNA network based on DE coding and non-coding RNAs showed that each miRNA targeted a number of lncRNAs and circRNAs. The link between part of the miRNAs in the network and cervical cancer has been validated in previous studies, and these miRNAs targeted the majority of the novel non-coding RNAs, thus suggesting that these novel non-coding RNAs may be involved in cervical cancer. Taken together, our study shows that DE non-coding RNAs could be further developed as diagnostic and therapeutic biomarkers of cervical cancer. The complex ceRNA network also lays the foundation for future research of the roles of coding and non-coding RNAs in cervical cancer.

Identification of Novel Long Non-coding and Circular RNAs in Human Papillomavirus-Mediated Cervical Cancer

Science.gov (United States)

Wang, Hongbo; Zhao, Yingchao; Chen, Mingyue; Cui, Jie

2017-01-01

Cervical cancer is the third most common cancer worldwide and the fourth leading cause of cancer-associated mortality in women. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) may play key roles in the carcinogenesis of different cancers; however, little is known about the mechanisms of lncRNAs and circRNAs in the progression and metastasis of cervical cancer. In this study, we explored the expression profiles of lncRNAs, circRNAs, miRNAs, and mRNAs in HPV16 (human papillomavirus genotype 16) mediated cervical squamous cell carcinoma and matched adjacent non-tumor (ATN) tissues from three patients with high-throughput RNA sequencing (RNA-seq). In total, we identified 19 lncRNAs, 99 circRNAs, 28 miRNAs, and 304 mRNAs that were commonly differentially expressed (DE) in different patients. Among the non-coding RNAs, 3 lncRNAs and 44 circRNAs are novel to our knowledge. Functional enrichment analysis showed that DE lncRNAs, miRNAs, and mRNAs were enriched in pathways crucial to cancer as well as other gene ontology (GO) terms. Furthermore, the co-expression network and function prediction suggested that all 19 DE lncRNAs could play different roles in the carcinogenesis and development of cervical cancer. The competing endogenous RNA (ceRNA) network based on DE coding and non-coding RNAs showed that each miRNA targeted a number of lncRNAs and circRNAs. The link between part of the miRNAs in the network and cervical cancer has been validated in previous studies, and these miRNAs targeted the majority of the novel non-coding RNAs, thus suggesting that these novel non-coding RNAs may be involved in cervical cancer. Taken together, our study shows that DE non-coding RNAs could be further developed as diagnostic and therapeutic biomarkers of cervical cancer. The complex ceRNA network also lays the foundation for future research of the roles of coding and non-coding RNAs in cervical cancer. PMID:28970820

Non-Coding RNAs and Endometrial Cancer

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Cristina Vallone

2018-03-01

Full Text Available Non-coding RNAs (ncRNAs are involved in the regulation of cell metabolism and neoplastic transformation. Recent studies have tried to clarify the significance of these information carriers in the genesis and progression of various cancers and their use as biomarkers for the disease; possible targets for the inhibition of growth and invasion by the neoplastic cells have been suggested. The significance of ncRNAs in lung cancer, bladder cancer, kidney cancer, and melanoma has been amply investigated with important results. Recently, the role of long non-coding RNAs (lncRNAs has also been included in cancer studies. Studies on the relation between endometrial cancer (EC and ncRNAs, such as small ncRNAs or micro RNAs (miRNAs, transfer RNAs (tRNAs, ribosomal RNAs (rRNAs, antisense RNAs (asRNAs, small nuclear RNAs (snRNAs, Piwi-interacting RNAs (piRNAs, small nucleolar RNAs (snoRNAs, competing endogenous RNAs (ceRNAs, lncRNAs, and long intergenic ncRNAs (lincRNAs have been published. The recent literature produced in the last three years was extracted from PubMed by two independent readers, which was then selected for the possible relation between ncRNAs, oncogenesis in general, and EC in particular.

Clinical implication of long noncoding RNA 91H expression profile in osteosarcoma patients

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Xia WK

2016-07-01

Full Text Available Wen-Kai Xia,1 Qing-Feng Lin,2 Dong Shen,2 Zhi-Li Liu,2 Jun Su,2 Wei-Dong Mao2 1Department of Nephrology, 2Department of Oncology, The Affiliated Jiangyin Hospital, School of Medicine, Southeast University, Jiangyin, Jiangsu, People’s Republic of China Abstract: Long noncoding RNAs have been documented as having widespread roles in carcinogenesis and cancer progression. However, roles of long noncoding RNAs in osteosarcoma remain unclear. This study is to investigate the clinical relevance and biological functions of long noncoding RNA 91H in osteosarcoma. Herein, we confirmed that 91H expression was notably increased in osteosarcoma patients and cell lines compared to healthy controls and normal human bone cell lines. High expression of 91H was significantly correlated with advanced clinical stage, chemotherapy after surgery, and tumor size >5 cm. Furthermore, 91H was an independent prognostic factor for overall survival in osteosarcoma patients after treatments. Additionally, the knockdown of 91H expression inhibited osteosarcoma cells’ proliferation and promoted their apoptosis in vitro. In summary, these findings indicate that 91H may be a novel biomarker for risk prognostication and also provide a clue to the molecular etiology of osteosarcoma. Keywords: long noncoding RNA, 91H, osteosarcoma, survival

Boundary Associated Long Noncoding RNA Mediates Long-Range Chromosomal Interactions.

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Ifeoma Jane Nwigwe

Full Text Available CCCTC binding factor (CTCF is involved in organizing chromosomes into mega base-sized, topologically associated domains (TADs along with other factors that define sub-TAD organization. CTCF-Cohesin interactions have been shown to be critical for transcription insulation activity as it stabilizes long-range interactions to promote proper gene expression. Previous studies suggest that heterochromatin boundary activity of CTCF may be independent of Cohesin, and there may be additional mechanisms for defining topological domains. Here, we show that a boundary site we previously identified known as CTCF binding site 5 (CBS5 from the homeotic gene cluster A (HOXA locus exhibits robust promoter activity. This promoter activity from the CBS5 boundary element generates a long noncoding RNA that we designate as boundary associated long noncoding RNA-1 (blncRNA1. Functional characterization of this RNA suggests that the transcript stabilizes long-range interactions at the HOXA locus and promotes proper expression of HOXA genes. Additionally, our functional analysis also shows that this RNA is not needed in the stabilization of CTCF-Cohesin interactions however CTCF-Cohesin interactions are critical in the transcription of blncRNA1. Thus, the CTCF-associated boundary element, CBS5, employs both Cohesin and noncoding RNA to establish and maintain topologically associated domains at the HOXA locus.

Confinement of Reinforced-Concrete Columns with Non-Code Compliant Confining Reinforcement plus Supplemental Pen-Binder

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Anang Kristianto

2012-11-01

Full Text Available One of the important requirements for earthquake resistant building related to confinement is the use of seismic hooks in the hoop or confining reinforcement of reinforced-concrete column elements. However, installation of a confining reinforcement with a 135-degree hook is not easy. Therefore, in practice, many construction workers apply a confining reinforcement with a 90-degreehook (non-code compliant. Based on research and records of recent earthquakes in Indonesia, the use of a non-code compliant confining reinforcement for concrete columns produces structures with poor seismic performance. This paper presents a study that introduces an additional element that is expected to improve the effectiveness of concrete columns confined with a non-code compliant confining reinforcement. The additional element, named a pen-binder, is used to keep the non-code compliant confining reinforcement in place. The effectiveness of this element under pure axial concentric loading was investigatedcomprehensively.The specimens tested in this study were 18 concrete columns,with a cross-section of 170 mm x 170 mm and a height of 480 mm. The main test variables were the material type of the pen-binder, the angle of the hook, and the confining reinforcement configuration.The test results indicate that adding pen-binders can effectively improve the strength and ductility of the column specimens confined with a non-code compliant confining reinforcement

Pms2 suppresses large expansions of the (GAA·TTCn sequence in neuronal tissues.

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Rebecka L Bourn

Full Text Available Expanded trinucleotide repeat sequences are the cause of several inherited neurodegenerative diseases. Disease pathogenesis is correlated with several features of somatic instability of these sequences, including further large expansions in postmitotic tissues. The presence of somatic expansions in postmitotic tissues is consistent with DNA repair being a major determinant of somatic instability. Indeed, proteins in the mismatch repair (MMR pathway are required for instability of the expanded (CAG·CTG(n sequence, likely via recognition of intrastrand hairpins by MutSβ. It is not clear if or how MMR would affect instability of disease-causing expanded trinucleotide repeat sequences that adopt secondary structures other than hairpins, such as the triplex/R-loop forming (GAA·TTC(n sequence that causes Friedreich ataxia. We analyzed somatic instability in transgenic mice that carry an expanded (GAA·TTC(n sequence in the context of the human FXN locus and lack the individual MMR proteins Msh2, Msh6 or Pms2. The absence of Msh2 or Msh6 resulted in a dramatic reduction in somatic mutations, indicating that mammalian MMR promotes instability of the (GAA·TTC(n sequence via MutSα. The absence of Pms2 resulted in increased accumulation of large expansions in the nervous system (cerebellum, cerebrum, and dorsal root ganglia but not in non-neuronal tissues (heart and kidney, without affecting the prevalence of contractions. Pms2 suppressed large expansions specifically in tissues showing MutSα-dependent somatic instability, suggesting that they may act on the same lesion or structure associated with the expanded (GAA·TTC(n sequence. We conclude that Pms2 specifically suppresses large expansions of a pathogenic trinucleotide repeat sequence in neuronal tissues, possibly acting independently of the canonical MMR pathway.

Investigation of a Quadruplex-Forming Repeat Sequence Highly Enriched in Xanthomonas and Nostoc sp.

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Charlotte Rehm

Full Text Available In prokaryotes simple sequence repeats (SSRs with unit sizes of 1-5 nucleotides (nt are causative for phase and antigenic variation. Although an increased abundance of heptameric repeats was noticed in bacteria, reports about SSRs of 6-9 nt are rare. In particular G-rich repeat sequences with the propensity to fold into G-quadruplex (G4 structures have received little attention. In silico analysis of prokaryotic genomes show putative G4 forming sequences to be abundant. This report focuses on a surprisingly enriched G-rich repeat of the type GGGNATC in Xanthomonas and cyanobacteria such as Nostoc. We studied in detail the genomes of Xanthomonas campestris pv. campestris ATCC 33913 (Xcc, Xanthomonas axonopodis pv. citri str. 306 (Xac, and Nostoc sp. strain PCC7120 (Ana. In all three organisms repeats are spread all over the genome with an over-representation in non-coding regions. Extensive variation of the number of repetitive units was observed with repeat numbers ranging from two up to 26 units. However a clear preference for four units was detected. The strong bias for four units coincides with the requirement of four consecutive G-tracts for G4 formation. Evidence for G4 formation of the consensus repeat sequences was found in biophysical studies utilizing CD spectroscopy. The G-rich repeats are preferably located between aligned open reading frames (ORFs and are under-represented in coding regions or between divergent ORFs. The G-rich repeats are preferentially located within a distance of 50 bp upstream of an ORF on the anti-sense strand or within 50 bp from the stop codon on the sense strand. Analysis of whole transcriptome sequence data showed that the majority of repeat sequences are transcribed. The genetic loci in the vicinity of repeat regions show increased genomic stability. In conclusion, we introduce and characterize a special class of highly abundant and wide-spread quadruplex-forming repeat sequences in bacteria.

Investigation of a Quadruplex-Forming Repeat Sequence Highly Enriched in Xanthomonas and Nostoc sp.

Science.gov (United States)

Rehm, Charlotte; Wurmthaler, Lena A; Li, Yuanhao; Frickey, Tancred; Hartig, Jörg S

2015-01-01

In prokaryotes simple sequence repeats (SSRs) with unit sizes of 1-5 nucleotides (nt) are causative for phase and antigenic variation. Although an increased abundance of heptameric repeats was noticed in bacteria, reports about SSRs of 6-9 nt are rare. In particular G-rich repeat sequences with the propensity to fold into G-quadruplex (G4) structures have received little attention. In silico analysis of prokaryotic genomes show putative G4 forming sequences to be abundant. This report focuses on a surprisingly enriched G-rich repeat of the type GGGNATC in Xanthomonas and cyanobacteria such as Nostoc. We studied in detail the genomes of Xanthomonas campestris pv. campestris ATCC 33913 (Xcc), Xanthomonas axonopodis pv. citri str. 306 (Xac), and Nostoc sp. strain PCC7120 (Ana). In all three organisms repeats are spread all over the genome with an over-representation in non-coding regions. Extensive variation of the number of repetitive units was observed with repeat numbers ranging from two up to 26 units. However a clear preference for four units was detected. The strong bias for four units coincides with the requirement of four consecutive G-tracts for G4 formation. Evidence for G4 formation of the consensus repeat sequences was found in biophysical studies utilizing CD spectroscopy. The G-rich repeats are preferably located between aligned open reading frames (ORFs) and are under-represented in coding regions or between divergent ORFs. The G-rich repeats are preferentially located within a distance of 50 bp upstream of an ORF on the anti-sense strand or within 50 bp from the stop codon on the sense strand. Analysis of whole transcriptome sequence data showed that the majority of repeat sequences are transcribed. The genetic loci in the vicinity of repeat regions show increased genomic stability. In conclusion, we introduce and characterize a special class of highly abundant and wide-spread quadruplex-forming repeat sequences in bacteria.

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

Science.gov (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

2012-01-01

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

Identification and characterization of long intergenic noncoding RNAs in bovine mammary glands.

Science.gov (United States)

Tong, Chao; Chen, Qiaoling; Zhao, Lili; Ma, Junfei; Ibeagha-Awemu, Eveline M; Zhao, Xin

2017-06-19

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.

Properties of non-coding DNA and identification of putative cis-regulatory elements in Theileria parva

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Guo Xiang

2008-12-01

Full Text Available Abstract Background Parasites in the genus Theileria cause lymphoproliferative diseases in cattle, resulting in enormous socio-economic losses. The availability of the genome sequences and annotation for T. parva and T. annulata has facilitated the study of parasite biology and their relationship with host cell transformation and tropism. However, the mechanism of transcriptional regulation in this genus, which may be key to understanding fundamental aspects of its parasitology, remains poorly understood. In this study, we analyze the evolution of non-coding sequences in the Theileria genome and identify conserved sequence elements that may be involved in gene regulation of these parasitic species. Results Intergenic regions and introns in Theileria are short, and their length distributions are considerably right-skewed. Intergenic regions flanked by genes in 5'-5' orientation tend to be longer and slightly more AT-rich than those flanked by two stop codons; intergenic regions flanked by genes in 3'-5' orientation have intermediate values of length and AT composition. Intron position is negatively correlated with intron length, and positively correlated with GC content. Using stringent criteria, we identified a set of high-quality orthologous non-coding sequences between T. parva and T. annulata, and determined the distribution of selective constraints across regions, which are shown to be higher close to translation start sites. A positive correlation between constraint and length in both intergenic regions and introns suggests a tight control over length expansion of non-coding regions. Genome-wide searches for functional elements revealed several conserved motifs in intergenic regions of Theileria genomes. Two such motifs are preferentially located within the first 60 base pairs upstream of transcription start sites in T. parva, are preferentially associated with specific protein functional categories, and have significant similarity to know

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

2016-01-01

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...

An expanding universe of the non-coding genome in cancer biology.

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Xue, Bin; He, Lin

2014-06-01

Neoplastic transformation is caused by accumulation of genetic and epigenetic alterations that ultimately convert normal cells into tumor cells with uncontrolled proliferation and survival, unlimited replicative potential and invasive growth [Hanahan,D. et al. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646-674]. Although the majority of the cancer studies have focused on the functions of protein-coding genes, emerging evidence has started to reveal the importance of the vast non-coding genome, which constitutes more than 98% of the human genome. A number of non-coding RNAs (ncRNAs) derived from the 'dark matter' of the human genome exhibit cancer-specific differential expression and/or genomic alterations, and it is increasingly clear that ncRNAs, including small ncRNAs and long ncRNAs (lncRNAs), play an important role in cancer development by regulating protein-coding gene expression through diverse mechanisms. In addition to ncRNAs, nearly half of the mammalian genomes consist of transposable elements, particularly retrotransposons. Once depicted as selfish genomic parasites that propagate at the expense of host fitness, retrotransposon elements could also confer regulatory complexity to the host genomes during development and disease. Reactivation of retrotransposons in cancer, while capable of causing insertional mutagenesis and genome rearrangements to promote oncogenesis, could also alter host gene expression networks to favor tumor development. Taken together, the functional significance of non-coding genome in tumorigenesis has been previously underestimated, and diverse transcripts derived from the non-coding genome could act as integral functional components of the oncogene and tumor suppressor network. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

ATXN2 trinucleotide repeat length correlates with risk of ALS

NARCIS (Netherlands)

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 W; Rademakers, Rosa; Robberecht, Wim; Rouleau, Guy A.; 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

2017-01-01

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

Non-radioactive detection of trinucleotide repeat size variability.

Science.gov (United States)

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

2014-03-06

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.

The role of retrotransposons in gene family expansions: insights from the mouse Abp gene family.

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Janoušek, Václav; Karn, Robert C; Laukaitis, Christina M

2013-05-29

Retrotransposons have been suggested to provide a substrate for non-allelic homologous recombination (NAHR) and thereby promote gene family expansion. Their precise role, however, is controversial. Here we ask whether retrotransposons contributed to the recent expansions of the Androgen-binding protein (Abp) gene families that occurred independently in the mouse and rat genomes. Using dot plot analysis, we found that the most recent duplication in the Abp region of the mouse genome is flanked by L1Md_T elements. Analysis of the sequence of these elements revealed breakpoints that are the relicts of the recombination that caused the duplication, confirming that the duplication arose as a result of NAHR using L1 elements as substrates. L1 and ERVII retrotransposons are considerably denser in the Abp regions than in one Mb flanking regions, while other repeat types are depleted in the Abp regions compared to flanking regions. L1 retrotransposons preferentially accumulated in the Abp gene regions after lineage separation and roughly followed the pattern of Abp gene expansion. By contrast, the proportion of shared vs. lineage-specific ERVII repeats in the Abp region resembles the rest of the genome. We confirmed the role of L1 repeats in Abp gene duplication with the identification of recombinant L1Md_T elements at the edges of the most recent mouse Abp gene duplication. High densities of L1 and ERVII repeats were found in the Abp gene region with abrupt transitions at the region boundaries, suggesting that their higher densities are tightly associated with Abp gene duplication. We observed that the major accumulation of L1 elements occurred after the split of the mouse and rat lineages and that there is a striking overlap between the timing of L1 accumulation and expansion of the Abp gene family in the mouse genome. Establishing a link between the accumulation of L1 elements and the expansion of the Abp gene family and identification of an NAHR-related breakpoint in

Non-coding RNAs and epigenome: de novo DNA methylation, allelic exclusion and X-inactivation

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V. A. Halytskiy

2013-12-01

Full Text Available Non-coding RNAs are widespread class of cell RNAs. They participate in many important processes in cells – signaling, posttranscriptional silencing, protein biosynthesis, splicing, maintenance of genome stability, telomere lengthening, X-inactivation. Nevertheless, activity of these RNAs is not restricted to posttranscriptional sphere, but cover also processes that change or maintain the epigenetic information. Non-coding RNAs can directly bind to the DNA targets and cause their repression through recruitment of DNA methyltransferases as well as chromatin modifying enzymes. Such events constitute molecular mechanism of the RNA-dependent DNA methylation. It is possible, that the RNA-DNA interaction is universal mechanism triggering DNA methylation de novo. Allelic exclusion can be also based on described mechanism. This phenomenon takes place, when non-coding RNA, which precursor is transcribed from one allele, triggers DNA methylation in all other alleles present in the cell. Note, that miRNA-mediated transcriptional silencing resembles allelic exclusion, because both miRNA gene and genes, which can be targeted by this miRNA, contain elements with the same sequences. It can be assumed that RNA-dependent DNA methylation and allelic exclusion originated with the purpose of counteracting the activity of mobile genetic elements. Probably, thinning and deregulation of the cellular non-coding RNA pattern allows reactivation of silent mobile genetic elements resulting in genome instability that leads to ageing and carcinogenesis. In the course of X-inactivation, DNA methylation and subsequent hete­rochromatinization of X chromosome can be triggered by direct hybridization of 5′-end of large non-coding RNA Xist with DNA targets in remote regions of the X chromosome.

Highly conserved non-coding sequences are associated with vertebrate development.

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Adam Woolfe

2005-01-01

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

JPH3 Repeat Expansions Cause a Progressive Akinetic-Rigid Syndrome with Severe Dementia and Putaminal Rim in a Five-Generation African-American Family

Science.gov (United States)

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

2012-01-01

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

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

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Singh Nagendra

2009-03-01

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

Cigarette smoke exposure-associated alterations to noncoding RNA

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Matthew Alan Maccani

2012-04-01

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

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

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Agathi-Vasiliki Goula

2013-07-01

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.

Pms2 suppresses large expansions of the (GAA·TTC)n sequence in neuronal tissues.

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Bourn, Rebecka L; De Biase, Irene; Pinto, Ricardo Mouro; Sandi, Chiranjeevi; Al-Mahdawi, Sahar; Pook, Mark A; Bidichandani, Sanjay I

2012-01-01

Expanded trinucleotide repeat sequences are the cause of several inherited neurodegenerative diseases. Disease pathogenesis is correlated with several features of somatic instability of these sequences, including further large expansions in postmitotic tissues. The presence of somatic expansions in postmitotic tissues is consistent with DNA repair being a major determinant of somatic instability. Indeed, proteins in the mismatch repair (MMR) pathway are required for instability of the expanded (CAG·CTG)(n) sequence, likely via recognition of intrastrand hairpins by MutSβ. It is not clear if or how MMR would affect instability of disease-causing expanded trinucleotide repeat sequences that adopt secondary structures other than hairpins, such as the triplex/R-loop forming (GAA·TTC)(n) sequence that causes Friedreich ataxia. We analyzed somatic instability in transgenic mice that carry an expanded (GAA·TTC)(n) sequence in the context of the human FXN locus and lack the individual MMR proteins Msh2, Msh6 or Pms2. The absence of Msh2 or Msh6 resulted in a dramatic reduction in somatic mutations, indicating that mammalian MMR promotes instability of the (GAA·TTC)(n) sequence via MutSα. The absence of Pms2 resulted in increased accumulation of large expansions in the nervous system (cerebellum, cerebrum, and dorsal root ganglia) but not in non-neuronal tissues (heart and kidney), without affecting the prevalence of contractions. Pms2 suppressed large expansions specifically in tissues showing MutSα-dependent somatic instability, suggesting that they may act on the same lesion or structure associated with the expanded (GAA·TTC)(n) sequence. We conclude that Pms2 specifically suppresses large expansions of a pathogenic trinucleotide repeat sequence in neuronal tissues, possibly acting independently of the canonical MMR pathway.

ncRNA-class Web Tool: Non-coding RNA feature extraction and pre-miRNA classification web tool

KAUST Repository

Kleftogiannis, Dimitrios A.; Theofilatos, Konstantinos A.; Papadimitriou, Stergios; Tsakalidis, Athanasios K.; Likothanassis, Spiridon D.; Mavroudi, Seferina P.

2012-01-01

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 ( http://150.140.142.24:82/Default.aspx ) 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.

Long Non-Coding RNA in Cancer

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Damjan Glavač

2013-02-01

Full Text Available Long non-coding RNAs (lncRNAs are pervasively transcribed in the genome and are emerging as new players in tumorigenesis due to their various functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. LncRNAs are deregulated in a number of cancers, demonstrating both oncogenic and tumor suppressive roles, thus suggesting their aberrant expression may be a substantial contributor in cancer development. In this review, we will summarize their emerging role in human cancer and discuss their perspectives in diagnostics as potential biomarkers.

Nezha, a novel active miniature inverted-repeat transposable element in cyanobacteria

International Nuclear Information System (INIS)

Zhou Fengfeng; Tran Thao; Xu Ying

2008-01-01

Miniature inverted-repeat transposable elements (MITEs) were first identified in plants and exerted extensive proliferations throughout eukaryotic and archaeal genomes. But very few MITEs have been characterized in bacteria. We identified a novel MITE, called Nezha, in cyanobacteria Anabaena variabilis ATCC 29413 and Nostoc sp. PCC 7120. Nezha, like most previously known MITEs in other organisms, is small in size, non-coding, carrying TIR and DR signals, and of potential to form a stable RNA secondary structure, and it tends to insert into A+T-rich regions. Recent transpositions of Nezha were observed in A. variabilis ATCC 29413 and Nostoc sp. PCC 7120, respectively. Nezha might have proliferated recently with aid from the transposase encoded by ISNpu3-like elements. A possible horizontal transfer event of Nezha from cyanobacteria to Polaromonas JS666 is also observed

nRC: non-coding RNA Classifier based on structural features.

Science.gov (United States)

Fiannaca, Antonino; La Rosa, Massimo; La Paglia, Laura; Rizzo, Riccardo; Urso, Alfonso

2017-01-01

Non-coding RNA (ncRNA) are small non-coding sequences involved in gene expression regulation of many biological processes and diseases. The recent discovery of a large set of different ncRNAs with biologically relevant roles has opened the way to develop methods able to discriminate between the different ncRNA classes. Moreover, the lack of knowledge about the complete mechanisms in regulative processes, together with the development of high-throughput technologies, has required the help of bioinformatics tools in addressing biologists and clinicians with a deeper comprehension of the functional roles of ncRNAs. In this work, we introduce a new ncRNA classification tool, nRC (non-coding RNA Classifier). Our approach is based on features extraction from the ncRNA secondary structure together with a supervised classification algorithm implementing a deep learning architecture based on convolutional neural networks. We tested our approach for the classification of 13 different ncRNA classes. We obtained classification scores, using the most common statistical measures. In particular, we reach an accuracy and sensitivity score of about 74%. The proposed method outperforms other similar classification methods based on secondary structure features and machine learning algorithms, including the RNAcon tool that, to date, is the reference classifier. nRC tool is freely available as a docker image at https://hub.docker.com/r/tblab/nrc/. The source code of nRC tool is also available at https://github.com/IcarPA-TBlab/nrc.

Therapeutic targeting of non-coding RNAs in cancer

Czech Academy of Sciences Publication Activity Database

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

2017-01-01

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

An expanding universe of noncoding RNAs.

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Storz, Gisela

2002-05-17

Noncoding RNAs (ncRNAs) have been found to have roles in a great variety of processes, including transcriptional regulation, chromosome replication, RNA processing and modification, messenger RNA stability and translation, and even protein degradation and translocation. Recent studies indicate that ncRNAs are far more abundant and important than initially imagined. These findings raise several fundamental questions: How many ncRNAs are encoded by a genome? Given the absence of a diagnostic open reading frame, how can these genes be identified? How can all the functions of ncRNAs be elucidated?

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

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Graner Andreas

2008-10-01

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

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain

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Marianne Goodwin

2015-08-01

Full Text Available For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNAexp. Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain, resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound-knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNAexp in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.

Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease

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Neal Scott J

2006-08-01

Full Text Available Abstract Background Many cases of frontotemporal dementia (FTD are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T. Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir, dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U. Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII. NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease. Methods We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63, including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available and with those of healthy controls (n = 94. High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats. For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract

Noncoding origins of anthropoid traits and a new null model of transposon functionalization.

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del Rosario, Ricardo C H; Rayan, Nirmala Arul; Prabhakar, Shyam

2014-09-01

Little is known about novel genetic elements that drove the emergence of anthropoid primates. We exploited the sequencing of the marmoset genome to identify 23,849 anthropoid-specific constrained (ASC) regions and confirmed their robust functional signatures. Of the ASC base pairs, 99.7% were noncoding, suggesting that novel anthropoid functional elements were overwhelmingly cis-regulatory. ASCs were highly enriched in loci associated with fetal brain development, motor coordination, neurotransmission, and vision, thus providing a large set of candidate elements for exploring the molecular basis of hallmark primate traits. We validated ASC192 as a primate-specific enhancer in proliferative zones of the developing brain. Unexpectedly, transposable elements (TEs) contributed to >56% of ASCs, and almost all TE families showed functional potential similar to that of nonrepetitive DNA. Three L1PA repeat-derived ASCs displayed coherent eye-enhancer function, thus demonstrating that the "gene-battery" model of TE functionalization applies to enhancers in vivo. Our study provides fundamental insights into genome evolution and the origins of anthropoid phenotypes and supports an elegantly simple new null model of TE exaptation. © 2014 del Rosario et al.; Published by Cold Spring Harbor Laboratory Press.

Identification of antisense long noncoding RNAs that function as SINEUPs in human cells.

Science.gov (United States)

Schein, Aleks; Zucchelli, Silvia; Kauppinen, Sakari; Gustincich, Stefano; Carninci, Piero

2016-09-20

Mammalian genomes encode numerous natural antisense long noncoding RNAs (lncRNAs) that regulate gene expression. Recently, an antisense lncRNA to mouse Ubiquitin carboxyl-terminal hydrolase L1 (Uchl1) was reported to increase UCHL1 protein synthesis, representing a new functional class of lncRNAs, designated as SINEUPs, for SINE element-containing translation UP-regulators. Here, we show that an antisense lncRNA to the human protein phosphatase 1 regulatory subunit 12A (PPP1R12A), named as R12A-AS1, which overlaps with the 5' UTR and first coding exon of the PPP1R12A mRNA, functions as a SINEUP, increasing PPP1R12A protein translation in human cells. The SINEUP activity depends on the aforementioned sense-antisense interaction and a free right Alu monomer repeat element at the 3' end of R12A-AS1. In addition, we identify another human antisense lncRNA with SINEUP activity. Our results demonstrate for the first time that human natural antisense lncRNAs can up-regulate protein translation, suggesting that endogenous SINEUPs may be widespread and present in many mammalian species.

Long noncoding RNAs responsive to Fusarium oxysporum infection in Arabidopsis thaliana.

Science.gov (United States)

Zhu, Qian-Hao; Stephen, Stuart; Taylor, Jennifer; Helliwell, Chris A; Wang, Ming-Bo

2014-01-01

Short noncoding RNAs have been demonstrated to play important roles in regulation of gene expression and stress responses, but the repertoire and functions of long noncoding RNAs (lncRNAs) remain largely unexplored, particularly in plants. To explore the role of lncRNAs in disease resistance, we used a strand-specific RNA-sequencing approach to identify lncRNAs responsive to Fusarium oxysporum infection in Arabidopsis thaliana. Antisense transcription was found in c. 20% of the annotated A. thaliana genes. Several noncoding natural antisense transcripts responsive to F. oxysporum infection were found in genes implicated in disease defense. While the majority of the novel transcriptionally active regions (TARs) were adjacent to annotated genes and could be an extension of the annotated transcripts, 159 novel intergenic TARs, including 20 F. oxysporum-responsive lncTARs, were identified. Ten F. oxysporum-induced lncTARs were functionally characterized using T-DNA insertion or RNA-interference knockdown lines, and five were demonstrated to be related to disease development. Promoter analysis suggests that some of the F. oxysporum-induced lncTARs are direct targets of transcription factor(s) responsive to pathogen attack. Our results demonstrated that strand-specific RNA sequencing is a powerful tool for uncovering hidden levels of transcriptome and that IncRNAs are important components of the antifungal networks in A. thaliana. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

Science.gov (United States)

Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

2015-12-04

Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

Dispersion Measure Variation of Repeating Fast Radio Burst Sources

Energy Technology Data Exchange (ETDEWEB)

Yang, Yuan-Pei; Zhang, Bing, E-mail: yypspore@gmail.com, E-mail: zhang@physics.unlv.edu [Kavli Institute for Astronomy and Astrophysics, Peking University, Beijing 100871 (China)

2017-09-20

The repeating fast radio burst (FRB) 121102 was recently localized in a dwarf galaxy at a cosmological distance. The dispersion measure (DM) derived for each burst from FRB 121102 so far has not shown significant evolution, even though an apparent increase was recently seen with newly detected VLA bursts. It is expected that more repeating FRB sources may be detected in the future. In this work, we investigate a list of possible astrophysical processes that might cause DM variation of a particular FRB source. The processes include (1) cosmological scale effects such as Hubble expansion and large-scale structure fluctuations; (2) FRB local effects such as gas density fluctuation, expansion of a supernova remnant (SNR), a pulsar wind nebula, and an H ii region; and (3) the propagation effect due to plasma lensing. We find that the DM variations contributed by the large-scale structure are extremely small, and any observable DM variation is likely caused by the plasma local to the FRB source. In addition to mechanisms that decrease DM over time, we suggest that an FRB source in an expanding SNR around a nearly neutral ambient medium during the deceleration (Sedov–Taylor and snowplow) phases or in a growing H ii region can increase DM. Some effects (e.g., an FRB source moving in an H ii region or plasma lensing) can produce either positive or negative DM variations. Future observations of DM variations of FRB 121102 and other repeating FRB sources can provide important clues regarding the physical origin of these sources.

Dispersion Measure Variation of Repeating Fast Radio Burst Sources

International Nuclear Information System (INIS)

Yang, Yuan-Pei; Zhang, Bing

2017-01-01

The repeating fast radio burst (FRB) 121102 was recently localized in a dwarf galaxy at a cosmological distance. The dispersion measure (DM) derived for each burst from FRB 121102 so far has not shown significant evolution, even though an apparent increase was recently seen with newly detected VLA bursts. It is expected that more repeating FRB sources may be detected in the future. In this work, we investigate a list of possible astrophysical processes that might cause DM variation of a particular FRB source. The processes include (1) cosmological scale effects such as Hubble expansion and large-scale structure fluctuations; (2) FRB local effects such as gas density fluctuation, expansion of a supernova remnant (SNR), a pulsar wind nebula, and an H ii region; and (3) the propagation effect due to plasma lensing. We find that the DM variations contributed by the large-scale structure are extremely small, and any observable DM variation is likely caused by the plasma local to the FRB source. In addition to mechanisms that decrease DM over time, we suggest that an FRB source in an expanding SNR around a nearly neutral ambient medium during the deceleration (Sedov–Taylor and snowplow) phases or in a growing H ii region can increase DM. Some effects (e.g., an FRB source moving in an H ii region or plasma lensing) can produce either positive or negative DM variations. Future observations of DM variations of FRB 121102 and other repeating FRB sources can provide important clues regarding the physical origin of these sources.

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

2002-01-01

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

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

2003-01-01

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

Expression of a novel non-coding mitochondrial RNA in human proliferating cells.

Science.gov (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

2007-01-01

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.

IW-Scoring: an Integrative Weighted Scoring framework for annotating and prioritizing genetic variations in the noncoding genome.

Science.gov (United States)

Wang, Jun; Dayem Ullah, Abu Z; Chelala, Claude

2018-01-30

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 http://www.snp-nexus.org/IW-Scoring/. © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

Repeat Sequence Proteins as Matrices for Nanocomposites

Energy Technology Data Exchange (ETDEWEB)

Drummy, L.; Koerner, H; Phillips, D; McAuliffe, J; Kumar, M; Farmer, B; Vaia, R; Naik, R

2009-01-01

Recombinant protein-inorganic nanocomposites comprised of exfoliated Na+ montmorillonite (MMT) in a recombinant protein matrix based on silk-like and elastin-like amino acid motifs (silk elastin-like protein (SELP)) were formed via a solution blending process. Charged residues along the protein backbone are shown to dominate long-range interactions, whereas the SELP repeat sequence leads to local protein/MMT compatibility. Up to a 50% increase in room temperature modulus and a comparable decrease in high temperature coefficient of thermal expansion occur for cast films containing 2-10 wt.% MMT.

Hominoid-specific de novo protein-coding genes originating from long non-coding RNAs.

Directory of Open Access Journals (Sweden)

Chen Xie

2012-09-01

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.

Fabrication of two-dimensional nanosheets via water freezing expansion exfoliation

International Nuclear Information System (INIS)

Li, Chen; Wang, Tailin; Wu, Yongzhong; Ma, Fukun; Zhao, Gang; Hao, Xiaopeng

2014-01-01

Layered materials, if exfoliated effectively, will exhibit several unique properties, offering great potential for diverse applications. To this end, in this study, we develop a novel, universal, and environmentally friendly method named as ‘water freezing expansion exfoliation’ for producing two-dimensional nanosheets. This method exploits the expansion in the volume of water upon freezing. When the water freezing expansion condition is reproduced in layered materials, the layers exfoliate to overcome the van der Waals force between them. The expansion process is performed by repeated cycling between 4 °C and −20 °C to effectively exfoliate layered materials of graphite, hexagonal boron nitride (h-BN), MoS 2 and WS 2 . Systematic characterization of the samples thus obtained using electron microscopy and optical studies substantiate the formation of thin flakes (graphene, h-BN, MoS 2 , and WS 2 nanosheets). The method demonstrated in this study is cost-effective and does not demand sophisticated equipment and stringent high temperature conditions. Given this general applicability, this method holds great promise for exfoliating layered materials that are sensitive to elevated temperature. (paper)

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

Science.gov (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

2016-01-01

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: http://purl.obolibrary.org/obo/ncro.owl.

Estradiol-Induced Transcriptional Regulation of Long Non-Coding RNA, HOTAIR.

Science.gov (United States)

Bhan, Arunoday; Mandal, Subhrangsu S

2016-01-01

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.

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

2011-01-01

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.

Dynamic Epigenetic Control of Highly Conserved Noncoding Elements

KAUST Repository

Seridi, Loqmane

2014-10-07

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.

Dynamic Epigenetic Control of Highly Conserved Noncoding Elements

KAUST Repository

Seridi, Loqmane; Ryu, Tae Woo; Ravasi, Timothy

2014-01-01

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.

RNA FISH for detecting expanded repeats in human diseases.

Science.gov (United States)

Urbanek, Martyna O; Krzyzosiak, Wlodzimierz J

2016-04-01

RNA fluorescence in situ hybridization (FISH) is a widely used technique for detecting transcripts in fixed cells and tissues. Many variants of RNA FISH have been proposed to increase signal strength, resolution and target specificity. The current variants of this technique facilitate the detection of the subcellular localization of transcripts at a single molecule level. Among the applications of RNA FISH are studies on nuclear RNA foci in diseases resulting from the expansion of tri-, tetra-, penta- and hexanucleotide repeats present in different single genes. The partial or complete retention of mutant transcripts forming RNA aggregates within the nucleoplasm has been shown in multiple cellular disease models and in the tissues of patients affected with these atypical mutations. Relevant diseases include, among others, myotonic dystrophy type 1 (DM1) with CUG repeats, Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) with CAG repeats, fragile X-associated tremor/ataxia syndrome (FXTAS) with CGG repeats, myotonic dystrophy type 2 (DM2) with CCUG repeats, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) with GGGGCC repeats and spinocerebellar ataxia type 32 (SCA32) with GGCCUG. In this article, we summarize the results obtained with FISH to examine RNA nuclear inclusions. We provide a detailed protocol for detecting RNAs containing expanded CAG and CUG repeats in different cellular models, including fibroblasts, lymphoblasts, induced pluripotent stem cells and murine and human neuronal progenitors. We also present the results of the first single-molecule FISH application in a cellular model of polyglutamine disease. Copyright © 2015 Elsevier Inc. All rights reserved.

An integrative approach to predicting the functional effects of small indels in non-coding regions of the human genome.

Science.gov (United States)

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

2017-10-06

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 indels.biocompute.org.uk. FATHMM-indel can accurately predict the functional impact and prioritise small indels throughout the whole non-coding genome.

In situ optical sequencing and structure analysis of a trinucleotide repeat genome region by localization microscopy after specific COMBO-FISH nano-probing

Science.gov (United States)

Stuhlmüller, M.; Schwarz-Finsterle, J.; Fey, E.; Lux, J.; Bach, M.; Cremer, C.; Hinderhofer, K.; Hausmann, M.; Hildenbrand, G.

2015-10-01

Trinucleotide repeat expansions (like (CGG)n) of chromatin in the genome of cell nuclei can cause neurological disorders such as for example the Fragile-X syndrome. Until now the mechanisms are not clearly understood as to how these expansions develop during cell proliferation. Therefore in situ investigations of chromatin structures on the nanoscale are required to better understand supra-molecular mechanisms on the single cell level. By super-resolution localization microscopy (Spectral Position Determination Microscopy; SPDM) in combination with nano-probing using COMBO-FISH (COMBinatorial Oligonucleotide FISH), novel insights into the nano-architecture of the genome will become possible. The native spatial structure of trinucleotide repeat expansion genome regions was analysed and optical sequencing of repetitive units was performed within 3D-conserved nuclei using SPDM after COMBO-FISH. We analysed a (CGG)n-expansion region inside the 5' untranslated region of the FMR1 gene. The number of CGG repeats for a full mutation causing the Fragile-X syndrome was found and also verified by Southern blot. The FMR1 promotor region was similarly condensed like a centromeric region whereas the arrangement of the probes labelling the expansion region seemed to indicate a loop-like nano-structure. These results for the first time demonstrate that in situ chromatin structure measurements on the nanoscale are feasible. Due to further methodological progress it will become possible to estimate the state of trinucleotide repeat mutations in detail and to determine the associated chromatin strand structural changes on the single cell level. In general, the application of the described approach to any genome region will lead to new insights into genome nano-architecture and open new avenues for understanding mechanisms and their relevance in the development of heredity diseases.

Targeting Non-Coding RNAs in Plants with the CRISPR-Cas Technology is a Challenge yet Worth Accepting.

Science.gov (United States)

Basak, Jolly; Nithin, Chandran

2015-01-01

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.

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

2015-11-01

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.

Circadian changes in long noncoding RNAs in the pineal gland

DEFF Research Database (Denmark)

Coon, Steven L; Munson, Peter J; Cherukuri, Praveen F

2012-01-01

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 ra...

Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse

Directory of Open Access Journals (Sweden)

Lu Lu

2010-11-01

Full Text Available Abstract Background Sexual dimorphism in brain gene expression has been recognized in several animal species. However, the relevant regulatory mechanisms remain poorly understood. To investigate whether sex-biased gene expression in mammalian brain is globally regulated or locally regulated in diverse brain structures, and to study the genomic organisation of brain-expressed sex-biased genes, we performed a large scale gene expression analysis of distinct brain regions in adult male and female mice. Results This study revealed spatial specificity in sex-biased transcription in the mouse brain, and identified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampus and 31 in the eye. Genes located on sex chromosomes were consistently over-represented in all brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealed Y-encoded male-biased transcripts and X-encoded female-biased transcripts known to escape X-inactivation. In addition, we identified novel coding and non-coding X-linked genes with female-biased expression in multiple tissues. Interestingly, the chromosomal positions of all of the female-biased non-coding genes are in close proximity to protein-coding genes that escape X-inactivation. This defines X-chromosome domains each of which contains a coding and a non-coding female-biased gene. Lack of repressive chromatin marks in non-coding transcribed loci supports the possibility that they escape X-inactivation. Moreover, RNA-DNA combined FISH experiments confirmed the biallelic expression of one such novel domain. Conclusion This study demonstrated that the amount of genes with sex-biased expression varies between individual brain regions in mouse. The sex-biased genes identified are localized on many chromosomes. At the same time, sexually dimorphic gene expression that is common to several parts of the brain is mostly restricted to the sex chromosomes. Moreover, the study uncovered

C9orf72 nucleotide repeat structures initiate molecular cascades of disease.

Science.gov (United States)

Haeusler, Aaron R; Donnelly, Christopher J; Periz, Goran; Simko, Eric A J; Shaw, Patrick G; Kim, Min-Sik; Maragakis, Nicholas J; Troncoso, Juan C; Pandey, Akhilesh; Sattler, Rita; Rothstein, Jeffrey D; Wang, Jiou

2014-03-13

A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.

Comprehensive reconstruction andvisualization of non-coding regulatorynetworks in human

Directory of Open Access Journals (Sweden)

Vincenzo eBonnici

2014-12-01

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 http://ncrnadb.scienze.univr.it/ncrnadb/. 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.

Long noncoding RNAs: Undeciphered cellular codes encrypting keys of colorectal cancer pathogenesis

Science.gov (United States)

Kim, Taewan; Croce, Carlo M.

2018-01-01

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

Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics.

Science.gov (United States)

Gussow, Ayal B; Copeland, Brett R; Dhindsa, Ryan S; Wang, Quanli; Petrovski, Slavé; Majoros, William H; Allen, Andrew S; Goldstein, David B

2017-01-01

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.

Methods for Using Small Non-Coding RNAs to Improve Recombinant Protein Expression in Mammalian Cells

Directory of Open Access Journals (Sweden)

Sarah Inwood

2018-01-01

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.

The emerging role of non-coding RNAs in drug addiction

Directory of Open Access Journals (Sweden)

Gregory Charles Sartor

2012-06-01

Full Text Available Prolonged drug use causes long-lasting neuroadaptations in reward-related brain areas that contribute to addiction. Despite significant amount of research dedicated to understanding the underlying mechanisms of addiction, the molecular underpinnings remain unclear. At the same time, much of the pervasive transcription that encompasses the human genome occurs in the nervous system and contributes to its heterogeneity and complexity. Recent evidence suggests that non-coding RNAs (ncRNAs play an important and dynamic role in transcriptional regulation, epigenetic signaling, stress response, and plasticity in the nervous system. Dysregulation of ncRNAs are thought to contribute to many, and perhaps all, neurological disorders, including addiction. Here, we review recent insights in the functional relevance of ncRNAs, including both microRNAs (miRNAs and long non-coding RNAs (lncRNAs, and then illustrate specific examples of ncRNA regulation in the context of drug addiction. We conclude that ncRNAs are importantly involved in the persistent neuroadaptations associated with addiction-related behaviors, and that therapies that target specific ncRNAs may represent new avenues for the treatment of drug addiction.

The roles of non-coding RNAs in cardiac regenerative medicine

Directory of Open Access Journals (Sweden)

Oi Kuan Choong

2017-06-01

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

Non-coding RNAs and heme oxygenase-1 in vaccinia virus infection

International Nuclear Information System (INIS)

Meseda, Clement A.; Srinivasan, Kumar; Wise, Jasen; Catalano, Jennifer; Yamada, Kenneth M.; Dhawan, Subhash

2014-01-01

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

Comprehensive discovery of noncoding RNAs in acute myeloid leukemia cell transcriptomes.

Science.gov (United States)

Zhang, Jin; Griffith, Malachi; Miller, Christopher A; Griffith, Obi L; Spencer, David H; Walker, Jason R; Magrini, Vincent; McGrath, Sean D; Ly, Amy; Helton, Nichole M; Trissal, Maria; Link, Daniel C; Dang, Ha X; Larson, David E; Kulkarni, Shashikant; Cordes, Matthew G; Fronick, Catrina C; Fulton, Robert S; Klco, Jeffery M; Mardis, Elaine R; Ley, Timothy J; Wilson, Richard K; Maher, Christopher A

2017-11-01

To detect diverse and novel RNA species comprehensively, we compared deep small RNA and RNA sequencing (RNA-seq) methods applied to a primary acute myeloid leukemia (AML) sample. We were able to discover previously unannotated small RNAs using deep sequencing of a library method using broader insert size selection. We analyzed the long noncoding RNA (lncRNA) landscape in AML by comparing deep sequencing from multiple RNA-seq library construction methods for the sample that we studied and then integrating RNA-seq data from 179 AML cases. This identified lncRNAs that are completely novel, differentially expressed, and associated with specific AML subtypes. Our study revealed the complexity of the noncoding RNA transcriptome through a combined strategy of strand-specific small RNA and total RNA-seq. This dataset will serve as an invaluable resource for future RNA-based analyses. Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

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 ...

Huntingtin gene repeat size variations affect risk of lifetime depression.

Science.gov (United States)

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; Oude Voshaar, Richard C; Roos, Raymund A C; Comijs, Hannie C; Penninx, Brenda W J H; van der Mast, Roos C; Aziz, N Ahmad

2017-12-11

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 depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = -0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression.

Functional long non-coding RNA transcription in Schizosaccharomyces pombe

OpenAIRE

Ard, Ryan Anthony

2016-01-01

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...

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

1994-09-01

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.

CONDOR: a database resource of developmentally associated conserved non-coding elements

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Smith Sarah

2007-08-01

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: http://condor.fugu.biology.qmul.ac.uk. 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.

The diversity and evolution of Wolbachia ankyrin repeat domain genes.

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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.

CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression

DEFF Research Database (Denmark)

Zaghloul, Eman M; Gissberg, Olof; Moreno, Pedro M D

2017-01-01

Huntington's disease (HD) is a fatal, neurodegenerative disorder in which patients suffer from mobility, psychological and cognitive impairments. Existing therapeutics are only symptomatic and do not significantly alter the disease progression or increase life expectancy. HD is caused by expansion....... Thus, reduction of both muHTT mRNA and protein levels would ideally be the most useful therapeutic option. We herein present a novel strategy for HD treatment using oligonucleotides (ONs) directly targeting the HTT trinucleotide repeat DNA. A partial, but significant and potentially long-term, HTT...

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.

2015-01-01

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

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)

1996-02-16

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.

Non-coding, mRNA-like RNAs database Y2K.

Science.gov (United States)

Erdmann, V A; Szymanski, M; Hochberg, A; Groot, N; Barciszewski, J

2000-01-01

In last few years much data has accumulated on various non-translatable RNA transcripts that are synthesised in different cells. They are lacking in protein coding capacity and it seems that they work mainly or exclusively at the RNA level. All known non-coding RNA transcripts are collected in the database: http://www. man.poznan.pl/5SData/ncRNA/index.html

Complete plastid genome sequencing of Trochodendraceae reveals a significant expansion of the inverted repeat and suggests a Paleogene divergence between the two extant species.

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Yan-xia Sun

Full Text Available The early-diverging eudicot order Trochodendrales contains only two monospecific genera, Tetracentron and Trochodendron. Although an extensive fossil record indicates that the clade is perhaps 100 million years old and was widespread throughout the Northern Hemisphere during the Paleogene and Neogene, the two extant genera are both narrowly distributed in eastern Asia. Recent phylogenetic analyses strongly support a clade of Trochodendrales, Buxales, and Gunneridae (core eudicots, but complete plastome analyses do not resolve the relationships among these groups with strong support. However, plastid phylogenomic analyses have not included data for Tetracentron. To better resolve basal eudicot relationships and to clarify when the two extant genera of Trochodendrales diverged, we sequenced the complete plastid genome of Tetracentron sinense using Illumina technology. The Tetracentron and Trochodendron plastomes possess the typical gene content and arrangement that characterize most angiosperm plastid genomes, but both genomes have the same unusual ∼4 kb expansion of the inverted repeat region to include five genes (rpl22, rps3, rpl16, rpl14, and rps8 that are normally found in the large single-copy region. Maximum likelihood analyses of an 83-gene, 88 taxon angiosperm data set yield an identical tree topology as previous plastid-based trees, and moderately support the sister relationship between Buxaceae and Gunneridae. Molecular dating analyses suggest that Tetracentron and Trochodendron diverged between 44-30 million years ago, which is congruent with the fossil record of Trochodendrales and with previous estimates of the divergence time of these two taxa. We also characterize 154 simple sequence repeat loci from the Tetracentron sinense and Trochodendron aralioides plastomes that will be useful in future studies of population genetic structure for these relict species, both of which are of conservation concern.

Unusual structures are present in DNA fragments containing super-long Huntingtin CAG repeats.

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Daniel Duzdevich

2011-02-01

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.

The noncoding-RNA landscape in cardiovascular health and disease

OpenAIRE

Vittoria Di Mauro; Maria Barandalla-Sobrados; Daniele Catalucci

2018-01-01

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 (ncRNA...

The Non-Coding Regulatory RNA Revolution in Archaea

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Diego Rivera Gelsinger

2018-03-01

Full Text Available Small non-coding RNAs (sRNAs are ubiquitously found in the three domains of life playing large-scale roles in gene regulation, transposable element silencing and defense against foreign elements. While a substantial body of experimental work has been done to uncover function of sRNAs in Bacteria and Eukarya, the functional roles of sRNAs in Archaea are still poorly understood. Recently, high throughput studies using RNA-sequencing revealed that sRNAs are broadly expressed in the Archaea, comprising thousands of transcripts within the transcriptome during non-challenged and stressed conditions. Antisense sRNAs, which overlap a portion of a gene on the opposite strand (cis-acting, are the most abundantly expressed non-coding RNAs and they can be classified based on their binding patterns to mRNAs (3′ untranslated region (UTR, 5′ UTR, CDS-binding. These antisense sRNAs target many genes and pathways, suggesting extensive roles in gene regulation. Intergenic sRNAs are less abundantly expressed and their targets are difficult to find because of a lack of complete overlap between sRNAs and target mRNAs (trans-acting. While many sRNAs have been validated experimentally, a regulatory role has only been reported for very few of them. Further work is needed to elucidate sRNA-RNA binding mechanisms, the molecular determinants of sRNA-mediated regulation, whether protein components are involved and how sRNAs integrate with complex regulatory networks.

Non-coding RNA networks in cancer.

Science.gov (United States)

Anastasiadou, Eleni; Jacob, Leni S; Slack, Frank J

2018-01-01

Thousands of unique non-coding RNA (ncRNA) sequences exist within cells. Work from the past decade has altered our perception of ncRNAs from 'junk' transcriptional products to functional regulatory molecules that mediate cellular processes including chromatin remodelling, transcription, post-transcriptional modifications and signal transduction. The networks in which ncRNAs engage can influence numerous molecular targets to drive specific cell biological responses and fates. Consequently, ncRNAs act as key regulators of physiological programmes in developmental and disease contexts. Particularly relevant in cancer, ncRNAs have been identified as oncogenic drivers and tumour suppressors in every major cancer type. Thus, a deeper understanding of the complex networks of interactions that ncRNAs coordinate would provide a unique opportunity to design better therapeutic interventions.

The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy.

Science.gov (United States)

Moore, Caroline J; Daly, Eileen M; Tassone, Flora; Tysoe, Carolyn; Schmitz, Nicole; Ng, Virginia; Chitnis, Xavier; McGuire, Philip; Suckling, John; Davies, Kay E; Hagerman, Randi J; Hagerman, Paul J; Murphy, Kieran C; Murphy, Declan G M

2004-12-01

Expanded trinucleotide repeats are associated with several neuropsychiatric disorders, including fragile X syndrome (FraX) which is the most common inherited form of mental retardation. It is currently thought that FraX results from having >200 CGG trinucleotide repeats, with consequent methylation of the fragile X mental retardation gene (FMR1) and loss of FMR1 protein (FMRP). Pre-mutation carriers of FraX (with 55-200 CGG trinucleotide repeats) were originally considered unaffected, although recent studies challenge this view. However, there are few studies on the effect of pre-mutation trinucleotide repeat expansion on the male human brain using quantitative MRI. Also the results of prior investigations may be confounded because people were selected on the basis of clinical and neurological features, and not genetic phenotype. We compared the brain anatomy of 20 adult male pre-mutation members of known FraX families with 20 healthy male controls. The two groups did not differ significantly in age, intelligence quotient (IQ) or handedness. We also investigated whether any observed effects were associated with: (i) ageing; (ii) expansion of pre-mutation CGG trinucleotide repeats; (iii) reduction in the percentage of lymphocytes staining with anti-FMRP antibodies [%FMRP(+) lymphocytes]; and (iv) elevation of FMR1 mRNA levels. Male pre-mutation carriers of FraX, compared with matched controls, had significantly less voxel density in several brain regions, including the cerebellum, amygdalo-hippocampal complex and thalamus. Within pre-mutation carriers of FraX, ageing, increases in the number of CGG trinucleotide repeats and decreases in %FMRP(+) lymphocytes were associated with decreasing voxel density of regions previously identified as decreased relative to controls. Regional grey and white matter density is significantly affected in male pre-mutation carriers of FraX recruited on the basis of genetic, not clinical, phenotype. The association of voxel density

Annotating non-coding regions of the genome.

Science.gov (United States)

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

2010-08-01

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.

Decoding the function of nuclear long non-coding RNAs.

Science.gov (United States)

Chen, Ling-Ling; Carmichael, Gordon G

2010-06-01

Long non-coding RNAs (lncRNAs) are mRNA-like, non-protein-coding RNAs that are pervasively transcribed throughout eukaryotic genomes. Rather than silently accumulating in the nucleus, many of these are now known or suspected to play important roles in nuclear architecture or in the regulation of gene expression. In this review, we highlight some recent progress in how lncRNAs regulate these important nuclear processes at the molecular level. Copyright 2010 Elsevier Ltd. All rights reserved.

Biocomputational prediction of small non-coding RNAs in Streptomyces

Czech Academy of Sciences Publication Activity Database

Pánek, Josef; Bobek, Jan; Mikulík, Karel; Basler, Marek; Vohradský, Jiří

2008-01-01

Roč. 9, č. 217 (2008), s. 1-14 ISSN 1471-2164 R&D Projects: GA ČR GP204/07/P361; GA ČR GA203/05/0106; GA ČR GA310/07/1009 Grant - others:XE(XE) EC Integrated Project ActinoGEN, LSHM-CT-2004-005224. Institutional research plan: CEZ:AV0Z50200510 Keywords : non-coding RNA * streptomyces * biocomputational prediction Subject RIV: IN - Informatics, Computer Science Impact factor: 3.926, year: 2008

Quantification of non-coding RNA target localization diversity and its application in cancers.

Science.gov (United States)

Cheng, Lixin; Leung, Kwong-Sak

2018-04-01

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 that 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.

A new method for species identification via protein-coding and non-coding DNA barcodes by combining machine learning with bioinformatic methods.

Science.gov (United States)

Zhang, Ai-bing; Feng, Jie; Ward, Robert D; Wan, Ping; Gao, Qiang; Wu, Jun; Zhao, Wei-zhong

2012-01-01

Species identification via DNA barcodes is contributing greatly to current bioinventory efforts. The initial, and widely accepted, proposal was to use the protein-coding cytochrome c oxidase subunit I (COI) region as the standard barcode for animals, but recently non-coding internal transcribed spacer (ITS) genes have been proposed as candidate barcodes for both animals and plants. However, achieving a robust alignment for non-coding regions can be problematic. Here we propose two new methods (DV-RBF and FJ-RBF) to address this issue for species assignment by both coding and non-coding sequences that take advantage of the power of machine learning and bioinformatics. We demonstrate the value of the new methods with four empirical datasets, two representing typical protein-coding COI barcode datasets (neotropical bats and marine fish) and two representing non-coding ITS barcodes (rust fungi and brown algae). Using two random sub-sampling approaches, we demonstrate that the new methods significantly outperformed existing Neighbor-joining (NJ) and Maximum likelihood (ML) methods for both coding and non-coding barcodes when there was complete species coverage in the reference dataset. The new methods also out-performed NJ and ML methods for non-coding sequences in circumstances of potentially incomplete species coverage, although then the NJ and ML methods performed slightly better than the new methods for protein-coding barcodes. A 100% success rate of species identification was achieved with the two new methods for 4,122 bat queries and 5,134 fish queries using COI barcodes, with 95% confidence intervals (CI) of 99.75-100%. The new methods also obtained a 96.29% success rate (95%CI: 91.62-98.40%) for 484 rust fungi queries and a 98.50% success rate (95%CI: 96.60-99.37%) for 1094 brown algae queries, both using ITS barcodes.

A new method for species identification via protein-coding and non-coding DNA barcodes by combining machine learning with bioinformatic methods.

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Ai-bing Zhang

Full Text Available Species identification via DNA barcodes is contributing greatly to current bioinventory efforts. The initial, and widely accepted, proposal was to use the protein-coding cytochrome c oxidase subunit I (COI region as the standard barcode for animals, but recently non-coding internal transcribed spacer (ITS genes have been proposed as candidate barcodes for both animals and plants. However, achieving a robust alignment for non-coding regions can be problematic. Here we propose two new methods (DV-RBF and FJ-RBF to address this issue for species assignment by both coding and non-coding sequences that take advantage of the power of machine learning and bioinformatics. We demonstrate the value of the new methods with four empirical datasets, two representing typical protein-coding COI barcode datasets (neotropical bats and marine fish and two representing non-coding ITS barcodes (rust fungi and brown algae. Using two random sub-sampling approaches, we demonstrate that the new methods significantly outperformed existing Neighbor-joining (NJ and Maximum likelihood (ML methods for both coding and non-coding barcodes when there was complete species coverage in the reference dataset. The new methods also out-performed NJ and ML methods for non-coding sequences in circumstances of potentially incomplete species coverage, although then the NJ and ML methods performed slightly better than the new methods for protein-coding barcodes. A 100% success rate of species identification was achieved with the two new methods for 4,122 bat queries and 5,134 fish queries using COI barcodes, with 95% confidence intervals (CI of 99.75-100%. The new methods also obtained a 96.29% success rate (95%CI: 91.62-98.40% for 484 rust fungi queries and a 98.50% success rate (95%CI: 96.60-99.37% for 1094 brown algae queries, both using ITS barcodes.

Enhancer evolution across 20 mammalian species

DEFF Research Database (Denmark)

Villar, Diego; Berthelot, Camille; Aldridge, Sarah

2015-01-01

The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders...... by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements....... These results provide important insight into the functional genetics underpinning mammalian regulatory evolution....

Shrub expansion in SW Greenland under modest regional warming

DEFF Research Database (Denmark)

Jørgensen, Rasmus Halfdan; Meilby, Henrik; Kollmann, Johannes

2013-01-01

Shrub expansion has been observed widely in tundra areas across the Arctic. This phenomenon has been partially attributed to increasing temperatures over the past century. However, relationships among shrub expansion, grazing, and human disturbance have been studied little. SW Greenland...... is a subarctic to low-arctic region with a long and complex land-use history and only modest temperature increases over the past 50 years (0.2 °C decade-1), but changes in shrub cover have not previously been studied in this region. We compiled historical photographs of vegetation in SW Greenland (1898......–1974) and repeated the photos in 2010 and 2011. Sixty-four photo pairs were cropped into 133 smaller units and classified by aspect, substrate stability, muskoxen grazing, and human disturbance. The photo material was evaluated by 22 experts with respect to changes in shrub cover, revealing a general increase across...

Non-Coding RNAs: Multi-Tasking Molecules in the Cell

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Anita Quintal Gomes

2013-07-01

Full Text Available In the last years it has become increasingly clear that the mammalian transcriptome is highly complex and includes a large number of small non-coding RNAs (sncRNAs and long noncoding RNAs (lncRNAs. Here we review the biogenesis pathways of the three classes of sncRNAs, namely short interfering RNAs (siRNAs, microRNAs (miRNAs and PIWI-interacting RNAs (piRNAs. These ncRNAs have been extensively studied and are involved in pathways leading to specific gene silencing and the protection of genomes against virus and transposons, for example. Also, lncRNAs have emerged as pivotal molecules for the transcriptional and post-transcriptional regulation of gene expression which is supported by their tissue-specific expression patterns, subcellular distribution, and developmental regulation. Therefore, we also focus our attention on their role in differentiation and development. SncRNAs and lncRNAs play critical roles in defining DNA methylation patterns, as well as chromatin remodeling thus having a substantial effect in epigenetics. The identification of some overlaps in their biogenesis pathways and functional roles raises the hypothesis that these molecules play concerted functions in vivo, creating complex regulatory networks where cooperation with regulatory proteins is necessary. We also highlighted the implications of biogenesis and gene expression deregulation of sncRNAs and lncRNAs in human diseases like cancer.

The interplay between noncoding RNAs and insulin in diabetes.

Science.gov (United States)

Tian, Yan; Xu, Jia; Du, Xiao; Fu, Xianghui

2018-04-10

Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, regulate various biological processes and are involved in the initiation and progression of human diseases. Insulin, a predominant hormone secreted from pancreatic β cells, is an essential factor in regulation of systemic metabolism through multifunctional insulin signaling. Insulin production and action are tightly controlled. Dysregulations of insulin production and action can impair metabolic homeostasis, and eventually lead to the development of multiple metabolic diseases, especially diabetes. Accumulating data indicates that ncRNAs modulate β cell mass, insulin synthesis, secretion and signaling, and their role in diabetes is dramatically emerging. This review summarizes our current knowledge of ncRNAs as regulators of insulin, with particular emphasis on the implications of this interplay in the development of diabetes. We outline the role of ncRNAs in pancreatic β cell mass and function, which is critical for insulin production and secretion. We also highlight the involvement of ncRNAs in insulin signaling in peripheral tissues including liver, muscle and adipose, and discuss ncRNA-mediated inter-organ crosstalk under diabetic conditions. A more in-depth understanding of the interplay between ncRNAs and insulin may afford valuable insights and novel therapeutic strategies for treatment of diabetes, as well as other human diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

Non-Coding RNAs are Differentially Expressed by Nocardia brasiliensis in Vitro and in Experimental Actinomycetoma.

Science.gov (United States)

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

2017-01-01

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.

Dinucleotide repeat polymorphism in Fms-like tyrosine kinase-1 (Flt-1 gene is not associated with preeclampsia

Directory of Open Access Journals (Sweden)

Park So-Yeon

2008-07-01

Full Text Available Abstract Background Preeclampsia is a major cause of maternal and perinatal mortality and morbidity. The etiology of preeclampsia remains unclear. Recently, it was shown that misregulation of fms-like tyrosine kinase-1 (Flt-1 in the peripheral blood mononuclear cells of pregnant women results in over-expression of the soluble splice variant of Flt-1, sFlt-1, producing an additional (extra-placental source of sFlt-1 that can contribute to the etiology of preeclampsia. The aim of this study was to investigate the relationship between preeclampsia and a dinucleotide (threonine-glycine; TGn repeat polymorphism in the 3' non-coding region of the Flt-1 gene. Methods The number of the d(TGn repeats was analyzed in 170 patients with preeclampsia and in 202 normotensive pregnancies. The region containing the dinucleotide repeat polymorphism of the Flt-1 gene was amplified by polymerase chain reaction (PCR from the DNA samples and was analyzed by direct PCR sequencing. Results We found 10 alleles of the dinucleotide repeat polymorphism and designated these as allele*12 (A1 through allele*23 (A12 according to the number of the TG repeats, from 12 to 23. The frequency of the 14-repeat allele (A3 was most abundant (63.82% in preeclampsia and 69.06% in controls, followed by the 21-repeat allele (A10; 28.53% in preeclampsia and 23.76% in controls. There was no significant difference in the allele frequency between patients with preeclampsia and normal controls. The most common genotype in preeclamptic and normotensive pregnancies was heterozygous (TG14/(TG21 (41.76% and homozygous (TG14/(TG14 (45.05%, respectively. However, the genotype frequencies were not significantly different between preeclamptic patients and controls. Conclusion This is the first study to characterize the dinucleotide repeat polymorphism of the Flt-1 gene in patients with preeclampsia. We found no differences in the allele or genotype frequencies between patients with preeclampsia and

Chromosome preference of disease genes and vectorization for the prediction of non-coding disease genes.

Science.gov (United States)

Peng, Hui; Lan, Chaowang; Liu, Yuansheng; Liu, Tao; Blumenstein, Michael; Li, Jinyan

2017-10-03

Disease-related protein-coding genes have been widely studied, but disease-related non-coding genes remain largely unknown. This work introduces a new vector to represent diseases, and applies the newly vectorized data for a positive-unlabeled learning algorithm to predict and rank disease-related long non-coding RNA (lncRNA) genes. This novel vector representation for diseases consists of two sub-vectors, one is composed of 45 elements, characterizing the information entropies of the disease genes distribution over 45 chromosome substructures. This idea is supported by our observation that some substructures (e.g., the chromosome 6 p-arm) are highly preferred by disease-related protein coding genes, while some (e.g., the 21 p-arm) are not favored at all. The second sub-vector is 30-dimensional, characterizing the distribution of disease gene enriched KEGG pathways in comparison with our manually created pathway groups. The second sub-vector complements with the first one to differentiate between various diseases. Our prediction method outperforms the state-of-the-art methods on benchmark datasets for prioritizing disease related lncRNA genes. The method also works well when only the sequence information of an lncRNA gene is known, or even when a given disease has no currently recognized long non-coding genes.

Low-Normal FMR1 CGG Repeat Length: Phenotypic Associations

Directory of Open Access Journals (Sweden)

Marsha eMailick

2014-09-01

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.

EG-10LONG NON-CODING RNAs IN GLIOBLASTOMA

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Pastori, Chiara; Kapranov, Philipp; Penas, Clara; Laurent, Georges St.; Ayad, Nagi; Wahlestedt, Claes

2014-01-01

Glioblastoma (GBM) is the most common, aggressive and incurable primary brain tumor in adults. Genome studies have confirmed that GBM is extremely heterogeneous with many genetically different subgroups. Consequently, there is much current interest in epigenetic drugs that may be active across genetically distinct tumors. In support of this, some epigenetic drugs has recently shown efficacy against several cancers including glioblastoma. Much recent interest has also been devoted to long non-coding RNAs (lncRNAs), which can modulate gene expression regulating chromatin architecture, in part through the interaction with epigenetic protein machineries. To date, however, only a few lncRNAs have been studied in human cancer. We therefore embarked on a comprehensive genomic and functional analysis of lncRNAs in GBM. Using the Helicos Single Molecule Sequencing platform glioblastoma samples were sequenced resulting in the identification of hundreds of dysregulated lncRNAs. Among these the lncRNA HOTAIR was found massively increased in GBM. This observation parallels findings in other cancers where HOTAIR's increased expression has been linked to poor prognosis due to metastatic events. Interestingly, here we show that in glioblastoma HOTAIR does not promote metastasis, but instead sustains the ability of these cells to proliferate. In fact, we demonstrate that HOTAIR knockdown in GBM strongly impairs cell proliferation and induces apoptosis in vitro and in vivo. Further, we implicate HOTAIR in the mechanism of action of certain epigenetic drugs. In summary, long noncoding RNAs (newly discovered epigenomic factors) play a vital role in GBM and deserve attention as entirely novel drug targets as well as biomarkers.

The specificity of long noncoding RNA expression.

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Gloss, Brian S; Dinger, Marcel E

2016-01-01

Over the last decade, long noncoding RNAs (lncRNAs) have emerged as a fundamental molecular class whose members play pivotal roles in the regulation of the genome. The observation of pervasive transcription of mammalian genomes in the early 2000s sparked a revolution in the understanding of information flow in eukaryotic cells and the incredible flexibility and dynamic nature of the transcriptome. As a molecular class, distinct loci yielding lncRNAs are set to outnumber those yielding mRNAs. However, like many important discoveries, the road leading to uncovering this diverse class of molecules that act through a remarkable repertoire of mechanisms, was not a straight one. The same characteristic that most distinguishes lncRNAs from mRNAs, i.e. their developmental-stage, tissue-, and cell-specific expression, was one of the major impediments to their discovery and recognition as potentially functional regulatory molecules. With growing numbers of lncRNAs being assigned to biological functions, the specificity of lncRNA expression is now increasingly recognized as a characteristic that imbues lncRNAs with great potential as biomarkers and for the development of highly targeted therapeutics. Here we review the history of lncRNA research and how technological advances and insight into biological complexity have gone hand-in-hand in shaping this revolution. We anticipate that as increasing numbers of these molecules, often described as the dark matter of the genome, are characterized and the structure-function relationship of lncRNAs becomes better understood, it may ultimately be feasible to decipher what these non-(protein)-coding genes encode. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. Copyright © 2015 Elsevier B.V. All rights reserved.

Noncoding RNAs in Cancer Medicine

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Laura Cerchia

2006-01-01

Full Text Available Several signalling proteins involved in cell growth and differentiation represent attractive candidate targets for cancer diagnosis and/or therapy since they can act as oncogenes. Because of their high specificity and low immunogeneicity, using artificial small noncoding RNA (ncRNAs as therapeutics has recently become a highly promising and rapidly expanding field of interest. Indeed, ncRNAs may either interfere with RNA transcription, stability, translation or directly hamper the function of the targets by binding to their surface. The recent finding that the expression of several genes is under the control of small single-stranded regulatory RNAs, including miRNAs, makes these genes as appropriate targets for ncRNA gene silencing. Furthermore, another class of small ncRNA, aptamers, act as high-affinity ligands and potential antagonists of disease-associated proteins. We will review here the recent and innovative methods that have been developed and the possible applications of ncRNAs as inhibitors or tracers in cancer medicine.

Application of FTA sample collection and DNA purification system on the determination of CTG trinucleotide repeat size by PCR-based Southern blotting.

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Hsiao, K M; Lin, H M; Pan, H; Li, T C; Chen, S S; Jou, S B; Chiu, Y L; Wu, M F; Lin, C C; Li, S Y

1999-01-01

Myotonic dystrophy (DM) is caused by a CTG trinucleotide expansion mutation at exon 15 of the myotonic dystrophy protein kinase gene. The clinical severity of this disease correlates with the length of the CTG trinucleotide repeats. Determination of the CTG repeat length has been primarily relied on by Southern blot analysis of restriction enzyme-digested genomic DNA. The development of PCR-based Southern blotting methodology provides a much more sensitive and simpler protocol for DM diagnosis. However, the quality of the template and the high (G+C) ratio of the amplified region hamper the use of PCR on the diagnosis of DM. A modified PCR protocol to amplify different lengths of CTG repeat region using various concentrations of 7deaza-dGTP has been reported (1). Here we describe a procedure including sample collection, DNA purification, and PCR analysis of CTG repeat length without using 7-deaza-dGTP. This protocol is very sensitive and convenient because only a small number of nucleate cells are needed for detection of CTG expansion. Therefore, it could be very useful in clinical and prenatal diagnosis as well as in prevalence study of DM.

Fork stalling and template switching as a mechanism for polyalanine tract expansion affecting the DYC mutant of HOXD13, a new murine model of synpolydactyly.

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Cocquempot, Olivier; Brault, Véronique; Babinet, Charles; Herault, Yann

2009-09-01

Polyalanine expansion diseases are proposed to result from unequal crossover of sister chromatids that increases the number of repeats. In this report we suggest an alternative mechanism we put forward while we investigated a new spontaneous mutant that we named "Dyc" for "Digit in Y and Carpe" phenotype. Phenotypic analysis revealed an abnormal limb patterning similar to that of the human inherited congenital disease synpolydactyly (SPD) and to the mouse mutant model Spdh. Both human SPD and mouse Spdh mutations affect the Hoxd13 gene within a 15-residue polyalanine-encoding repeat in the first exon of the gene, leading to a dominant negative HOXD13. Genetic analysis of the Dyc mutant revealed a trinucleotide expansion in the polyalanine-encoding region of the Hoxd13 gene resulting in a 7-alanine expansion. However, unlike the Spdh mutation, this expansion cannot result from a simple duplication of a short segment. Instead, we propose the fork stalling and template switching (FosTeS) described for generation of nonrecurrent genomic rearrangements as a possible mechanism for the Dyc polyalanine extension, as well as for other polyalanine expansions described in the literature and that could not be explained by unequal crossing over.

Long Non-coding RNAs in Response to Genotoxic Stress

Institute of Scientific and Technical Information of China (English)

Xiaoman Li; Dong Pan; Baoquan Zhao; Burong Hu

2016-01-01

Long non-coding RNAs(lncRNAs) are increasingly involved in diverse biological processes.Upon DNA damage,the DNA damage response(DDR) elicits a complex signaling cascade,which includes the induction of lncRNAs.LncRNA-mediated DDR is involved in non-canonical and canonical manners.DNA-damage induced lncRNAs contribute to the regulation of cell cycle,apoptosis,and DNA repair,thereby playing a key role in maintaining genome stability.This review summarizes the emerging role of lncRNAs in DNA damage and repair.

A Network-Based Algorithm for Clustering Multivariate Repeated Measures Data

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Koslovsky, Matthew; Arellano, John; Schaefer, Caroline; Feiveson, Alan; Young, Millennia; Lee, Stuart

2017-01-01

The National Aeronautics and Space Administration (NASA) Astronaut Corps is a unique occupational cohort for which vast amounts of measures data have been collected repeatedly in research or operational studies pre-, in-, and post-flight, as well as during multiple clinical care visits. In exploratory analyses aimed at generating hypotheses regarding physiological changes associated with spaceflight exposure, such as impaired vision, it is of interest to identify anomalies and trends across these expansive datasets. Multivariate clustering algorithms for repeated measures data may help parse the data to identify homogeneous groups of astronauts that have higher risks for a particular physiological change. However, available clustering methods may not be able to accommodate the complex data structures found in NASA data, since the methods often rely on strict model assumptions, require equally-spaced and balanced assessment times, cannot accommodate missing data or differing time scales across variables, and cannot process continuous and discrete data simultaneously. To fill this gap, we propose a network-based, multivariate clustering algorithm for repeated measures data that can be tailored to fit various research settings. Using simulated data, we demonstrate how our method can be used to identify patterns in complex data structures found in practice.

Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA

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Paul Halley

2014-01-01

Full Text Available Apolipoprotein A1 (APOA1 is the major protein component of high-density lipoprotein (HDL in plasma. We have identified an endogenously expressed long noncoding natural antisense transcript, APOA1-AS, which acts as a negative transcriptional regulator of APOA1 both in vitro and in vivo. Inhibition of APOA1-AS in cultured cells resulted in the increased expression of APOA1 and two neighboring genes in the APO cluster. Chromatin immunoprecipitation (ChIP analyses of a ∼50 kb chromatin region flanking the APOA1 gene demonstrated that APOA1-AS can modulate distinct histone methylation patterns that mark active and/or inactive gene expression through the recruitment of histone-modifying enzymes. Targeting APOA1-AS with short antisense oligonucleotides also enhanced APOA1 expression in both human and monkey liver cells and induced an increase in hepatic RNA and protein expression in African green monkeys. Furthermore, the results presented here highlight the significant local modulatory effects of long noncoding antisense RNAs and demonstrate the therapeutic potential of manipulating the expression of these transcripts both in vitro and in vivo.

Comprehensive Reconstruction and Visualization of Non-Coding Regulatory Networks in Human

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Bonnici, Vincenzo; Russo, Francesco; Bombieri, Nicola; Pulvirenti, Alfredo; Giugno, Rosalba

2014-01-01

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 http://ncrnadb.scienze.univr.it/ncrnadb/. 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. PMID:25540777

Comprehensive reconstruction and visualization of non-coding regulatory networks in human.

Science.gov (United States)

Bonnici, Vincenzo; Russo, Francesco; Bombieri, Nicola; Pulvirenti, Alfredo; Giugno, Rosalba

2014-01-01

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 http://ncrnadb.scienze.univr.it/ncrnadb/. 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.

Roles of Non-Coding RNA in Sugarcane-Microbe Interaction.

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Thiebaut, Flávia; Rojas, Cristian A; Grativol, Clícia; Calixto, Edmundo P da R; Motta, Mariana R; Ballesteros, Helkin G F; Peixoto, Barbara; de Lima, Berenice N S; Vieira, Lucas M; Walter, Maria Emilia; de Armas, Elvismary M; Entenza, Júlio O P; Lifschitz, Sergio; Farinelli, Laurent; Hemerly, Adriana S; Ferreira, Paulo C G

2017-12-20

Studies have highlighted the importance of non-coding RNA regulation in plant-microbe interaction. However, the roles of sugarcane microRNAs (miRNAs) in the regulation of disease responses have not been investigated. Firstly, we screened the sRNA transcriptome of sugarcane infected with Acidovorax avenae . Conserved and novel miRNAs were identified. Additionally, small interfering RNAs (siRNAs) were aligned to differentially expressed sequences from the sugarcane transcriptome. Interestingly, many siRNAs aligned to a transcript encoding a copper-transporter gene whose expression was induced in the presence of A. avenae , while the siRNAs were repressed in the presence of A. avenae . Moreover, a long intergenic non-coding RNA was identified as a potential target or decoy of miR408. To extend the bioinformatics analysis, we carried out independent inoculations and the expression patterns of six miRNAs were validated by quantitative reverse transcription-PCR (qRT-PCR). Among these miRNAs, miR408-a copper-microRNA-was downregulated. The cleavage of a putative miR408 target, a laccase, was confirmed by a modified 5'RACE (rapid amplification of cDNA ends) assay. MiR408 was also downregulated in samples infected with other pathogens, but it was upregulated in the presence of a beneficial diazotrophic bacteria. Our results suggest that regulation by miR408 is important in sugarcane sensing whether microorganisms are either pathogenic or beneficial, triggering specific miRNA-mediated regulatory mechanisms accordingly.

Roles of Non-Coding RNA in Sugarcane-Microbe Interaction

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Grativol, Clícia; Motta, Mariana R.; Ballesteros, Helkin G. F.; Peixoto, Barbara; Vieira, Lucas M.; Walter, Maria Emilia; de Armas, Elvismary M.; Entenza, Júlio O. P.; Lifschitz, Sergio; Farinelli, Laurent; Hemerly, Adriana S.

2017-01-01

Studies have highlighted the importance of non-coding RNA regulation in plant-microbe interaction. However, the roles of sugarcane microRNAs (miRNAs) in the regulation of disease responses have not been investigated. Firstly, we screened the sRNA transcriptome of sugarcane infected with Acidovorax avenae. Conserved and novel miRNAs were identified. Additionally, small interfering RNAs (siRNAs) were aligned to differentially expressed sequences from the sugarcane transcriptome. Interestingly, many siRNAs aligned to a transcript encoding a copper-transporter gene whose expression was induced in the presence of A. avenae, while the siRNAs were repressed in the presence of A. avenae. Moreover, a long intergenic non-coding RNA was identified as a potential target or decoy of miR408. To extend the bioinformatics analysis, we carried out independent inoculations and the expression patterns of six miRNAs were validated by quantitative reverse transcription-PCR (qRT-PCR). Among these miRNAs, miR408—a copper-microRNA—was downregulated. The cleavage of a putative miR408 target, a laccase, was confirmed by a modified 5′RACE (rapid amplification of cDNA ends) assay. MiR408 was also downregulated in samples infected with other pathogens, but it was upregulated in the presence of a beneficial diazotrophic bacteria. Our results suggest that regulation by miR408 is important in sugarcane sensing whether microorganisms are either pathogenic or beneficial, triggering specific miRNA-mediated regulatory mechanisms accordingly. PMID:29657296

Roles of Non-Coding RNA in Sugarcane-Microbe Interaction

Directory of Open Access Journals (Sweden)

Flávia Thiebaut

2017-12-01

Full Text Available Studies have highlighted the importance of non-coding RNA regulation in plant-microbe interaction. However, the roles of sugarcane microRNAs (miRNAs in the regulation of disease responses have not been investigated. Firstly, we screened the sRNA transcriptome of sugarcane infected with Acidovorax avenae. Conserved and novel miRNAs were identified. Additionally, small interfering RNAs (siRNAs were aligned to differentially expressed sequences from the sugarcane transcriptome. Interestingly, many siRNAs aligned to a transcript encoding a copper-transporter gene whose expression was induced in the presence of A. avenae, while the siRNAs were repressed in the presence of A. avenae. Moreover, a long intergenic non-coding RNA was identified as a potential target or decoy of miR408. To extend the bioinformatics analysis, we carried out independent inoculations and the expression patterns of six miRNAs were validated by quantitative reverse transcription-PCR (qRT-PCR. Among these miRNAs, miR408—a copper-microRNA—was downregulated. The cleavage of a putative miR408 target, a laccase, was confirmed by a modified 5′RACE (rapid amplification of cDNA ends assay. MiR408 was also downregulated in samples infected with other pathogens, but it was upregulated in the presence of a beneficial diazotrophic bacteria. Our results suggest that regulation by miR408 is important in sugarcane sensing whether microorganisms are either pathogenic or beneficial, triggering specific miRNA-mediated regulatory mechanisms accordingly.

Decoding the Emerging Patterns Exhibited in Non-coding RNAs Characteristic of Lung Cancer with Regard to their Clinical Significance.

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Sonea, Laura; Buse, Mihail; Gulei, Diana; Onaciu, Anca; Simon, Ioan; Braicu, Cornelia; Berindan-Neagoe, Ioana

2018-05-01

Lung cancer continues to be the leading topic concerning global mortality rate caused by can-cer; it needs to be further investigated to reduce these dramatic unfavorable statistic data. Non-coding RNAs (ncRNAs) have been shown to be important cellular regulatory factors and the alteration of their expression levels has become correlated to extensive number of pathologies. Specifically, their expres-sion profiles are correlated with development and progression of lung cancer, generating great interest for further investigation. This review focuses on the complex role of non-coding RNAs, namely miR-NAs, piwi-interacting RNAs, small nucleolar RNAs, long non-coding RNAs and circular RNAs in the process of developing novel biomarkers for diagnostic and prognostic factors that can then be utilized for personalized therapies toward this devastating disease. To support the concept of personalized medi-cine, we will focus on the roles of miRNAs in lung cancer tumorigenesis, their use as diagnostic and prognostic biomarkers and their application for patient therapy.

Identification of putative noncoding RNA genes in the Burkholderia cenocepacia J2315 genome

DEFF Research Database (Denmark)

Coenye, T.; Drevinek, P.; Mahenthiralingam, E.

2007-01-01

Noncoding RNA (ncRNA) genes are not involved in the production of mRNA and proteins, but produce transcripts that function directly as structural or regulatory RNAs. In the present study, the presence of ncRNA genes in the genome of Burkholderia cenocepacia J2315 was evaluated by combining...

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

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

2018-03-14

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

Long non-coding RNA expression profile in cervical cancer tissues

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Zhu, Hua; Chen, Xiangjian; Hu, Yan; Shi, Zhengzheng; Zhou, Qing; Zheng, Jingjie; Wang, Yifeng

2017-01-01

Cervical cancer (CC), one of the most common types of cancer of the female population, presents an enormous challenge in diagnosis and treatment. Long non-coding (lnc)RNAs, non-coding (nc)RNAs with length >200 nucleotides, have been identified to be associated with multiple types of cancer, including CC. This class of nc transcripts serves an important role in tumor suppression and oncogenic signaling pathways. In the present study, the microarray method was used to obtain the expression profile of lncRNAs and protein-coding mRNAs and to compare the expression of lncRNAs between CC tissues and corresponding adjacent non-cancerous tissues in order to screen potential lncRNAs for associations with CC. Overall, 3356 lncRNAs with significantly different expression pattern in CC tissues compared with adjacent non-cancerous tissues were identified, while 1,857 of them were upregulated. These differentially expressed lncRNAs were additionally classified into 5 subgroups. Reverse transcription quantitative polymerase chain reactions were performed to validate the expression pattern of 5 random selected lncRNAs, and 2lncRNAs were identified to have significantly different expression in CC samples compared with adjacent non-cancerous tissues. This finding suggests that those lncRNAs with different expression may serve important roles in the development of CC, and the expression data may provide information for additional study on the involvement of lncRNAs in CC. PMID:28789353

LncRNAWiki: harnessing community knowledge in collaborative curation of human long non-coding RNAs

KAUST Repository

Ma, L.; Li, A.; Zou, D.; Xu, X.; Xia, L.; Yu, J.; Bajic, Vladimir B.; Zhang, Z.

2014-01-01

Long non-coding RNAs (lncRNAs) perform a diversity of functions in numerous important biological processes and are implicated in many human diseases. In this report we present lncRNAWiki (http://lncrna.big.ac.cn), a wiki-based platform that is open

Long non-coding RNA TUG1 promotes endometrial cancer development via inhibiting miR-299 and miR-34a-5p.

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Liu, Lifen; Chen, Xin; Zhang, Ying; Hu, Yanrong; Shen, Xiaoqing; Zhu, Weipei

2017-05-09

It is generally known that the human genome makes a large amount of noncoding RNAs compared with coding genes. Long non-coding RNAs (lncRNAs) which composed of more than 200 nucleotides have been described as the largest subclass of the non-coding transcriptome in human noncoding RNAs. Existing research shows that lncRNAs exerted biological functions in various tumors via participating in both oncogenic and tumor suppressing pathways. The previous studies indicated that lncRNA taurine upregulated 1 (TUG1) play important roles in the initiation and progression of malignancies. In this study,based on previous research, we investigated the expression and biological role of the lncRNA-TUG1. We analyzed the relationship between lncRNA-TUG1and endometrial carcinoma (EC) in a total 104 EC carcinoma specimens, compared with that in normal tissues. We found that lncRNA-TUG1 expression in cancer tissues was significantly higher than that in adjacent tissues. Through a series of experiments, the results demonstrated that lncRNA-TUG1 enhances the evolution and progression of EC through inhibiting miR-299 and miR-34a-5p.

Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice.

Science.gov (United States)

Guo, Jun; Zhou, Yuan; Cheng, Yafen; Fang, Weiwei; Hu, Gang; Wei, Jie; Lin, Yajun; Man, Yong; Guo, Lixin; Sun, Mingxiao; Cui, Qinghua; Li, Jian

2018-01-01

Recent studies have suggested that changes in non-coding mRNA play a key role in the progression of non-alcoholic fatty liver disease (NAFLD). Metformin is now recommended and effective for the treatment of NAFLD. We hope the current analyses of the non-coding mRNA transcriptome will provide a better presentation of the potential roles of mRNAs and long non-coding RNAs (lncRNAs) that underlie NAFLD and metformin intervention. The present study mainly analysed changes in the coding transcriptome and non-coding RNAs after the application of a five-week metformin intervention. Liver samples from three groups of mice were harvested for transcriptome profiling, which covered mRNA, lncRNA, microRNA (miRNA) and circular RNA (circRNA), using a microarray technique. A systematic alleviation of high-fat diet (HFD)-induced transcriptome alterations by metformin was observed. The metformin treatment largely reversed the correlations with diabetes-related pathways. Our analysis also suggested interaction networks between differentially expressed lncRNAs and known hepatic disease genes and interactions between circRNA and their disease-related miRNA partners. Eight HFD-responsive lncRNAs and three metformin-responsive lncRNAs were noted due to their widespread associations with disease genes. Moreover, seven miRNAs that interacted with multiple differentially expressed circRNAs were highlighted because they were likely to be associated with metabolic or liver diseases. The present study identified novel changes in the coding transcriptome and non-coding RNAs in the livers of NAFLD mice after metformin treatment that might shed light on the underlying mechanism by which metformin impedes the progression of NAFLD. © 2018 The Author(s). Published by S. Karger AG, Basel.

Position and stability of the mandibular incisors after rapid maxillary expansion

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Darcy Flávio Nouer

Full Text Available Objective: To make a cephalometric evaluation of the position and stability of the mandibular incisors immediately after rapid maxillaryexpansion and after a containment period of five months. Methods: The sample consisted of 21 schoolchildren, aged between 6 years and 11 months and 11 years, with mixed dentition, posterior reverse articulation (posterior cross bite, and erupted permanent first molars. The children were randomly divided into two groups: Group1 (composed of eleven children, in whom the encapsulated rapid maxilla expander was used, and Group 2 (composed of ten children, inwhom the conventional Hyrax expander was used. Three lateral teleradiographs of each individual were taken: before treatment, after rapid maxillary expansion, and after a containment period of five months. The cephalometric measurements used for analyzing the incisors were: /1.NB, /1-NB, /1-Line I, IMPA and /1-Jr. The data were submitted to the Dalhberg test, to calculate the error of repeatability, and to ANOVA (p<0.05. Results: The result showed significant difference between the adopted mechanics, but showed no difference between the initial measures, those after rapid expansion of the maxilla and final measures for all the distances, except for /1-Jr. Conclusion: Rapid maxillary expansion, using the encapsulated appliance or Hyrax, caused no significant alteration in the distances: /1.NB, /1-NB, /1-Line I, IMPA; before, after rapid maxillary expansion and after containment.

DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing.

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Saveliev, Alexander; Everett, Christopher; Sharpe, Tammy; Webster, Zoë; Festenstein, Richard

2003-04-24

Gene repression is crucial to the maintenance of differentiated cell types in multicellular organisms, whereas aberrant silencing can lead to disease. The organization of DNA into chromatin and heterochromatin is implicated in gene silencing. In chromatin, DNA wraps around histones, creating nucleosomes. Further condensation of chromatin, associated with large blocks of repetitive DNA sequences, is known as heterochromatin. Position effect variegation (PEV) occurs when a gene is located abnormally close to heterochromatin, silencing the affected gene in a proportion of cells. Here we show that the relatively short triplet-repeat expansions found in myotonic dystrophy and Friedreich's ataxia confer variegation of expression on a linked transgene in mice. Silencing was correlated with a decrease in promoter accessibility and was enhanced by the classical PEV modifier heterochromatin protein 1 (HP1). Notably, triplet-repeat-associated variegation was not restricted to classical heterochromatic regions but occurred irrespective of chromosomal location. Because the phenomenon described here shares important features with PEV, the mechanisms underlying heterochromatin-mediated silencing might have a role in gene regulation at many sites throughout the mammalian genome and modulate the extent of gene silencing and hence severity in several triplet-repeat diseases.

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

Science.gov (United States)

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

2018-02-20

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

Noncoding RNAs and HIV: viral manipulation of host dark matter to shape the cellular environment

Directory of Open Access Journals (Sweden)

Samantha eBarichievy

2015-03-01

Full Text Available On October 28th 1943 Winston Churchill said we shape our buildings, and afterwards our buildings shape us (Humes, 1994. Churchill was pondering how and when to rebuild the British House of Commons, which had been destroyed by enemy bombs on May 10th 1941. The old House had been small and insufficient to hold all its members, but was restored to its original form in 1950 in order to recapture the convenience and dignity that the building had shaped into its parliamentary members. The circular loop whereby buildings or dwellings are shaped and go on to shape those that reside in them is also true of pathogens and their hosts. As obligate parasites, pathogens need to alter their cellular host environments to ensure survival. Typically pathogens modify cellular transcription profiles and in doing so, the pathogen in turn is affected, thereby closing the loop. As key orchestrators of gene expression, noncoding RNAs provide a vast and extremely precise set of tools for pathogens to target in order to shape the cellular environment. This review will focus on host noncoding RNAs that are manipulated by the infamous intracellular pathogen, the Human Immunodeficiency Virus (HIV. We will briefly describe both short and long host noncoding RNAs and discuss how HIV gains control of these factors to ensure widespread dissemination throughout the host as well as the establishment of lifelong, chronic infection.

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

Science.gov (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

2017-01-01

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

Both noncoding and protein-coding RNAs contribute to gene expression evolution in the primate brain.

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Babbitt, Courtney C; Fedrigo, Olivier; Pfefferle, Adam D; Boyle, Alan P; Horvath, Julie E; Furey, Terrence S; Wray, Gregory A

2010-01-18

Despite striking differences in cognition and behavior between humans and our closest primate relatives, several studies have found little evidence for adaptive change in protein-coding regions of genes expressed primarily in the brain. Instead, changes in gene expression may underlie many cognitive and behavioral differences. Here, we used digital gene expression: tag profiling (here called Tag-Seq, also called DGE:tag profiling) to assess changes in global transcript abundance in the frontal cortex of the brains of 3 humans, 3 chimpanzees, and 3 rhesus macaques. A substantial fraction of transcripts we identified as differentially transcribed among species were not assayed in previous studies based on microarrays. Differentially expressed tags within coding regions are enriched for gene functions involved in synaptic transmission, transport, oxidative phosphorylation, and lipid metabolism. Importantly, because Tag-Seq technology provides strand-specific information about all polyadenlyated transcripts, we were able to assay expression in noncoding intragenic regions, including both sense and antisense noncoding transcripts (relative to nearby genes). We find that many noncoding transcripts are conserved in both location and expression level between species, suggesting a possible functional role. Lastly, we examined the overlap between differential gene expression and signatures of positive selection within putative promoter regions, a sign that these differences represent adaptations during human evolution. Comparative approaches may provide important insights into genes responsible for differences in cognitive functions between humans and nonhuman primates, as well as highlighting new candidate genes for studies investigating neurological disorders.

Flavivirus RNAi suppression: decoding non-coding RNA.

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Pijlman, Gorben P

2014-08-01

Flaviviruses are important human pathogens that are transmitted by invertebrate vectors, mostly mosquitoes and ticks. During replication in their vector, flaviviruses are subject to a potent innate immune response known as antiviral RNA interference (RNAi). This defense mechanism is associated with the production of small interfering (si)RNA that lead to degradation of viral RNA. To what extent flaviviruses would benefit from counteracting antiviral RNAi is subject of debate. Here, the experimental evidence to suggest the existence of flavivirus RNAi suppressors is discussed. I will highlight the putative role of non-coding, subgenomic flavivirus RNA in suppression of RNAi in insect and mammalian cells. Novel insights from ongoing research will reveal how arthropod-borne viruses modulate innate immunity including antiviral RNAi. Copyright © 2014 Elsevier B.V. All rights reserved.

Long noncoding RNA in hematopoiesis and immunity.

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Satpathy, Ansuman T; Chang, Howard Y

2015-05-19

Dynamic gene expression during cellular differentiation is tightly coordinated by transcriptional and post-transcriptional mechanisms. An emerging theme is the central role of long noncoding RNAs (lncRNAs) in the regulation of this specificity. Recent advances demonstrate that lncRNAs are expressed in a lineage-specific manner and control the development of several cell types in the hematopoietic system. Moreover, specific lncRNAs are induced to modulate innate and adaptive immune responses. lncRNAs can function via RNA-DNA, RNA-RNA, and RNA-protein target interactions. As a result, they affect several stages of gene regulation, including chromatin modification, mRNA biogenesis, and protein signaling. We discuss recent advances, future prospects, and challenges in understanding the roles of lncRNAs in immunity and immune-mediated diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

A study of Huntington disease-like syndromes in black South African patients reveals a single SCA2 mutation and a unique distribution of normal alleles across five repeat loci.

Science.gov (United States)

Baine, Fiona K; Peerbhai, Nabeelah; Krause, Amanda

2018-07-15

Huntington disease (HD) is a progressive neurodegenerative disease, characterised by a triad of movement disorder, emotional and behavioural disturbances and cognitive impairment. The underlying cause is an expanded CAG repeat in the huntingtin gene. For a small proportion of patients presenting with HD-like symptoms, the mutation in this gene is not identified and they are said to have a HD "phenocopy". South Africa has the highest number of recorded cases of an African-specific phenocopy, Huntington disease-like 2 (HDL2), caused by a repeat expansion in the junctophilin-3 gene. However, a significant proportion of black patients with clinical symptoms suggestive of HD still test negative for HD and HDL2. This study thus aimed to investigate five other loci associated with HD phenocopy syndromes - ATN1, ATXN2, ATXN7, TBP and C9orf72. In a sample of patients in whom HD and HDL2 had been excluded, a single expansion was identified in the ATXN2 gene, confirming a diagnosis of Spinocerebellar ataxia 2. The results indicate that common repeat expansion disorders do not contribute significantly to the HD-like phenotype in black South African patients. Importantly, allele sizing reveals unique distributions of normal repeat lengths across the associated loci in the African population studied. Copyright © 2018 Elsevier B.V. All rights reserved.

Specific Regional and Age-Related Small Noncoding RNA Expression Patterns Within Superior Temporal Gyrus of Typical Human Brains Are Less Distinct in Autism Brains.

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Stamova, Boryana; Ander, Bradley P; Barger, Nicole; Sharp, Frank R; Schumann, Cynthia M

2015-12-01

Small noncoding RNAs play a critical role in regulating messenger RNA throughout brain development and when altered could have profound effects leading to disorders such as autism spectrum disorders (ASD). We assessed small noncoding RNAs, including microRNA and small nucleolar RNA, in superior temporal sulcus association cortex and primary auditory cortex in typical and ASD brains from early childhood to adulthood. Typical small noncoding RNA expression profiles were less distinct in ASD, both between regions and changes with age. Typical micro-RNA coexpression associations were absent in ASD brains. miR-132, miR-103, and miR-320 micro-RNAs were dysregulated in ASD and have previously been associated with autism spectrum disorders. These diminished region- and age-related micro-RNA expression profiles are in line with previously reported findings of attenuated messenger RNA and long noncoding RNA in ASD brain. This study demonstrates alterations in superior temporal sulcus in ASD, a region implicated in social impairment, and is the first to demonstrate molecular alterations in the primary auditory cortex. © The Author(s) 2015.

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

2017-01-01

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

Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features

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Mahoney, Colin J.; Beck, Jon; Rohrer, Jonathan D.; Lashley, Tammaryn; Mok, Kin; Shakespeare, Tim; Yeatman, Tom; Warrington, Elizabeth K.; Schott, Jonathan M.; Fox, Nick C.; Rossor, Martin N.; Hardy, John; Collinge, John; Revesz, Tamas; Mead, Simon

2012-01-01

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases

Long noncoding RNAs as Organizers of Nuclear Architecture.

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Cheng, Lu; Ming, Hui; Zhu, Minzhe; Wen, Bo

2016-03-01

In the eukaryotic cell nucleus, chromatin and its associated macromolecules must be organized into a higher-ordered conformation to function normally. However, mechanisms underlying the organization and dynamics of the nucleus remain unclear. Long noncoding RNAs (lncRNAs), i.e., transcripts longer than 200 nucleotides with little or no protein-coding capacity, are increasingly recognized as important regulators in diverse biological processes. Recent studies have shown that some lncRNAs are involved in various aspects of genome organization, including the facilitation of chromosomal interactions and establishment of nuclear bodies, suggesting that lncRNAs act as general organizers of the nuclear architecture. Here, we discuss recent advances in this emerging and intriguing field.

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

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Sofia Fertuzinhos

2014-03-01

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.

Long Non-Coding RNAs Associated with Metabolic Traits in Human White Adipose Tissue

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Hui Gao

2018-04-01

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

CsrB, a noncoding regulatory RNA, is required for BarA-dependent expression of biocontrol traits in Rahnella aquatilis HX2.

Science.gov (United States)

Mei, Li; Xu, Sanger; Lu, Peng; Lin, Haiping; Guo, Yanbin; Wang, Yongjun

2017-01-01

Rahnella aquatilis is ubiquitous and its certain strains have the applicative potent as a plant growth-promoting rhizobacteria. R. aquatilis HX2 is a biocontrol agent to produce antibacterial substance (ABS) and showed efficient biocontrol against crown gall caused by Agrobacterium vitis on sunflower and grapevine plants. The regulatory network of the ABS production and biocontrol activity is still limited known. In this study, a transposon-mediated mutagenesis strategy was used to investigate the regulators that involved in the biocontrol activity of R. aquatilis HX2. A 366-nt noncoding RNA CsrB was identified in vitro and in vivo, which regulated ABS production and biocontrol activity against crown gall on sunflower plants, respectively. The predicted product of noncoding RNA CsrB contains 14 stem-loop structures and an additional ρ-independent terminator harpin, with 23 characteristic GGA motifs in the loops and other unpaired regions. CsrB is required for ABS production and biocontrol activity in the biocontrol regulation by a two-component regulatory system BarA/UvrY in R. aquatilis HX2. The noncoding RNA CsrB regulates BarA-dependent ABS production and biocontrol activity in R. aquatilis HX2. To the best of our knowledge, this is the first report of noncoding RNA as a regulator for biocontrol function in R. aquatilis.

Thermal expansion

International Nuclear Information System (INIS)

Yun, Y.

2015-01-01

Thermal expansion of fuel pellet is an important property which limits the lifetime of the fuels in reactors, because it affects both the pellet and cladding mechanical interaction and the gap conductivity. By fitting a number of available measured data, recommended equations have been presented and successfully used to estimate thermal expansion coefficient of the nuclear fuel pellet. However, due to large scatter of the measured data, non-consensus data have been omitted in formulating the equations. Also, the equation is strongly governed by the lack of appropriate experimental data. For those reasons, it is important to develop theoretical methodologies to better describe thermal expansion behaviour of nuclear fuel. In particular, first-principles and molecular dynamics simulations have been certainly contributed to predict reliable thermal expansion without fitting the measured data. Furthermore, the two theoretical techniques have improved on understanding the change of fuel dimension by describing the atomic-scale processes associated with lattice expansion in the fuels. (author)

The role of non-coding RNAs in cytoplasmic male sterility in flowering plants

Czech Academy of Sciences Publication Activity Database

Štorchová, Helena

2017-01-01

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

Low-temperature thermal expansion

International Nuclear Information System (INIS)

Collings, E.W.

1986-01-01

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

Integration and visualization of non-coding RNA and protein interaction networks

OpenAIRE

Junge, Alexander; Refsgaard, Jan Christian; Garde, Christian; Pan, Xiaoyong; Santos Delgado, Alberto; Anthon, Christian; Alkan, Ferhat; von Mering, Christian; Workman, Christopher; Jensen, Lars Juhl; Gorodkin, Jan

2015-01-01

Non-coding RNAs (ncRNAs) fulfill a diverse set of biological functions relying on interactions with other molecular entities. The advent of new experimental and computational approaches makes it possible to study ncRNAs and their associations on an unprecedented scale. We present RAIN (RNA Association and Interaction Networks) - a database that combines ncRNA-ncRNA, ncRNA-mRNA and ncRNA-protein interactions with large-scale protein association networks available in the STRING database. By int...

Noncoding RNA of Glutamine Synthetase I Modulates Antibiotic Production in Streptomyces coelicolor A3(2)

NARCIS (Netherlands)

D'Alia, Davide; Nieselt, Kay; Steigele, Stephan; Mueller, Jonas; Verburg, Ilse; Takano, Eriko; Alia, Davide D’; Müller, Jonas

Overexpression of antisense chromosomal cis-encoded noncoding RNAss (ncRNAs) in glutamine synthetase I resulted in a decrease in growth, protein synthesis, and antibiotic production in Streptomyces coelicolor. In addition, we predicted 3,597 cis-encoded ncRNAs and validated 13 of them

Alteration of Epigenetic Regulation by Long Noncoding RNAs in Cancer

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Mariangela Morlando

2018-02-01

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.

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.

2014-01-01

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

Revisiting genotype-phenotype overlap in neurogenetics: triplet-repeat expansions mimicking spastic paraplegias.

Science.gov (United States)

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

2012-09-01

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.

De novo Transcriptome Sequencing Reveals a Considerable Bias in the Incidence of Simple Sequence Repeats towards the Downstream of ‘Pre-miRNAs’ of Black Pepper

Science.gov (United States)

Joy, Nisha; Asha, Srinivasan; Mallika, Vijayan; Soniya, Eppurathu Vasudevan

2013-01-01

Next generation sequencing has an advantageon transformational development of species with limited available sequence data as it helps to decode the genome and transcriptome. We carried out the de novo sequencing using illuminaHiSeq™ 2000 to generate the first leaf transcriptome of black pepper (Piper nigrum L.), an important spice variety native to South India and also grown in other tropical regions. Despite the economic and biochemical importance of pepper, a scientifically rigorous study at the molecular level is far from complete due to lack of sufficient sequence information and cytological complexity of its genome. The 55 million raw reads obtained, when assembled using Trinity program generated 2,23,386 contigs and 1,28,157 unigenes. Reports suggest that the repeat-rich genomic regions give rise to small non-coding functional RNAs. MicroRNAs (miRNAs) are the most abundant type of non-coding regulatory RNAs. In spite of the widespread research on miRNAs, little is known about the hair-pin precursors of miRNAs bearing Simple Sequence Repeats (SSRs). We used the array of transcripts generated, for the in silico prediction and detection of ‘43 pre-miRNA candidates bearing different types of SSR motifs’. The analysis identified 3913 different types of SSR motifs with an average of one SSR per 3.04 MB of thetranscriptome. About 0.033% of the transcriptome constituted ‘pre-miRNA candidates bearing SSRs’. The abundance, type and distribution of SSR motifs studied across the hair-pin miRNA precursors, showed a significant bias in the position of SSRs towards the downstream of predicted ‘pre-miRNA candidates’. The catalogue of transcripts identified, together with the demonstration of reliable existence of SSRs in the miRNA precursors, permits future opportunities for understanding the genetic mechanism of black pepper and likely functions of ‘tandem repeats’ in miRNAs. PMID:23469176

The interplay of long non-coding RNAs and MYC in cancer

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Michael J. Hamilton

2015-12-01

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.

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

2012-01-01

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....

Rfam: annotating families of non-coding RNA sequences.

Science.gov (United States)

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

2015-01-01

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.

A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool.

Science.gov (United States)

Manterola, Lorea; Guruceaga, Elizabeth; Gállego Pérez-Larraya, Jaime; González-Huarriz, Marisol; Jauregui, Patricia; Tejada, Sonia; Diez-Valle, Ricardo; Segura, Victor; Samprón, Nicolás; Barrena, Cristina; Ruiz, Irune; Agirre, Amaia; Ayuso, Angel; Rodríguez, Javier; González, Alvaro; Xipell, Enric; Matheu, Ander; López de Munain, Adolfo; Tuñón, Teresa; Zazpe, Idoya; García-Foncillas, Jesús; Paris, Sophie; Delattre, Jean Yves; Alonso, Marta M

2014-04-01

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.

Negative thermal expansion materials: technological key for control of thermal expansion

OpenAIRE

Koshi Takenaka

2012-01-01

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...

Comparisons between Arabidopsis thaliana and Drosophila melanogaster in relation to Coding and Noncoding Sequence Length and Gene Expression

Directory of Open Access Journals (Sweden)

Rachel Caldwell

2015-01-01

Full Text Available There is a continuing interest in the analysis of gene architecture and gene expression to determine the relationship that may exist. Advances in high-quality sequencing technologies and large-scale resource datasets have increased the understanding of relationships and cross-referencing of expression data to the large genome data. Although a negative correlation between expression level and gene (especially transcript length has been generally accepted, there have been some conflicting results arising from the literature concerning the impacts of different regions of genes, and the underlying reason is not well understood. The research aims to apply quantile regression techniques for statistical analysis of coding and noncoding sequence length and gene expression data in the plant, Arabidopsis thaliana, and fruit fly, Drosophila melanogaster, to determine if a relationship exists and if there is any variation or similarities between these species. The quantile regression analysis found that the coding sequence length and gene expression correlations varied, and similarities emerged for the noncoding sequence length (5′ and 3′ UTRs between animal and plant species. In conclusion, the information described in this study provides the basis for further exploration into gene regulation with regard to coding and noncoding sequence length.

A 72-year-old Danish puzzle resolved--comparative analysis of phenotypes in families with different-sized HOXD13 polyalanine expansions

DEFF Research Database (Denmark)

Kjær, Klaus Wilbrandt; Hansen, Lars; Eiberg, Hans

2005-01-01

A phenotype-genotype correlation was previously described for carriers of different sized of polyalanine expansions in HOXD13. We report on a detailed comparison of 55 members (approximately 220 limbs) from 4 Danish families with duplications of 21 or 27 bp, expanding the polyalanine repeat from ...

Following Surgically Assisted Rapid Palatal Expansion, Do Tooth-Borne or Bone-Borne Appliances Provide More Skeletal Expansion and Dental Expansion?

Science.gov (United States)

Hamedi-Sangsari, Adrien; Chinipardaz, Zahra; Carrasco, Lee

2017-10-01

The aim of this study was to compare outcome measurements of skeletal and dental expansion with bone-borne (BB) versus tooth-borne (TB) appliances after surgically assisted rapid palatal expansion (SARPE). This study was performed to provide quantitative measurements that will help the oral surgeon and orthodontist in selecting the appliance with, on average, the greatest amount of skeletal expansion and the least amount of dental expansion. A computerized database search was performed using PubMed, EBSCO, Cochrane, Scopus, Web of Science, and Google Scholar on publications in reputable oral surgery and orthodontic journals. A systematic review and meta-analysis was completed with the predictor variable of expansion appliance (TB vs BB) and outcome measurement of expansion (in millimeters). Of 487 articles retrieved from the 6 databases, 5 articles were included, 4 with cone-beam computed tomographic (CBCT) data and 1 with non-CBCT 3-dimensional cast data. There was a significant difference in skeletal expansion (standardized mean difference [SMD], 0.92; 95% confidence interval [CI], 0.54-1.30; P appliances. However, there was no significant difference in dental expansion (SMD, 0.05; 95% CI, -0.24 to 0.34; P = .03). According to the literature, to achieve more effective skeletal expansion and minimize dental expansion after SARPE, a BB appliance should be favored. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Evaluation of temporary non-code repairs in safety class 3 piping systems

International Nuclear Information System (INIS)

Godha, P.C.; Kupinski, M.; Azevedo, N.F.

1996-01-01

Temporary non-ASME Code repairs in safety class 3 pipe and piping components are permissible during plant operation in accordance with Nuclear Regulatory Commission Generic Letter 90-05. However, regulatory acceptance of such repairs requires the licensee to undertake several timely actions. Consistent with the requirements of GL 90-05, this paper presents an overview of the detailed evaluation and relief request process. The technical criteria encompasses both ductile and brittle piping materials. It also lists appropriate evaluation methods that a utility engineer can select to perform a structural integrity assessment for design basis loading conditions to support the use of temporary non-Code repair for degraded piping components. Most use of temporary non-code repairs at a nuclear generating station is in the service water system which is an essential safety related system providing the ultimate heat sink for various plant systems. Depending on the plant siting, the service water system may use fresh water or salt water as the cooling medium. Various degradation mechanisms including general corrosion, erosion/corrosion, pitting, microbiological corrosion, galvanic corrosion, under-deposit corrosion or a combination thereof continually challenge the pressure boundary structural integrity. A good source for description of corrosion degradation in cooling water systems is provided in a cited reference

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.

2016-01-01

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

3' terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing.

Science.gov (United States)

Goldfarb, Katherine C; Cech, Thomas R

2013-09-21

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.

Principles of Long Noncoding RNA Evolution Derived from Direct Comparison of Transcriptomes in 17 Species

Directory of Open Access Journals (Sweden)

Hadas Hezroni

2015-05-01

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.

The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition

OpenAIRE

Sun, Junfeng; Ding, Chaohui; Yang, Zhen; Liu, Tao; Zhang, Xiefu; Zhao, Chunlin; Wang, Jiaxiang

2016-01-01

Background Long intergenic non-coding RNAs (lncRNAs) are a class of non-coding RNAs that are involved in gene expression regulation. Taurine up-regulated gene 1 (TUG1) is a cancer progression related lncRNA in some tumor oncogenesis; however, its role in colorectal cancer (CRC) remains unclear. In this study, we determined the expression patterns of TUG1 in CRC patients and explored its effect on CRC cell metastasis using cultured representative CRC cell lines. Methods The expression levels o...

A critical role for noncoding 5S rRNA in regulating Mdmx stability.

Science.gov (United States)

Li, Muyang; Gu, Wei

2011-09-16

Both p53 and Mdmx are ubiquitinated and degraded by the same E3 ligase Mdm2; interestingly, however, while p53 is rapidly degraded by Mdm2, Mdmx is a stable protein in most cancer cells. Thus, the mechanism by which Mdmx is degraded by Mdm2 needs further elucidation. Here, we identified the noncoding 5S rRNA as a major component of Mdmx-associated complexes from human cells. We show that 5S rRNA acts as a natural inhibitor of Mdmx degradation by Mdm2. RNAi-mediated knockdown of endogenous 5S rRNA, while not affecting p53 levels, significantly induces Mdmx degradation and, subsequently, activates p53-dependent growth arrest. Notably, 5S rRNA binds the RING domain of Mdmx and blocks its ubiquitination by Mdm2, whereas Mdm2-mediated p53 ubiquitination remains intact. These results provide insights into the differential effects on p53 and Mdmx by Mdm2 in vivo and reveal a critical role for noncoding 5S rRNA in modulating the p53-Mdmx axis. Copyright © 2011 Elsevier Inc. All rights reserved.

Integration and visualization of non-coding RNA and protein interaction networks

DEFF Research Database (Denmark)

Junge, Alexander; Refsgaard, Jan Christian; Garde, Christian

Non-coding RNAs (ncRNAs) fulfill a diverse set of biological functions relying on interactions with other molecular entities. The advent of new experimental and computational approaches makes it possible to study ncRNAs and their associations on an unprecedented scale. We present RAIN (RNA Associ......) co-occurrences found by text mining Medline abstracts. Each resource was assigned a reliability score by assessing its agreement with a gold standard set of microRNA-target interactions. RAIN is available at: http://rth.dk/resources/rain...

The Long Noncoding RNA Landscape of the Mouse Eye.

Science.gov (United States)

Chen, Weiwei; Yang, Shuai; Zhou, Zhonglou; Zhao, Xiaoting; Zhong, Jiayun; Reinach, Peter S; Yan, Dongsheng

2017-12-01

Long noncoding RNAs (lncRNAs) are important regulators of diverse biological functions. However, an extensive in-depth analysis of their expression profile and function in mammalian eyes is still lacking. Here we describe comprehensive landscapes of stage-dependent and tissue-specific lncRNA expression in the mouse eye. Affymetrix transcriptome array profiled lncRNA signatures from six different ocular tissue subsets (i.e., cornea, lens, retina, RPE, choroid, and sclera) in newborn and 8-week-old mice. Quantitative RT-PCR analysis validated array findings. Cis analyses and Gene Ontology (GO) annotation of protein-coding genes adjacent to signature lncRNA loci clarified potential lncRNA roles in maintaining tissue identity and regulating eye maturation during the aforementioned phase. In newborn and 8-week-old mice, we identified 47,332 protein-coding and noncoding gene transcripts. LncRNAs comprise 19,313 of these transcripts annotated in public data banks. During this maturation phase of these six different tissue subsets, more than 1000 lncRNAs expression levels underwent ≥2-fold changes. qRT-PCR analysis confirmed part of the gene microarray analysis results. K-means clustering identified 910 lncRNAs in the P0 groups and 686 lncRNAs in the postnatal 8-week-old groups, suggesting distinct tissue-specific lncRNA clusters. GO analysis of protein-coding genes proximal to lncRNA signatures resolved close correlations with their tissue-specific functional maturation between P0 and 8 weeks of age in the 6 tissue subsets. Characterizating maturational changes in lncRNA expression patterns as well as tissue-specific lncRNA signatures in six ocular tissues suggest important contributions made by lncRNA to the control of developmental processes in the mouse eye.

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.

2010-01-01

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.

The Ecological Genomics of Fungi: Repeated Elements in Filamentous Fungi with a Focus on Wood-Decay Fungi

Energy Technology Data Exchange (ETDEWEB)

Murat, Claude [INRA, Nancy, France; Payen, Thibaut [INRA, Nancy, France; Petitpierre, Denis [INRA, Nancy, France; Labbe, Jessy L [ORNL

2013-01-01

In the last decade, the genome of several dozen filamentous fungi have been sequenced. Interestingly, vast diversity in genome size was observed (Fig. 2.1) with 14-fold differences between the 9 Mb of the human pathogenic dandruff fungus (Malassezia globosa; Xu, Saunders, et al., 2007) and the 125 Mb of the ectomycorrhizal black truffle of P rigord (Tuber melanosporum; Martin, Kohler, et al., 2010). Recently, Raffaele and Kamoun (2012) highlighted that the genomes of several lineages of filamentous plant pathogens have been shaped by repeat-driven expansion. Indeed, repeated elements are ubiquitous in all prokaryote and eukaryote genomes; however, their frequencies can vary from just a minor percentage of the genome to more that 60 percent of the genome. Repeated elements can be classified in two major types: satellites DNA and transposable elements. In this chapter, the different types of repeated elements and how these elements can impact genome and gene repertoire will be described. Also, an intriguing link between the transposable elements richness and diversity and the ecological niche will be highlighted.

Next generation dilatometer for highest accuracy thermal expansion measurement of ZERODUR®

Science.gov (United States)

Jedamzik, Ralf; Engel, Axel; Kunisch, Clemens; Westenberger, Gerhard; Fischer, Peter; Westerhoff, Thomas

2015-09-01

In the recent years, the ever tighter tolerance for the Coefficient of thermal expansion (CTE) of IC Lithography component materials is requesting significant progress in the metrology accuracy to determine this property as requested. ZERODUR® is known for its extremely low CTE between 0°C to 50°C. The current measurement of the thermal expansion coefficient is done using push rod dilatometer measurement systems developed at SCHOTT. In recent years measurements have been published showing the excellent CTE homogeneity of ZERODUR® in the one-digit ppb/K range using these systems. The verifiable homogeneity was limited by the CTE(0°C, 50°C) measurement repeatability in the range of ± 1.2 ppb/K of the current improved push rod dilatometer setup using an optical interferometer as detector instead of an inductive coil. With ZERODUR® TAILORED, SCHOTT introduced a low thermal expansion material grade that can be adapted to individual customer application temperature profiles. The basis for this product is a model that has been developed in 2010 for better understanding of the thermal expansion behavior under given temperature versus time conditions. The CTE behavior predicted by the model has proven to be in very good alignment with the data determined in the thermal expansions measurements. The measurements to determine the data feeding the model require a dilatometer setup with excellent stability and accuracy for long measurement times of several days. In the past few years SCHOTT spent a lot of effort to drive a dilatometer measurement technology based on the push rod setup to its limit, to fulfill the continuously demand for higher CTE accuracy and deeper material knowledge of ZERODUR®. This paper reports on the status of the dilatometer technology development at SCHOTT.

Paraspeckles: Where Long Noncoding RNA Meets Phase Separation.

Science.gov (United States)

Fox, Archa H; Nakagawa, Shinichi; Hirose, Tetsuro; Bond, Charles S

2018-02-01

Long noncoding RNA (lncRNA) molecules are some of the newest and least understood players in gene regulation. Hence, we need good model systems with well-defined RNA and protein components. One such system is paraspeckles - protein-rich nuclear organelles built around a specific lncRNA scaffold. New discoveries show how paraspeckles are formed through multiple RNA-protein and protein-protein interactions, some of which involve extensive polymerization, and others with multivalent interactions driving phase separation. Once formed, paraspeckles influence gene regulation through sequestration of component proteins and RNAs, with subsequent depletion in other compartments. Here we focus on the dual aspects of paraspeckle structure and function, revealing an emerging role for these dynamic bodies in a multitude of cellular settings. Copyright © 2017 Elsevier Ltd. All rights reserved.

Role of Exosomal Noncoding RNAs in Lung Carcinogenesis

Directory of Open Access Journals (Sweden)

Tao Sun

2015-01-01

Full Text Available Lung cancer is the major cause of cancer death worldwide. Novel, recently discovered classes of noncoding RNAs (ncRNAs have diverse functional and regulatory activities and increasing evidence suggests crucial roles for deregulated ncRNAs in the onset and progression of cancer, including lung cancer. Exosomes are small extracellular membrane vesicles of endocytic origin that are released by many cells and are found in most body fluids. Tumor-derived exosomes mediate tumorigenesis by facilitating tumor growth and metastasis. MicroRNAs (miRNAs are a subclass of ncRNAs that are present in exosomes. miRNAs are taken up by neighboring or distant cells and modulate various functions of recipient cells. Here, we review exosome-derived ncRNAs with a focus on miRNAs and their role in lung cancer biology.

Evaluation of Agency Non-Code Layered Pressure Vessels (LPVs)

Science.gov (United States)

Prosser, William H.

2014-01-01

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.

Decoding the usefulness of non-coding RNAs as breast cancer markers.

Science.gov (United States)

Amorim, Maria; Salta, Sofia; Henrique, Rui; Jerónimo, Carmen

2016-09-15

Although important advances in the management of breast cancer (BC) have been recently accomplished, it still constitutes the leading cause of cancer death in women worldwide. BC is a heterogeneous and complex disease, making clinical prediction of outcome a very challenging task. In recent years, gene expression profiling emerged as a tool to assist in clinical decision, enabling the identification of genetic signatures that better predict prognosis and response to therapy. Nevertheless, translation to routine practice has been limited by economical and technical reasons and, thus, novel biomarkers, especially those requiring non-invasive or minimally invasive collection procedures, while retaining high sensitivity and specificity might represent a significant development in this field. An increasing amount of evidence demonstrates that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are aberrantly expressed in several cancers, including BC. miRNAs are of particular interest as new, easily accessible, cost-effective and non-invasive tools for precise management of BC patients because they circulate in bodily fluids (e.g., serum and plasma) in a very stable manner, enabling BC assessment and monitoring through liquid biopsies. This review focus on how ncRNAs have the potential to answer present clinical needs in the personalized management of patients with BC and comprehensively describes the state of the art on the role of ncRNAs in the diagnosis, prognosis and prediction of response to therapy in BC.

Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression

OpenAIRE

Zhai, Hui-yuan; Sui, Ming-hua; Yu, Xiao; Qu, Zhen; Hu, Jin-chen; Sun, Hai-qing; Zheng, Hai-tao; Zhou, Kai; Jiang, Li-xin

2016-01-01

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...

C9orf72 expansion presenting as an eating disorder.

Science.gov (United States)

Sanders, Peter; Ewing, Isobel; Ahmad, Kate

2016-03-01

This report describes a 64-year-old woman with a strong family history of motor neuron disease, whose diagnosis of behavioural variant frontotemporal dementia was delayed due to her initial presentation with atypical manifestations, including restriction of oral intake resulting in low weight, disordered eating and anxiety. Upon investigation, she was found to be a carrier of the C9orf72 hexanucleotide repeat expansion. Our case supports previous publications asserting that C9orf72 mutation carriers manifest with diverse clinical syndromes, and expands the phenotype to include anorexia and food refusal as potential features of the condition. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Negative thermal expansion materials

International Nuclear Information System (INIS)

Evans, J.S.O.

1997-01-01

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.)

Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging.

Science.gov (United States)

Grammatikakis, Ioannis; Panda, Amaresh C; Abdelmohsen, Kotb; Gorospe, Myriam

2014-12-01

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.

Roles, Functions, and Mechanisms of Long Non-coding RNAs in Cancer

Directory of Open Access Journals (Sweden)

Yiwen Fang

2016-02-01

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.

Negative thermal expansion materials: technological key for control of thermal expansion.

Science.gov (United States)

Takenaka, Koshi

2012-02-01

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 practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

Negative thermal expansion materials: technological key for control of thermal expansion

Directory of Open Access Journals (Sweden)

Koshi Takenaka

2012-01-01

Full Text Available 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 practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

Negative thermal expansion materials: technological key for control of thermal expansion

International Nuclear Information System (INIS)

Takenaka, Koshi

2012-01-01

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 practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade. (topical review)

Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome

Directory of Open Access Journals (Sweden)

Chantal Sellier

2013-03-01

Full Text Available Fragile X-associated tremor/ataxia syndrome (FXTAS is an inherited neurodegenerative disorder caused by the expansion of 55–200 CGG repeats in the 5′ UTR of FMR1. These expanded CGG repeats are transcribed and accumulate in nuclear RNA aggregates that sequester one or more RNA-binding proteins, thus impairing their functions. Here, we have identified that the double-stranded RNA-binding protein DGCR8 binds to expanded CGG repeats, resulting in the partial sequestration of DGCR8 and its partner, DROSHA, within CGG RNA aggregates. Consequently, the processing of microRNAs (miRNAs is reduced, resulting in decreased levels of mature miRNAs in neuronal cells expressing expanded CGG repeats and in brain tissue from patients with FXTAS. Finally, overexpression of DGCR8 rescues the neuronal cell death induced by expression of expanded CGG repeats. These results support a model in which a human neurodegenerative disease originates from the alteration, in trans, of the miRNA-processing machinery.

Thermal expansion of coking coals

Energy Technology Data Exchange (ETDEWEB)

Orlik, M.; Klimek, J. (Vyzkumny a Zkusebni Ustav Nova Hut, Ostrava (Czechoslovakia))

1992-12-01

Analyzes expansion of coal mixtures in coke ovens during coking. Methods for measuring coal expansion on both a laboratory and pilot plant scale are comparatively evaluated. The method, developed, tested and patented in Poland by the Institute for Chemical Coal Processing in Zabrze (Polish standard PN-73/G-04522), is discussed. A laboratory device developed by the Institute for measuring coal expansion is characterized. Expansion of black coal from 10 underground mines in the Ostrava-Karvina coal district and from 9 coal mines in the Upper Silesia basin in Poland is comparatively evaluated. Investigations show that coal expansion reaches a maximum for coal types with a volatile matter ranging from 20 to 25%. With increasing volatile matter in coal, its expansion decreases. Coal expansion increases with increasing swelling index. Coal expansion corresponds with coal dilatation. With increasing coal density its expansion increases. Coal mixtures should be selected in such a way that their expansion does not cause a pressure exceeding 40 MPa. 11 refs.

Specificity Protein (Sp) Transcription Factors and Metformin Regulate Expression of the Long Non-coding RNA HULC

Science.gov (United States)

There is evidence that specificity protein 1 (Sp1) transcription factor (TF) regulates expression of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) cells. RNA interference (RNAi) studies showed that among several lncRNAs expressed in HepG2, SNU-449 and SK-Hep-1...

Identification of small non-coding RNA classes expressed in swine whole blood during HP-PRRSV infection

Science.gov (United States)

It has been established that reduced susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) has a genetic component. This genetic component may take the form of small non-coding RNAs (sncRNA), which are molecules that function as regulators of gene expression. Various sncRNAs ...

Virial Expansion Bounds

Science.gov (United States)

Tate, Stephen James

2013-10-01

In the 1960s, the technique of using cluster expansion bounds in order to achieve bounds on the virial expansion was developed by Lebowitz and Penrose (J. Math. Phys. 5:841, 1964) and Ruelle (Statistical Mechanics: Rigorous Results. Benjamin, Elmsford, 1969). This technique is generalised to more recent cluster expansion bounds by Poghosyan and Ueltschi (J. Math. Phys. 50:053509, 2009), which are related to the work of Procacci (J. Stat. Phys. 129:171, 2007) and the tree-graph identity, detailed by Brydges (Phénomènes Critiques, Systèmes Aléatoires, Théories de Jauge. Les Houches 1984, pp. 129-183, 1986). The bounds achieved by Lebowitz and Penrose can also be sharpened by doing the actual optimisation and achieving expressions in terms of the Lambert W-function. The different bound from the cluster expansion shows some improvements for bounds on the convergence of the virial expansion in the case of positive potentials, which are allowed to have a hard core.

Development of Genetic Testing for Fragile X Syndrome and Associated Disorders, and Estimates of the Prevalence of FMR1 Expansion Mutations

Directory of Open Access Journals (Sweden)

James N. Macpherson

2016-11-01

Full Text Available The identification of a trinucleotide (CGG expansion as the chief mechanism of mutation in Fragile X syndrome in 1991 heralded a new chapter in molecular diagnostic genetics and generated a new perspective on mutational mechanisms in human genetic disease, which rapidly became a central paradigm (“dynamic mutation” as more and more of the common hereditary neurodevelopmental disorders were ascribed to this novel class of mutation. The progressive expansion of a CGG repeat in the FMR1 gene from “premutation” to “full mutation” provided an explanation for the “Sherman paradox,” just as similar expansion mechanisms in other genes explained the phenomenon of “anticipation” in their pathogenesis. Later, FMR1 premutations were unexpectedly found associated with two other distinct phenotypes: primary ovarian insufficiency and tremor-ataxia syndrome. This review will provide a historical perspective on procedures for testing and reporting of Fragile X syndrome and associated disorders, and the population genetics of FMR1 expansions, including estimates of prevalence and the influence of AGG interspersions on the rate and probability of expansion.

The Regulatory Effects of Long Noncoding RNA-ANCR on Dental Tissue-Derived Stem Cells

Directory of Open Access Journals (Sweden)

Qian Jia

2016-01-01

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.

Analysis of simple sequence repeats in the Gaeumannomyces graminis var. tritici genome and the development of microsatellite markers.

Science.gov (United States)

Li, Wei; Feng, Yanxia; Sun, Haiyan; Deng, Yuanyu; Yu, Hanshou; Chen, Huaigu

2014-11-01

Understanding the genetic structure of Gaeumannomyces graminis var. tritici is essential for the establishment of efficient disease control strategies. It is becoming clear that microsatellites, or simple sequence repeats (SSRs), play an important role in genome organization and phenotypic diversity, and are a large source of genetic markers for population genetics and meiotic maps. In this study, we examined the G. graminis var. tritici genome (1) to analyze its pattern of SSRs, (2) to compare it with other plant pathogenic filamentous fungi, such as Magnaporthe oryzae and M. poae, and (3) to identify new polymorphic SSR markers for genetic diversity. The G. graminis var. tritici genome was rich in SSRs; a total 13,650 SSRs have been identified with mononucleotides being the most common motifs. In coding regions, the densities of tri- and hexanucleotides were significantly higher than in noncoding regions. The di-, tri-, tetra, penta, and hexanucleotide repeats in the G. graminis var. tritici genome were more abundant than the same repeats in M. oryzae and M. poae. From 115 devised primers, 39 SSRs are polymorphic with G. graminis var. tritici isolates, and 8 primers were randomly selected to analyze 116 isolates from China. The number of alleles varied from 2 to 7 and the expected heterozygosity (He) from 0.499 to 0.837. In conclusion, SSRs developed in this study were highly polymorphic, and our analysis indicated that G. graminis var. tritici is a species with high genetic diversity. The results provide a pioneering report for several applications, such as the assessment of population structure and genetic diversity of G. graminis var. tritici.

Overview of long non-coding RNA and mRNA expression in response to methamphetamine treatment in vitro

NARCIS (Netherlands)

Xiong, Kun; Long, Lingling; Zhang, Xudong; Qu, Hongke; Deng, Haixiao; Ding, Yanjun; Cai, Jifeng; Wang, Shuchao; Wang, Mi; Liao, Lvshuang; Huang, Jufang; Yi, Chun-Xia; Yan, Jie

2017-01-01

Long non-coding RNAs (IncRNAs) display multiple functions including regulation of neuronal injury. However, their impact in methamphetamine (METH)-induced neurotoxicity has rarely been reported. Here, using microarray analysis, we investigated the expression profiling of lncRNAs and mRNAs in primary

Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation

Science.gov (United States)

Shen, Fei-Ran; Kuang, Hao; Hu, Feng-Xia; Wu, Hui; Huang, Qing-Zhen; Liang, Fei-Xiang; Qiao, Kai-Ming; Li, Jia; Wang, Jing; Liu, Yao; Zhang, Lei; He, Min; Zhang, Ying; Zuo, Wen-Liang; Sun, Ji-Rong; Shen, Bao-Gen

2017-10-01

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 owing to a martensitic magnetostructural transition. The major finding is that the thermal expansion behavior can be totally controlled by modulating the crystallinity degree and phase transition from atomic scale. Self-compensation effect leads to ultra-low thermal expansion with a linear expansion coefficient as small as +0.68 × 10-6/K over a wide temperature range around room temperature. The present study opens an avenue to reach ZTE particularly from the large class of giant NTE materials based on phase transition.

Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation

Directory of Open Access Journals (Sweden)

Fei-Ran Shen

2017-10-01

Full Text Available 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 owing to a martensitic magnetostructural transition. The major finding is that the thermal expansion behavior can be totally controlled by modulating the crystallinity degree and phase transition from atomic scale. Self-compensation effect leads to ultra-low thermal expansion with a linear expansion coefficient as small as +0.68 × 10−6/K over a wide temperature range around room temperature. The present study opens an avenue to reach ZTE particularly from the large class of giant NTE materials based on phase transition.

Exploring genomic dark matter: A critical assessment of the performance of homology search methods on noncoding RNA

DEFF Research Database (Denmark)

Freyhult, E.; Bollback, J. P.; Gardner, P. P.

2006-01-01

Homology search is one of the most ubiquitous bioinformatic tasks, yet it is unknown how effective the currently available tools are for identifying noncoding RNAs (ncRNAs). In this work, we use reliable ncRNA data sets to assess the effectiveness of methods such as BLAST, FASTA, HMMer, and Infer......Homology search is one of the most ubiquitous bioinformatic tasks, yet it is unknown how effective the currently available tools are for identifying noncoding RNAs (ncRNAs). In this work, we use reliable ncRNA data sets to assess the effectiveness of methods such as BLAST, FASTA, HMMer......, and Infernal. Surprisingly, the most popular homology search methods are often the least accurate. As a result, many studies have used inappropriate tools for their analyses. On the basis of our results, we suggest homology search strategies using the currently available tools and some directions for future...

Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation

OpenAIRE

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

2017-01-01

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...

Impact of Noncoding Satellite Repeats on Pancreatic Cancer Metastasis

Science.gov (United States)

2015-11-01

that certain HIV RT inhibitors ( ddC ) could block the generation of HSATII DNA/RNA hybrids, which had anti-cancer effects in 3D and in xenografts (see...effects in 3D and xenografts compared to 2D culture. Indeed, we find that using the RT inhibitor ddC or using HSATII sequence specific locked...Fig. 5: NRTI ddC differential effect in SW620 cell line grown in (A) 2D vs (B) 3D. NRTI ddC with significant reduction in SW620 xenograft (C

Thermal expansion of granite rocks

International Nuclear Information System (INIS)

Stephansson, O.

1978-04-01

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

Hexanucleotide Repeats in ALS/FTD Form Length-Dependent RNA Foci, Sequester RNA Binding Proteins, and Are Neurotoxic

Directory of Open Access Journals (Sweden)

Youn-Bok Lee

2013-12-01

Full Text Available The GGGGCC (G4C2 intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD. Intranuclear neuronal RNA foci have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 38× and 72× G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.

Lncident: A Tool for Rapid Identification of Long Noncoding RNAs Utilizing Sequence Intrinsic Composition and Open Reading Frame Information

Directory of Open Access Journals (Sweden)

Siyu Han

2016-01-01

Full Text Available More and more studies have demonstrated that long noncoding RNAs (lncRNAs play critical roles in diversity of biological process and are also associated with various types of disease. How to rapidly identify lncRNAs and messenger RNA is the fundamental step to uncover the function of lncRNAs identification. Here, we present a novel method for rapid identification of lncRNAs utilizing sequence intrinsic composition features and open reading frame information based on support vector machine model, named as Lncident (LncRNAs identification. The 10-fold cross-validation and ROC curve are used to evaluate the performance of Lncident. The main advantage of Lncident is high speed without the loss of accuracy. Compared with the exiting popular tools, Lncident outperforms Coding-Potential Calculator, Coding-Potential Assessment Tool, Coding-Noncoding Index, and PLEK. Lncident is also much faster than Coding-Potential Calculator and Coding-Noncoding Index. Lncident presents an outstanding performance on microorganism, which offers a great application prospect to the analysis of microorganism. In addition, Lncident can be trained by users’ own collected data. Furthermore, R package and web server are simultaneously developed in order to maximize the convenience for the users. The R package “Lncident” can be easily installed on multiple operating system platforms, as long as R is supported.

Nonparametric modeling and analysis of association between Huntington's disease onset and CAG repeats.

Science.gov (United States)

Ma, Yanyuan; Wang, Yuanjia

2014-04-15

Huntington's disease (HD) is a neurodegenerative disorder with a dominant genetic mode of inheritance caused by an expansion of CAG repeats on chromosome 4. Typically, a longer sequence of CAG repeat length is associated with increased risk of experiencing earlier onset of HD. Previous studies of the association between HD onset age and CAG length have favored a logistic model, where the CAG repeat length enters the mean and variance components of the logistic model in a complex exponential-linear form. To relax the parametric assumption of the exponential-linear association to the true HD onset distribution, we propose to leave both mean and variance functions of the CAG repeat length unspecified and perform semiparametric estimation in this context through a local kernel and backfitting procedure. Motivated by including family history of HD information available in the family members of participants in the Cooperative Huntington's Observational Research Trial (COHORT), we develop the methodology in the context of mixture data, where some subjects have a positive probability of being risk free. We also allow censoring on the age at onset of disease and accommodate covariates other than the CAG length. We study the theoretical properties of the proposed estimator and derive its asymptotic distribution. Finally, we apply the proposed methods to the COHORT data to estimate the HD onset distribution using a group of study participants and the disease family history information available on their family members. Copyright © 2013 John Wiley & Sons, Ltd.

Solution of Stochastic Nonlinear PDEs Using Automated Wiener-Hermite Expansion

KAUST Repository

Al-Juhani, Amnah

2014-01-06

The solution of the stochastic differential equations (SDEs) using Wiener-Hermite expansion (WHE) has the advantage of converting the problem to a system of deterministic equations that can be solved efficiently using the standard deterministic numerical methods [1]. The main statistics, such as the mean, covariance, and higher order statistical moments, can be calculated by simple formulae involving only the deterministic Wiener-Hermite coefficients. In WHE approach, there is no randomness directly involved in the computations. One does not have to rely on pseudo random number generators, and there is no need to solve the SDEs repeatedly for many realizations. Instead, the deterministic system is solved only once. For previous research efforts see [2, 4].

Non-coding RNAs and plant male sterility: current knowledge and future prospects.

Science.gov (United States)

Mishra, Ankita; Bohra, Abhishek

2018-02-01

Latest outcomes assign functional role to non-coding (nc) RNA molecules in regulatory networks that confer male sterility to plants. Male sterility in plants offers great opportunity for improving crop performance through application of hybrid technology. In this respect, cytoplasmic male sterility (CMS) and sterility induced by photoperiod (PGMS)/temperature (TGMS) have greatly facilitated development of high-yielding hybrids in crops. Participation of non-coding (nc) RNA molecules in plant reproductive development is increasingly becoming evident. Recent breakthroughs in rice definitively associate ncRNAs with PGMS and TGMS. In case of CMS, the exact mechanism through which the mitochondrial ORFs exert influence on the development of male gametophyte remains obscure in several crops. High-throughput sequencing has enabled genome-wide discovery and validation of these regulatory molecules and their target genes, describing their potential roles performed in relation to CMS. Discovery of ncRNA localized in plant mtDNA with its possible implication in CMS induction is intriguing in this respect. Still, conclusive evidences linking ncRNA with CMS phenotypes are currently unavailable, demanding complementing genetic approaches like transgenics to substantiate the preliminary findings. Here, we review the recent literature on the contribution of ncRNAs in conferring male sterility to plants, with an emphasis on microRNAs. Also, we present a perspective on improved understanding about ncRNA-mediated regulatory pathways that control male sterility in plants. A refined understanding of plant male sterility would strengthen crop hybrid industry to deliver hybrids with improved performance.

Genomic sequence around butterfly wing development genes: annotation and comparative analysis.

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Inês C Conceição

Full Text Available BACKGROUND: Analysis of genomic sequence allows characterization of genome content and organization, and access beyond gene-coding regions for identification of functional elements. BAC libraries, where relatively large genomic regions are made readily available, are especially useful for species without a fully sequenced genome and can increase genomic coverage of phylogenetic and biological diversity. For example, no butterfly genome is yet available despite the unique genetic and biological properties of this group, such as diversified wing color patterns. The evolution and development of these patterns is being studied in a few target species, including Bicyclus anynana, where a whole-genome BAC library allows targeted access to large genomic regions. METHODOLOGY/PRINCIPAL FINDINGS: We characterize ∼1.3 Mb of genomic sequence around 11 selected genes expressed in B. anynana developing wings. Extensive manual curation of in silico predictions, also making use of a large dataset of expressed genes for this species, identified repetitive elements and protein coding sequence, and highlighted an expansion of Alcohol dehydrogenase genes. Comparative analysis with orthologous regions of the lepidopteran reference genome allowed assessment of conservation of fine-scale synteny (with detection of new inversions and translocations and of DNA sequence (with detection of high levels of conservation of non-coding regions around some, but not all, developmental genes. CONCLUSIONS: The general properties and organization of the available B. anynana genomic sequence are similar to the lepidopteran reference, despite the more than 140 MY divergence. Our results lay the groundwork for further studies of new interesting findings in relation to both coding and non-coding sequence: 1 the Alcohol dehydrogenase expansion with higher similarity between the five tandemly-repeated B. anynana paralogs than with the corresponding B. mori orthologs, and 2 the high

Exploiting BAC-end sequences for the mining, characterization and utility of new short sequences repeat (SSR) markers in Citrus.

Science.gov (United States)

Biswas, Manosh Kumar; Chai, Lijun; Mayer, Christoph; Xu, Qiang; Guo, Wenwu; Deng, Xiuxin

2012-05-01

The aim of this study was to develop a large set of microsatellite markers based on publicly available BAC-end sequences (BESs), and to evaluate their transferability, discriminating capacity of genotypes and mapping ability in Citrus. A set of 1,281 simple sequence repeat (SSR) markers were developed from the 46,339 Citrus clementina BAC-end sequences (BES), of them 20.67% contained SSR longer than 20 bp, corresponding to roughly one perfect SSR per 2.04 kb. The most abundant motifs were di-nucleotide (16.82%) repeats. Among all repeat motifs (TA/AT)n is the most abundant (8.38%), followed by (AG/CT)n (4.51%). Most of the BES-SSR are located in the non-coding region, but 1.3% of BES-SSRs were found to be associated with transposable element (TE). A total of 400 novel SSR primer pairs were synthesized and their transferability and polymorphism tested on a set of 16 Citrus and Citrus relative's species. Among these 333 (83.25%) were successfully amplified and 260 (65.00%) showed cross-species transferability with Poncirus trifoliata and Fortunella sp. These cross-species transferable markers could be useful for cultivar identification, for genomic study of Citrus, Poncirus and Fortunella sp. Utility of the developed SSR marker was demonstrated by identifying a set of 118 markers each for construction of linkage map of Citrus reticulata and Poncirus trifoliata. Genetic diversity and phylogenetic relationship among 40 Citrus and its related species were conducted with the aid of 25 randomly selected SSR primer pairs and results revealed that citrus genomic SSRs are superior to genic SSR for genetic diversity and germplasm characterization of Citrus spp.

Resonant state expansions

International Nuclear Information System (INIS)

Lind, P.

1993-02-01

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.)

Repeated range expansions and inter-/postglacial recolonization routes of Sargentodoxa cuneata (Oliv.) Rehd. et Wils. (Lardizabalaceae) in subtropical China revealed by chloroplast phylogeography.

Science.gov (United States)

Tian, Shuang; Lei, Shu-Qing; Hu, Wan; Deng, Ling-Li; Li, Bo; Meng, Qing-Lin; Soltis, Douglas E; Soltis, Pamela S; Fan, Deng-Mei; Zhang, Zhi-Yong

2015-04-01

Most plant phylogeographic studies in subtropical China have stressed the importance of multiple refugia and limited admixture among refugia. Little attention has been paid to range expansion and recolonization routes in this region. In this study, we implemented a phylogeographic survey on Sargentodoxa cuneata, a widespread woody deciduous climber in subtropical China to determine if it conforms to the expansion-contraction (EC) model during the Pleistocene. Sequence variation of two chloroplast intergenic spacers (IGSs) in 369 individuals from 54 populations of S. cuneata was examined. Twenty-six chloroplast haplotypes were recovered. One of these (H5) occurred across the range of S. cuneata and was absent from only 13 populations. Sixteen of the 26 haplotypes were connected to H5 by one mutation and displayed a star-like pattern in the haplotype network. All chloroplast haplotypes clustered into two lineages (A and B) in a Bayesian tree, and most haplotypes (18 out of 26) originated during the mid-Pleistocene (0.63-1.07Ma). Demographic analyses detected a recent range expansion that occurred at 95.98ka (CI: 61.7-112.53ka) for Lineage A. The genetic signature of an ancient range expansion after the Middle Pleistocene Transition (MPT) was also evident. Three recolonization routes were identified in subtropical China. The results suggest that temperate plants in subtropical China may conform to the EC model to some extent. However, the genetic signature from multiple historical processes may complicate the phylogeographic patterns of organisms in the region due to the mild Pleistocene climate. This study provides a new perspective for understanding the evolutionary history of temperate plants in subtropical China. Copyright © 2015 Elsevier Inc. All rights reserved.

Ontological function annotation of long non-coding RNAs through hierarchical multi-label classification.

Science.gov (United States)

Zhang, Jingpu; Zhang, Zuping; Wang, Zixiang; Liu, Yuting; Deng, Lei

2018-05-15

Long non-coding RNAs (lncRNAs) are an enormous collection of functional non-coding RNAs. Over the past decades, a large number of novel lncRNA genes have been identified. However, most of the lncRNAs remain function uncharacterized at present. Computational approaches provide a new insight to understand the potential functional implications of lncRNAs. Considering that each lncRNA may have multiple functions and a function may be further specialized into sub-functions, here we describe NeuraNetL2GO, a computational ontological function prediction approach for lncRNAs using hierarchical multi-label classification strategy based on multiple neural networks. The neural networks are incrementally trained level by level, each performing the prediction of gene ontology (GO) terms belonging to a given level. In NeuraNetL2GO, we use topological features of the lncRNA similarity network as the input of the neural networks and employ the output results to annotate the lncRNAs. We show that NeuraNetL2GO achieves the best performance and the overall advantage in maximum F-measure and coverage on the manually annotated lncRNA2GO-55 dataset compared to other state-of-the-art methods. The source code and data are available at http://denglab.org/NeuraNetL2GO/. leideng@csu.edu.cn. Supplementary data are available at Bioinformatics online.

Global Intersection of Long Non-Coding RNAs with Processed and Unprocessed Pseudogenes in the Human Genome

Directory of Open Access Journals (Sweden)

Michael John Milligan

2016-03-01

Full Text Available Pseudogenes are abundant in the human genome and had long been thought of purely as nonfunctional gene fossils. Recent observations point to a role for pseudogenes in regulating genes transcriptionally and post-transcriptionally in human cells. To computationally interrogate the network space of integrated pseudogene and long non-coding RNA regulation in the human transcriptome, we developed and implemented an algorithm to identify all long non-coding RNA (lncRNA transcripts that overlap the genomic spans, and specifically the exons, of any human pseudogenes in either sense or antisense orientation. As inputs to our algorithm, we imported three public repositories of pseudogenes: GENCODE v17 (processed and unprocessed, Ensembl 72; Retroposed Pseudogenes V5 (processed only and Yale Pseudo60 (processed and unprocessed, Ensembl 60; two public lncRNA catalogs: Broad Institute, GENCODE v17; NCBI annotated piRNAs; and NHGRI clinical variants. The data sets were retrieved from the UCSC Genome Database using the UCSC Table Browser. We identified 2277 loci containing exon-to-exon overlaps between pseudogenes, both processed and unprocessed, and long non-coding RNA genes. Of these loci we identified 1167 with Genbank EST and full-length cDNA support providing direct evidence of transcription on one or both strands with exon-to-exon overlaps. The analysis converged on 313 pseudogene-lncRNA exon-to-exon overlaps that were bidirectionally supported by both full-length cDNAs and ESTs. In the process of identifying transcribed pseudogenes, we generated a comprehensive, positionally non-redundant encyclopedia of human pseudogenes, drawing upon multiple, and formerly disparate public pseudogene repositories. Collectively, these observations suggest that pseudogenes are pervasively transcribed on both strands and are common drivers of gene regulation.

Repeating and non-repeating fast radio bursts from binary neutron star mergers

Science.gov (United States)

Yamasaki, Shotaro; Totani, Tomonori; Kiuchi, Kenta

2018-04-01

Most fast radio bursts (FRB) do not show evidence of repetition, and such non-repeating FRBs may be produced at the time of a merger of binary neutron stars (BNS), provided that the BNS merger rate is close to the high end of the currently possible range. However, the merger environment is polluted by dynamical ejecta, which may prohibit the radio signal from propagating. We examine this by using a general-relativistic simulation of a BNS merger, and show that the ejecta appears about 1 ms after the rotation speed of the merged star becomes the maximum. Therefore there is a time window in which an FRB signal can reach outside, and the short duration of non-repeating FRBs can be explained by screening after ejecta formation. A fraction of BNS mergers may leave a rapidly rotating and stable neutron star, and such objects may be the origin of repeating FRBs like FRB 121102. We show that a merger remnant would appear as a repeating FRB on a time scale of ˜1-10 yr, and expected properties are consistent with the observations of FRB 121102. We construct an FRB rate evolution model that includes these two populations of repeating and non-repeating FRBs from BNS mergers, and show that the detection rate of repeating FRBs relative to non-repeating ones rapidly increases with improving search sensitivity. This may explain why only the repeating FRB 121102 was discovered by the most sensitive FRB search with Arecibo. Several predictions are made, including the appearance of a repeating FRB 1-10 yr after a BNS merger that is localized by gravitational waves and subsequent electromagnetic radiation.

microRNA-9 targets the long non-coding RNA MALAT1 for degradation in the nucleus

DEFF Research Database (Denmark)

Leucci, Eleonora; Patella, Francesca; Waage, Johannes

2013-01-01

-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...

Self-force calculations with matched expansions and quasinormal mode sums

International Nuclear Information System (INIS)

Casals, Marc; Dolan, Sam; Ottewill, Adrian C.; Wardell, Barry

2009-01-01

Accurate modeling of gravitational wave emission by extreme-mass ratio inspirals is essential for their detection by the LISA mission. A leading perturbative approach involves the calculation of the self-force acting upon the smaller orbital body. In this work, we present the first application of the Poisson-Wiseman-Anderson method of 'matched expansions' to compute the self-force acting on a point particle moving in a curved spacetime. The method employs two expansions for the Green function, which are, respectively, valid in the 'quasilocal' and 'distant past' regimes, and which may be matched together within the normal neighborhood. We perform our calculation in a static region of the spherically symmetric Nariai spacetime (dS 2 xS 2 ), in which scalar-field perturbations are governed by a radial equation with a Poeschl-Teller potential (frequently used as an approximation to the Schwarzschild radial potential) whose solutions are known in closed form. The key new ingredients in our study are (i) very high order quasilocal expansions and (ii) expansion of the distant past Green function in quasinormal modes. In combination, these tools enable a detailed study of the properties of the scalar-field Green function. We demonstrate that the Green function is singular whenever x and x ' are connected by a null geodesic, and apply asymptotic methods to determine the structure of the Green function near the null wave front. We show that the singular part of the Green function undergoes a transition each time the null wave front passes through a caustic point, following a repeating fourfold sequence δ(σ), 1/πσ, -δ(σ), -1/πσ, etc., where σ is Synge's world function. The matched-expansion method provides insight into the nonlocal properties of the self-force. We show that the self-force generated by the segment of the worldline lying outside the normal neighborhood is not negligible. We apply the matched-expansion method to compute the scalar self-force acting on

3′ terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing

Science.gov (United States)

2013-01-01

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

An Abundant Class of Non-coding DNA Can Prevent Stochastic Gene Silencing in the C. elegans Germline

DEFF Research Database (Denmark)

Frøkjær-Jensen, Christian; Jain, Nimit; Hansen, Loren

2016-01-01

/or structure. Here, we demonstrate that a pervasive non-coding DNA feature in Caenorhabditis elegans, characterized by 10-base pair periodic An/Tn-clusters (PATCs), can license transgenes for germline expression within repressive chromatin domains. Transgenes containing natural or synthetic PATCs are resistant...

Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction.

Science.gov (United States)

De Filippis, Vincenzo; Acquasaliente, Laura; Pontarollo, Giulia; Peterle, Daniele

2018-01-01

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.

Up-regulation of Long Non-coding RNA TUG1 in Hibernating Thirteen-lined Ground Squirrels

Directory of Open Access Journals (Sweden)

Jacques J. Frigault

2016-04-01

Full Text Available Mammalian hibernation is associated with multiple physiological, biochemical, and molecular changes that allow animals to endure colder temperatures. We hypothesize that long non-coding RNAs (lncRNAs, a group of non-coding transcripts with diverse functions, are differentially expressed during hibernation. In this study, expression levels of lncRNAs H19 and TUG1 were assessed via qRT-PCR in liver, heart, and skeletal muscle tissues of the hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus. TUG1 transcript levels were significantly elevated 1.94-fold in skeletal muscle of hibernating animals when compared with euthermic animals. Furthermore, transcript levels of HSF2 also increased 2.44-fold in the skeletal muscle in hibernating animals. HSF2 encodes a transcription factor that can be negatively regulated by TUG1 levels and that influences heat shock protein expression. Thus, these observations support the differential expression of the TUG1–HSF2 axis during hibernation. To our knowledge, this study provides the first evidence for differential expression of lncRNAs in torpid ground squirrels, adding lncRNAs as another group of transcripts modulated in this mammalian species during hibernation.

Isotropic Negative Thermal Expansion Metamaterials.

Science.gov (United States)

Wu, Lingling; Li, Bo; Zhou, Ji

2016-07-13

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.

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

Indian Academy of Sciences (India)

2013-12-04

Dec 4, 2013 ... 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- mal DNA (rDNA) polymorphisms in Old Portuguese bread and durum wheat cultivars. Considering the rRNA genes.

Does query expansion limit our learning? A comparison of social-based expansion to content-based expansion for medical queries on the internet.

Science.gov (United States)

Pentoney, Christopher; Harwell, Jeff; Leroy, Gondy

2014-01-01

Searching for medical information online is a common activity. While it has been shown that forming good queries is difficult, Google's query suggestion tool, a type of query expansion, aims to facilitate query formation. However, it is unknown how this expansion, which is based on what others searched for, affects the information gathering of the online community. To measure the impact of social-based query expansion, this study compared it with content-based expansion, i.e., what is really in the text. We used 138,906 medical queries from the AOL User Session Collection and expanded them using Google's Autocomplete method (social-based) and the content of the Google Web Corpus (content-based). We evaluated the specificity and ambiguity of the expansion terms for trigram queries. We also looked at the impact on the actual results using domain diversity and expansion edit distance. Results showed that the social-based method provided more precise expansion terms as well as terms that were less ambiguous. Expanded queries do not differ significantly in diversity when expanded using the social-based method (6.72 different domains returned in the first ten results, on average) vs. content-based method (6.73 different domains, on average).

RNA expression in a cartilaginous fish cell line reveals ancient 3′ noncoding regions highly conserved in vertebrates

Science.gov (United States)

Forest, David; Nishikawa, Ryuhei; Kobayashi, Hiroshi; Parton, Angela; Bayne, Christopher J.; Barnes, David W.

2007-01-01

We have established a cartilaginous fish cell line [Squalus acanthias embryo cell line (SAE)], a mesenchymal stem cell line derived from the embryo of an elasmobranch, the spiny dogfish shark S. acanthias. Elasmobranchs (sharks and rays) first appeared >400 million years ago, and existing species provide useful models for comparative vertebrate cell biology, physiology, and genomics. Comparative vertebrate genomics among evolutionarily distant organisms can provide sequence conservation information that facilitates identification of critical coding and noncoding regions. Although these genomic analyses are informative, experimental verification of functions of genomic sequences depends heavily on cell culture approaches. Using ESTs defining mRNAs derived from the SAE cell line, we identified lengthy and highly conserved gene-specific nucleotide sequences in the noncoding 3′ UTRs of eight genes involved in the regulation of cell growth and proliferation. Conserved noncoding 3′ mRNA regions detected by using the shark nucleotide sequences as a starting point were found in a range of other vertebrate orders, including bony fish, birds, amphibians, and mammals. Nucleotide identity of shark and human in these regions was remarkably well conserved. Our results indicate that highly conserved gene sequences dating from the appearance of jawed vertebrates and representing potential cis-regulatory elements can be identified through the use of cartilaginous fish as a baseline. Because the expression of genes in the SAE cell line was prerequisite for their identification, this cartilaginous fish culture system also provides a physiologically valid tool to test functional hypotheses on the role of these ancient conserved sequences in comparative cell biology. PMID:17227856

Decoding the non-coding RNAs in Alzheimer's disease.

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Schonrock, Nicole; Götz, Jürgen

2012-11-01

Non-coding RNAs (ncRNAs) are integral components of biological networks with fundamental roles in regulating gene expression. They can integrate sequence information from the DNA code, epigenetic regulation and functions of multimeric protein complexes to potentially determine the epigenetic status and transcriptional network in any given cell. Humans potentially contain more ncRNAs than any other species, especially in the brain, where they may well play a significant role in human development and cognitive ability. This review discusses their emerging role in Alzheimer's disease (AD), a human pathological condition characterized by the progressive impairment of cognitive functions. We discuss the complexity of the ncRNA world and how this is reflected in the regulation of the amyloid precursor protein and Tau, two proteins with central functions in AD. By understanding this intricate regulatory network, there is hope for a better understanding of disease mechanisms and ultimately developing diagnostic and therapeutic tools.

Twisting right to left: A…A mismatch in a CAG trinucleotide repeat overexpansion provokes left-handed Z-DNA conformation.

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Noorain Khan

2015-04-01

Full Text Available Conformational polymorphism of DNA is a major causative factor behind several incurable trinucleotide repeat expansion disorders that arise from overexpansion of trinucleotide repeats located in coding/non-coding regions of specific genes. Hairpin DNA structures that are formed due to overexpansion of CAG repeat lead to Huntington's disorder and spinocerebellar ataxias. Nonetheless, DNA hairpin stem structure that generally embraces B-form with canonical base pairs is poorly understood in the context of periodic noncanonical A…A mismatch as found in CAG repeat overexpansion. Molecular dynamics simulations on DNA hairpin stems containing A…A mismatches in a CAG repeat overexpansion show that A…A dictates local Z-form irrespective of starting glycosyl conformation, in sharp contrast to canonical DNA duplex. Transition from B-to-Z is due to the mechanistic effect that originates from its pronounced nonisostericity with flanking canonical base pairs facilitated by base extrusion, backbone and/or base flipping. Based on these structural insights we envisage that such an unusual DNA structure of the CAG hairpin stem may have a role in disease pathogenesis. As this is the first study that delineates the influence of a single A…A mismatch in reversing DNA helicity, it would further have an impact on understanding DNA mismatch repair.

A Unified Model for Repeating and Non-repeating Fast Radio Bursts

International Nuclear Information System (INIS)

Bagchi, Manjari

2017-01-01

The model that fast radio bursts (FRBs) are caused by plunges of asteroids onto neutron stars can explain both repeating and non-repeating bursts. If a neutron star passes through an asteroid belt around another star, there would be a series of bursts caused by a series of asteroid impacts. Moreover, the neutron star would cross the same belt repetitively if it were in a binary with the star hosting the asteroid belt, leading to a repeated series of bursts. I explore the properties of neutron star binaries that could lead to the only known repeating FRB so far (FRB121102). In this model, the next two epochs of bursts are expected around 2017 February 27 and 2017 December 18. On the other hand, if the asteroid belt is located around the neutron star itself, then a chance fall of an asteroid from that belt onto the neutron star would lead to a non-repeating burst. Even a neutron star grazing an asteroid belt can lead to a non-repeating burst caused by just one asteroid plunge during the grazing. This is possible even when the neutron star is in a binary with the asteroid-hosting star, if the belt and the neutron star orbit are non-coplanar.

A Unified Model for Repeating and Non-repeating Fast Radio Bursts

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Bagchi, Manjari, E-mail: manjari@imsc.res.in [The Institute of Mathematical Sciences (IMSc-HBNI), 4th Cross Road, CIT Campus, Taramani, Chennai 600113 (India)

2017-04-01

The model that fast radio bursts (FRBs) are caused by plunges of asteroids onto neutron stars can explain both repeating and non-repeating bursts. If a neutron star passes through an asteroid belt around another star, there would be a series of bursts caused by a series of asteroid impacts. Moreover, the neutron star would cross the same belt repetitively if it were in a binary with the star hosting the asteroid belt, leading to a repeated series of bursts. I explore the properties of neutron star binaries that could lead to the only known repeating FRB so far (FRB121102). In this model, the next two epochs of bursts are expected around 2017 February 27 and 2017 December 18. On the other hand, if the asteroid belt is located around the neutron star itself, then a chance fall of an asteroid from that belt onto the neutron star would lead to a non-repeating burst. Even a neutron star grazing an asteroid belt can lead to a non-repeating burst caused by just one asteroid plunge during the grazing. This is possible even when the neutron star is in a binary with the asteroid-hosting star, if the belt and the neutron star orbit are non-coplanar.

Repeatability of Cryogenic Multilayer Insulation

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

2017-12-01

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.

Insights into inner ear-specific gene regulation: epigenetics and non-coding RNAs in inner ear development and regeneration

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Avraham, Karen B.

2016-01-01

The vertebrate inner ear houses highly specialized sensory organs, tuned to detect and encode sound, head motion and gravity. Gene expression programs under the control of transcription factors orchestrate the formation and specialization of the non-sensory inner ear labyrinth and its sensory constituents. More recently, epigenetic factors and non-coding RNAs emerged as an additional layer of gene regulation, both in inner ear development and disease. In this review, we provide an overview on how epigenetic modifications and non-coding RNAs, in particular microRNAs (miRNAs), influence gene expression and summarize recent discoveries that highlight their critical role in the proper formation of the inner ear labyrinth and its sensory organs. In contrast to non-mammalian vertebrates, adult mammals lack the ability to regenerate inner ear mechano-sensory hair cells. Finally, we discuss recent insights into how epigenetic factors and miRNAs may facilitate, or in the case of mammals, restrict sensory hair cell regeneration. PMID:27836639

Expansion of PD-1-positive effector CD4 T cells in an experimental model of SLE: contribution to the self-organized criticality theory.

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Miyazaki, Yumi; Tsumiyama, Ken; Yamane, Takashi; Ito, Mitsuhiro; Shiozawa, Shunichi

2013-04-18

We have developed a systems biology concept to explain the origin of systemic autoimmunity. From our studies of systemic lupus erythematosus (SLE) we have concluded that this disease is the inevitable consequence of over-stimulating the host's immune system by repeated exposure to antigen to levels that surpass a critical threshold, which we term the system's "self-organized criticality". We observed that overstimulation of CD4 T cells in mice led to the development of autoantibody-inducing CD4 T cells (aiCD4 T) capable of generating various autoantibodies and pathological lesions identical to those observed in SLE. We show here that this is accompanied by the significant expansion of a novel population of effector T cells characterized by expression of programmed death-1 (PD-1)-positive, CD27(low), CD127(low), CCR7(low) and CD44(high)CD62L(low) markers, as well as increased production of IL-2 and IL-6. In addition, repeated immunization caused the expansion of CD8 T cells into fully-matured cytotoxic T lymphocytes (CTL) that express Ly6C(high)CD122(high) effector and memory markers. Thus, overstimulation with antigen leads to the expansion of a novel effector CD4 T cell population that expresses an unusual memory marker, PD-1, and that may contribute to the pathogenesis of SLE.

Evaluation of Agency Non-Code Layered Pressure Vessels (LPVs) . Volume 2; Appendices

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Prosser, William H.

2014-01-01

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.

Deployment Repeatability

Science.gov (United States)

2016-04-01

evaluating the deployment repeatability builds upon the testing or analysis of deployment kinematics (Chapter 6) and adds repetition. Introduction...material yield or failure during a test. For the purposes of this chapter, zero shift will refer to permanent changes in the structure, while reversible ...the content of other chapters in this book: Gravity Compensation (Chapter 4) and Deployment Kinematics and Dynamics (Chapter 6). Repeating the

A robust and efficient stepwise regression method for building sparse polynomial chaos expansions

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Abraham, Simon, E-mail: Simon.Abraham@ulb.ac.be [Vrije Universiteit Brussel (VUB), Department of Mechanical Engineering, Research Group Fluid Mechanics and Thermodynamics, Pleinlaan 2, 1050 Brussels (Belgium); Raisee, Mehrdad [School of Mechanical Engineering, College of Engineering, University of Tehran, P.O. Box: 11155-4563, Tehran (Iran, Islamic Republic of); Ghorbaniasl, Ghader; Contino, Francesco; Lacor, Chris [Vrije Universiteit Brussel (VUB), Department of Mechanical Engineering, Research Group Fluid Mechanics and Thermodynamics, Pleinlaan 2, 1050 Brussels (Belgium)

2017-03-01

Polynomial Chaos (PC) expansions are widely used in various engineering fields for quantifying uncertainties arising from uncertain parameters. The computational cost of classical PC solution schemes is unaffordable as the number of deterministic simulations to be calculated grows dramatically with the number of stochastic dimension. This considerably restricts the practical use of PC at the industrial level. A common approach to address such problems is to make use of sparse PC expansions. This paper presents a non-intrusive regression-based method for building sparse PC expansions. The most important PC contributions are detected sequentially through an automatic search procedure. The variable selection criterion is based on efficient tools relevant to probabilistic method. Two benchmark analytical functions are used to validate the proposed algorithm. The computational efficiency of the method is then illustrated by a more realistic CFD application, consisting of the non-deterministic flow around a transonic airfoil subject to geometrical uncertainties. To assess the performance of the developed methodology, a detailed comparison is made with the well established LAR-based selection technique. The results show that the developed sparse regression technique is able to identify the most significant PC contributions describing the problem. Moreover, the most important stochastic features are captured at a reduced computational cost compared to the LAR method. The results also demonstrate the superior robustness of the method by repeating the analyses using random experimental designs.

Malignant transformation of colonic epithelial cells by a colon-derived long noncoding RNA

International Nuclear Information System (INIS)

Franklin, Jeffrey L.; Rankin, Carl R.; Levy, Shawn; Snoddy, Jay R.; Zhang, Bing; Washington, Mary Kay; Thomson, J. Michael; Whitehead, Robert H.; Coffey, Robert J.

2013-01-01

Highlights: •Non-coding RNAs are found in the colonic crypt progenitor compartment. •Colonocytes transformed by ncNRFR are highly invasive and metastatic. •ncNRFR has a region similar to the miRNA, let-7 family. •ncNRFR expression alters let-7 activity as measured by reporter construct. •ncNRFR expression upregulates let-7b targets. -- Abstract: Recent progress has been made in the identification of protein-coding genes and miRNAs that are expressed in and alter the behavior of colonic epithelia. However, the role of long non-coding RNAs (lncRNAs) in colonic homeostasis is just beginning to be explored. By gene expression profiling of post-mitotic, differentiated tops and proliferative, progenitor-compartment bottoms of microdissected adult mouse colonic crypts, we identified several lncRNAs more highly expressed in crypt bottoms. One identified lncRNA, designated non-coding Nras functional RNA (ncNRFR), resides within the Nras locus but appears to be independent of the Nras coding transcript. Stable overexpression of ncNRFR in non-transformed, conditionally immortalized mouse colonocytes results in malignant transformation, as determined by growth in soft agar and formation of highly invasive tumors in nude mice. Moreover, ncNRFR appears to inhibit the function of the tumor suppressor let-7. These results suggest precise regulation of ncNRFR is necessary for proper cell growth in the colonic crypt, and its misregulation results in neoplastic transformation

Developmental programming of long non-coding RNAs during postnatal liver maturation in mice.

Directory of Open Access Journals (Sweden)

Lai Peng

Full Text Available The liver is a vital organ with critical functions in metabolism, protein synthesis, and immune defense. Most of the liver functions are not mature at birth and many changes happen during postnatal liver development. However, it is unclear what changes occur in liver after birth, at what developmental stages they occur, and how the developmental processes are regulated. Long non-coding RNAs (lncRNAs are involved in organ development and cell differentiation. Here, we analyzed the transcriptome of lncRNAs in mouse liver from perinatal (day -2 to adult (day 60 by RNA-Sequencing, with an attempt to understand the role of lncRNAs in liver maturation. We found around 15,000 genes expressed, including about 2,000 lncRNAs. Most lncRNAs were expressed at a lower level than coding RNAs. Both coding RNAs and lncRNAs displayed three major ontogenic patterns: enriched at neonatal, adolescent, or adult stages. Neighboring coding and non-coding RNAs showed the trend to exhibit highly correlated ontogenic expression patterns. Gene ontology (GO analysis revealed that some lncRNAs enriched at neonatal ages have their neighbor protein coding genes also enriched at neonatal ages and associated with cell proliferation, immune activation related processes, tissue organization pathways, and hematopoiesis; other lncRNAs enriched at adolescent ages have their neighbor protein coding genes associated with different metabolic processes. These data reveal significant functional transition during postnatal liver development and imply the potential importance of lncRNAs in liver maturation.

Non-coding RNAs in endometriosis: a narrative review.

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

2018-04-25

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

A 3' UTR-Derived Small RNA Provides the Regulatory Noncoding Arm of the Inner Membrane Stress Response.

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Chao, Yanjie; Vogel, Jörg

2016-02-04

Small RNAs (sRNAs) from conserved noncoding genes are crucial regulators in bacterial signaling pathways but have remained elusive in the Cpx response to inner membrane stress. Here we report that an alternative biogenesis pathway releasing the conserved mRNA 3' UTR of stress chaperone CpxP as an ∼60-nt sRNA provides the noncoding arm of the Cpx response. This so-called CpxQ sRNA, generated by general mRNA decay through RNase E, acts as an Hfq-dependent repressor of multiple mRNAs encoding extracytoplasmic proteins. Both CpxQ and the Cpx pathway are required for cell survival under conditions of dissipation of membrane potential. Our discovery of CpxQ illustrates how the conversion of a transcribed 3' UTR into an sRNA doubles the output of a single mRNA to produce two factors with spatially segregated functions during inner membrane stress: a chaperone that targets problematic proteins in the periplasm and a regulatory RNA that dampens their synthesis in the cytosol. Copyright © 2016 Elsevier Inc. All rights reserved.

Energy expansion planning by considering electrical and thermal expansion simultaneously

International Nuclear Information System (INIS)

Abbasi, Ali Reza; Seifi, Ali Reza

2014-01-01

Highlights: • This paper focused on the expansion planning optimization of energy systems. • Employing two form of energy: the expansion of electrical and thermal energies. • The main objective is to minimize the costs. • A new Modified Honey Bee Mating Optimization (MHBMO) algorithm is applied. - Abstract: This study focused on the expansion planning optimization of energy systems employing two forms of energy: the expansion of electrical and thermal energies simultaneously. The main objective of this investigation is confirming network adequacy by adding new equipment to the network, over a given planning horizon. The main objective of the energy expansion planning (EEP) is to minimize the real energy loss, voltage deviation and the total cost of installation equipments. Since the objectives are different and incommensurable, it is difficult to solve the problem by the conventional approaches that may optimize a single objective. So, the meta-heuristic algorithm is applied to this problem. Here, Honey Bee Mating Optimization algorithm (HBMO) as a new evolutionary optimization algorithm is utilized. In order to improve the total ability of HBMO for the global search and exploration, a new modification process is suggested such a way that the algorithm will search the total search space globally. Also, regarding the uncertainties of the new complicated energy systems, in this paper for the first time, the EEP problem is investigated in a stochastic environment by the use of probabilistic load flow technique based on Point Estimate Method (PEM). In order to evaluate the feasibility and effectiveness of the proposed algorithm, two modified test systems are used as case studies

Reconfigurable multiport EPON repeater

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

2009-11-01

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.

Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion.

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Koutsis, G; Karadima, G; Pandraud, A; Sweeney, M G; Paudel, R; Houlden, H; Wood, N W; Panas, M

2012-09-01

Huntington’s disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes formutations causing HDL2, SCA17, SCA1, SCA2, SCA3,SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.

Evolutionary analysis reveals regulatory and functional landscape of coding and non-coding RNA editing.

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Zhang, Rui; Deng, Patricia; Jacobson, Dionna; Li, Jin Billy

2017-02-01

Adenosine-to-inosine RNA editing diversifies the transcriptome and promotes functional diversity, particularly in the brain. A plethora of editing sites has been recently identified; however, how they are selected and regulated and which are functionally important are largely unknown. Here we show the cis-regulation and stepwise selection of RNA editing during Drosophila evolution and pinpoint a large number of functional editing sites. We found that the establishment of editing and variation in editing levels across Drosophila species are largely explained and predicted by cis-regulatory elements. Furthermore, editing events that arose early in the species tree tend to be more highly edited in clusters and enriched in slowly-evolved neuronal genes, thus suggesting that the main role of RNA editing is for fine-tuning neurological functions. While nonsynonymous editing events have been long recognized as playing a functional role, in addition to nonsynonymous editing sites, a large fraction of 3'UTR editing sites is evolutionarily constrained, highly edited, and thus likely functional. We find that these 3'UTR editing events can alter mRNA stability and affect miRNA binding and thus highlight the functional roles of noncoding RNA editing. Our work, through evolutionary analyses of RNA editing in Drosophila, uncovers novel insights of RNA editing regulation as well as its functions in both coding and non-coding regions.

Evaluation of Long Stress-Induced Non-coding Transcripts 5 Polymorphism in Iranian Patients with Bladder Cancer

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Mahla Nazari

2016-07-01

Full Text Available Background: Bladder cancer (BC is the most commonly diagnosed genitourinary cancer in Iran, presented in both men and women. BC is a multifactorial trait resulting from the complex interaction between several genes and environmental factors. Long stress-induced non-coding transcript 5 (LSINCT5, a member of the long non-coding RNAs, is abundantly expressed in high proliferative cells, as well as the cells vulnerable to cellular stress in response to chemical carcinogens. This case-control study aimed to determine any association between LSINCT5 rs2962586 polymorphism and bladder cancer. Materials and Methods: A group of 150 patients with BC were compared with 143 subjects as a control group. Genotyping of the rs2962586 polymorphism was done using tetra- primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR method. Results: Genotype and allele distribution were not significantly different between the case and control groups. Smoking was found to be the confounding risk factor for bladder cancer. Conclusion: Considering the result of our analyses, it seems that LSINCT5 could not affect individual susceptibility to BC among Iranian patients, however, it can be considered as a disease predictor among smokers.

Expansion joints for LMFBR

International Nuclear Information System (INIS)

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

1980-01-01

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

The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.

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Ciura, Sorana; Sellier, Chantal; Campanari, Maria-Letizia; Charlet-Berguerand, Nicolas; Kabashi, Edor

2016-08-02

The most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is repeat expansion of a hexanucleotide sequence (GGGGCC) within the C9orf72 genomic sequence. To elucidate the functional role of C9orf72 in disease pathogenesis, we identified certain molecular interactors of this factor. We determined that C9orf72 exists in a complex with SMCR8 and WDR41 and that this complex acts as a GDP/GTP exchange factor for RAB8 and RAB39, 2 RAB GTPases involved in macroautophagy/autophagy. Consequently, C9orf72 depletion in neuronal cultures leads to accumulation of unresolved aggregates of SQSTM1/p62 and phosphorylated TARDBP/TDP-43. However, C9orf72 reduction does not lead to major neuronal toxicity, suggesting that a second stress may be required to induce neuronal cell death. An intermediate size of polyglutamine repeats within ATXN2 is an important genetic modifier of ALS-FTD. We found that coexpression of intermediate polyglutamine repeats (30Q) of ATXN2 combined with C9orf72 depletion increases the aggregation of ATXN2 and neuronal toxicity. These results were confirmed in zebrafish embryos where partial C9orf72 knockdown along with intermediate (but not normal) repeat expansions in ATXN2 causes locomotion deficits and abnormal axonal projections from spinal motor neurons. These results demonstrate that C9orf72 plays an important role in the autophagy pathway while genetically interacting with another major genetic risk factor, ATXN2, to contribute to ALS-FTD pathogenesis.

nocoRNAc: Characterization of non-coding RNAs in prokaryotes

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Nieselt Kay

2011-01-01

Full Text Available Abstract Background The interest in non-coding RNAs (ncRNAs constantly rose during the past few years because of the wide spectrum of biological processes in which they are involved. This led to the discovery of numerous ncRNA genes across many species. However, for most organisms the non-coding transcriptome still remains unexplored to a great extent. Various experimental techniques for the identification of ncRNA transcripts are available, but as these methods are costly and time-consuming, there is a need for computational methods that allow the detection of functional RNAs in complete genomes in order to suggest elements for further experiments. Several programs for the genome-wide prediction of functional RNAs have been developed but most of them predict a genomic locus with no indication whether the element is transcribed or not. Results We present NOCORNAc, a program for the genome-wide prediction of ncRNA transcripts in bacteria. NOCORNAc incorporates various procedures for the detection of transcriptional features which are then integrated with functional ncRNA loci to determine the transcript coordinates. We applied RNAz and NOCORNAc to the genome of Streptomyces coelicolor and detected more than 800 putative ncRNA transcripts most of them located antisense to protein-coding regions. Using a custom design microarray we profiled the expression of about 400 of these elements and found more than 300 to be transcribed, 38 of them are predicted novel ncRNA genes in intergenic regions. The expression patterns of many ncRNAs are similarly complex as those of the protein-coding genes, in particular many antisense ncRNAs show a high expression correlation with their protein-coding partner. Conclusions We have developed NOCORNAc, a framework that facilitates the automated characterization of functional ncRNAs. NOCORNAc increases the confidence of predicted ncRNA loci, especially if they contain transcribed ncRNAs. NOCORNAc is not restricted to

Up-regulation of Long Non-coding RNA TUG1 in Hibernating Thirteen-lined Ground Squirrels.

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Frigault, Jacques J; Lang-Ouellette, Daneck; Morin, Pier

2016-04-01

Mammalian hibernation is associated with multiple physiological, biochemical, and molecular changes that allow animals to endure colder temperatures. We hypothesize that long non-coding RNAs (lncRNAs), a group of non-coding transcripts with diverse functions, are differentially expressed during hibernation. In this study, expression levels of lncRNAsH19 and TUG1 were assessed via qRT-PCR in liver, heart, and skeletal muscle tissues of the hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus). TUG1 transcript levels were significantly elevated 1.94-fold in skeletal muscle of hibernating animals when compared with euthermic animals. Furthermore, transcript levels of HSF2 also increased 2.44-fold in the skeletal muscle in hibernating animals. HSF2 encodes a transcription factor that can be negatively regulated by TUG1 levels and that influences heat shock protein expression. Thus, these observations support the differential expression of the TUG1-HSF2 axis during hibernation. To our knowledge, this study provides the first evidence for differential expression of lncRNAs in torpid ground squirrels, adding lncRNAs as another group of transcripts modulated in this mammalian species during hibernation. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels.

Science.gov (United States)

Lu, Yunqi; Hu, Zhongyi; Mangala, Lingegowda S; Stine, Zachary E; Hu, Xiaowen; Jiang, Dahai; Xiang, Yan; Zhang, Youyou; Pradeep, Sunila; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; DeMarzo, Angelo M; Sood, Anil K; Zhang, Lin; Dang, Chi V

2018-01-01

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers. Significance: These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. Cancer Res; 78(1); 64-74. ©2017 AACR . ©2017 American Association for Cancer Research.

Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells.

Science.gov (United States)

Kwon, Ilmin; Xiang, Siheng; Kato, Masato; Wu, Leeju; Theodoropoulos, Pano; Wang, Tao; Kim, Jiwoong; Yun, Jonghyun; Xie, Yang; McKnight, Steven L

2014-09-05

Many RNA regulatory proteins controlling pre-messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death. Copyright © 2014, American Association for the Advancement of Science.

Expansion joints for LMFBR

Energy Technology Data Exchange (ETDEWEB)

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

1979-10-15

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 development reviewed. 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.

Interplay of noncoding RNAs, mRNAs, and proteins during the growth of eukaryotic cells

International Nuclear Information System (INIS)

Zhdanov, V. P.

2010-01-01

Numerous biological functions of noncoding RNAs (ncRNAs) in eukaryotic cells are based primarily on their ability to pair with target mRNAs and then either to prevent translation or to result in rapid degradation of the mRNA-ncRNA complex. Using a general model describing this scenario, we show that ncRNAs may help to maintain constant mRNA and protein concentrations during the growth of cells. The possibility of observation of this effect on the global scale is briefly discussed.

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

1996-08-09

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.

Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis

DEFF Research Database (Denmark)

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

2012-01-01

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...... of genes with developmental functions. The temporal expression profile of lncRNAs revealed two novel properties: lncRNAs are expressed in narrower time windows than protein-coding genes and are specifically enriched in early-stage embryos. In addition, several lncRNAs show tissue-specific expression...... 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...

Expansions for Coulomb wave functions

NARCIS (Netherlands)

Boersma, J.

1969-01-01

In this paper we derive a number of expansions for Whittaker functions, regular and irregular Coulomb wave functions. The main result consists of a new expansion for the irregular Coulomb wave functions of orders zero and one in terms of regular Coulomb wave functions. The latter expansions are

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155

OpenAIRE

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-01-01

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in ...

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

Science.gov (United States)

Usdin, Karen; Hayward, Bruce E.; Kumari, Daman; Lokanga, Rachel A.; Sciascia, Nicholas; Zhao, Xiao-Nan

2014-01-01

The Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor/ataxia syndrome (FXTAS), the fertility disorder, Fragile X-associated primary ovarian insufficiency (FXPOI) and the intellectual disability, Fragile X syndrome (FXS). The pathology in all these diseases is related to the number of CGG/CCG-repeats in the 5′ UTR of the Fragile X mental retardation 1 (FMR1) gene. The repeats are prone to continuous expansion and the increase in repeat number has paradoxical effects on gene expression increasing transcription on mid-sized alleles and decreasing it on longer ones. In some cases the repeats can simultaneously both increase FMR1 mRNA production and decrease the levels of the FMR1 gene product, Fragile X mental retardation 1 protein (FMRP). Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by an FMRP deficiency, the clinical picture is turning out to be more complex than once appreciated. Added complications result from the fact that increasing repeat numbers make the alleles somatically unstable. Thus many individuals have a complex mixture of different sized alleles in different cells. Furthermore, it has become apparent that the eponymous fragile site, once thought to be no more than a useful diagnostic criterion, may have clinical consequences for females who inherit chromosomes that express this site. This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility. It will also touch on what current and future options are for ameliorating some of these effects. PMID:25101111

On the classification of long non-coding RNAs

KAUST Repository

Ma, Lina

2013-06-01

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.

Conformal expansions and renormalons

Energy Technology Data Exchange (ETDEWEB)

Rathsman, J.

2000-02-07

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.

Functional and Structural Characterization of a Receptor-Like Kinase Involved in Germination and Cell Expansion in Arabidopsis

Science.gov (United States)

Wu, Zhen; Liang, Shan; Song, Wen; Lin, Guangzhong; Wang, Weiguang; Zhang, Heqiao; Han, Zhifu; Chai, Jijie

2017-01-01

Leucine-rich repeat receptor-like kinases (LRR-RLKs) are widespread in different plant species and play important roles in growth and development. Germination inhibition is vital for the completion of seed maturation and cell expansion is a fundamental cellular process driving plant growth. Here, we report genetic and structural characterizations of a functionally uncharacterized LRR-RLK, named GRACE (Germination Repression and Cell Expansion receptor-like kinase). Overexpression of GRACE in Arabidopsis exhibited delayed germination, enlarged cotyledons, rosette leaves and stubbier petioles. Conversely, these phenotypes were reversed in the T-DNA insertion knock-down mutant grace-1 plants. A crystal structure of the extracellular domain of GRACE (GRACE-LRR) determined at the resolution of 3.0 Å revealed that GRACE-LRR assumed a right-handed super-helical structure with an island domain (ID). Structural comparison showed that structure of the ID in GRACE-LRR is strikingly different from those observed in other LRR-RLKs. This structural observation implies that GRACE might perceive a new ligand for signaling. Collectively, our data support roles of GRACE in repressing seed germination and promoting cell expansion of Arabidopsis, presumably by perception of unknown ligand(s). PMID:29213277

Bearing-Mounting Concept Accommodates Thermal Expansion

Science.gov (United States)

Nespodzany, Robert; Davis, Toren S.

1995-01-01

Pins or splines allow radial expansion without slippage. Design concept for mounting rotary bearing accommodates differential thermal expansion between bearing and any structure(s) to which bearing connected. Prevents buildup of thermal stresses by allowing thermal expansion to occur freely but accommodating expansion in such way not to introduce looseness. Pin-in-slot configuration also maintains concentricity.

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.

Science.gov (United States)

Wu, Deng-Chyang; Wang, Sophie S W; Liu, Chung-Jung; Wuputra, Kenly; Kato, Kohsuke; Lee, Yen-Liang; Lin, Ying-Chu; Tsai, Ming-Ho; Ku, Chia-Chen; Lin, Wen-Hsin; Wang, Shin-Wei; Kishikawa, Shotaro; Noguchi, Michiya; Wu, Chu-Chieh; Chen, Yi-Ting; Chai, Chee-Yin; Lin, Chen-Lung Steve; Kuo, Kung-Kai; Yang, Ya-Han; Miyoshi, Hiroyuki; Nakamura, Yukio; Saito, Shigeo; Nagata, Kyosuke; Lin, Chang-Shen; Yokoyama, Kazunari K

2017-10-01

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128. © 2017 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC

International Nuclear Information System (INIS)

Congrains, Ada; Kamide, Kei; Katsuya, Tomohiro; Yasuda, Osamu; Oguro, Ryousuke; Yamamoto, Koichi; Ohishi, Mitsuru; Rakugi, Hiromi

2012-01-01

Highlights: ► ANRIL maps in the strongest susceptibility locus for cardiovascular disease. ► Silencing of ANRIL leads to altered expression of tissue remodeling-related genes. ► The effects of ANRIL on gene expression are splicing variant specific. ► ANRIL affects progression of cardiovascular disease by regulating proliferation and apoptosis pathways. -- Abstract: ANRIL is a newly discovered non-coding RNA lying on the strongest genetic susceptibility locus for cardiovascular disease (CVD) in the chromosome 9p21 region. Genome-wide association studies have been linking polymorphisms in this locus with CVD and several other major diseases such as diabetes and cancer. The role of this non-coding RNA in atherosclerosis progression is still poorly understood. In this study, we investigated the implication of ANRIL in the modulation of gene sets directly involved in atherosclerosis. We designed and tested siRNA sequences to selectively target two exons (exon 1 and exon 19) of the transcript and successfully knocked down expression of ANRIL in human aortic vascular smooth muscle cells (HuAoVSMC). We used a pathway-focused RT-PCR array to profile gene expression changes caused by ANRIL knock down. Notably, the genes affected by each of the siRNAs were different, suggesting that different splicing variants of ANRIL might have distinct roles in cell physiology. Our results suggest that ANRIL splicing variants play a role in coordinating tissue remodeling, by modulating the expression of genes involved in cell proliferation, apoptosis, extra-cellular matrix remodeling and inflammatory response to finally impact in the risk of cardiovascular disease and other pathologies.

The leucine-rich repeat structure.

Science.gov (United States)

Bella, J; Hindle, K L; McEwan, P A; Lovell, S C

2008-08-01

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.

Population genetics and new insight into range of CAG repeats of spinocerebellar ataxia type 3 in the Han Chinese population.

Directory of Open Access Journals (Sweden)

Shi-Rui Gan

Full Text Available Spinocerebellar ataxia type 3 (SCA3, also called Machado-Joseph disease (MJD, is one of the most common SCAs worldwide and caused by a CAG repeat expansion located in ATXN3 gene. Based on the CAG repeat numbers, alleles of ATXN3 can be divided into normal alleles (ANs, intermediate alleles (AIs and expanded alleles (AEs. It was controversial whether the frequency of large normal alleles (large ANs is related to the prevalence of SCA3 or not. And there were huge chaos in the comprehension of the specific numbers of the range of CAG repeats which is fundamental for genetic analysis of SCA3. To illustrate these issues, we made a novel CAG repeat ladder to detect CAG repeats of ATXN3 in 1003 unrelated Chinese normal individuals and studied haplotypes defined by three single nucleotide polymorphisms (SNPs closed to ATXN3. We found that the number of CAG repeats ranged from 13 to 49, among them, 14 was the most common number. Positive skew, the highest frequency of large ANs and 4 AIs which had never been reported before were found. Also, AEs and large ANs shared the same haplotypes defined by the SNPs. Based on these data and other related studies, we presumed that de novo mutations of ATXN3 emerging from large ANs are at least one survival mechanisms of mutational ATXN3 and we can redefine the range of CAG repeats as: ANs≤44, 45 ≤AIs ≤49 and AEs≥50.

Genome-wide identification and functional prediction of nitrogen-responsive intergenic and intronic long non-coding RNAs in maize (Zea mays L.).

Science.gov (United States)

Lv, Yuanda; Liang, Zhikai; Ge, Min; Qi, Weicong; Zhang, Tifu; Lin, Feng; Peng, Zhaohua; Zhao, Han

2016-05-11

Nitrogen (N) is an essential and often limiting nutrient to plant growth and development. Previous studies have shown that the mRNA expressions of numerous genes are regulated by nitrogen supplies; however, little is known about the expressed non-coding elements, for example long non-coding RNAs (lncRNAs) that control the response of maize (Zea mays L.) to nitrogen. LncRNAs are a class of non-coding RNAs larger than 200 bp, which have emerged as key regulators in gene expression. In this study, we surveyed the intergenic/intronic lncRNAs in maize B73 leaves at the V7 stage under conditions of N-deficiency and N-sufficiency using ribosomal RNA depletion and ultra-deep total RNA sequencing approaches. By integration with mRNA expression profiles and physiological evaluations, 7245 lncRNAs and 637 nitrogen-responsive lncRNAs were identified that exhibited unique expression patterns. Co-expression network analysis showed that the nitrogen-responsive lncRNAs were enriched mainly in one of the three co-expressed modules. The genes in the enriched module are mainly involved in NADH dehydrogenase activity, oxidative phosphorylation and the nitrogen compounds metabolic process. We identified a large number of lncRNAs in maize and illustrated their potential regulatory roles in response to N stress. The results lay the foundation for further in-depth understanding of the molecular mechanisms of lncRNAs' role in response to nitrogen stresses.

Cloning and over expression of non-coding RNA rprA in E.coli and its resistance to Kanamycin without osmotic shock.

Science.gov (United States)

Sahni, Azita; Hajjari, Mohammadreza; Raheb, Jamshid; Foroughmand, Ali Mohammad; Asgari, Morteza

2017-01-01

Recent reports have indicated that small RNAs have key roles in the response of the E.coli to stress and also in the regulating of virulence factors. It seems that some small non-coding RNAs are involved in multidrug resistance. Previous studies have indicated that rprA can increase the tolerance to Kanamycin in RcsB-deficient Escherichia coli K-12 following osmotic shock. The current study aims to clone and over-express the non-coding RNA rprA in E.coli and investigate its effect on the bacterial resistance to Kanamycin without any osmotic shock. For this purpose, rprA gene was amplified by the PCR and then cloned into the PET-28a (+) vector. The recombinant plasmid was transformed into wild type E.coli BL21 (DE3). The over expression was induced by IPTG and confirmed by qRT-PCR. The resistance to the kanamycin was then measured in different times by spectrophotometry. The statistical analysis showed that the rprA can increase the resistance to Kanamycin in Ecoli K12. The interaction between rprA and rpoS was reviewed and analyzed by in silico methods. The results showed that the bacteria with over-expressed rprA were more resistant to Kanamycin. The present study is an important step to prove the role of non-coding RNA rprA in bacterial resistance. The data can be the basis for future works and can also help to develop and deliver next-generation antibiotics.

Non-coding RNAs: New therapeutic targets and opportunities for hepatocellular carcinoma

Directory of Open Access Journals (Sweden)

Yu Cuiyun

2016-02-01

Full Text Available Non-coding RNAs (ncRNA are RNA molecules without protein coding functions owing to the lack of an open reading frame (ORF. Based on the length, ncRNAs can be divided into long and short ncRNAs; short ncRNAs include miRNAs and piRNAs. Hepatocellular carcinoma (HCC is among the most frequent forms of cancer worldwide and its incidence is increasing rapidly. Studies have found that ncRNAs are likely to play a crucial role in a variety of biological processes including the pathogenesis and progression of HCC. In this review, we summarized the regulation mechanism and biological functions of ncRNAs in HCC with respect to its application in HCC diagnosis, therapy and prognosis.

δ expansion applied to quantum electrodynamics

International Nuclear Information System (INIS)

Bender, C.M.; Boettcher, S.; Milton, K.A.

1992-01-01

A recently proposed technique known as the δ expansion provides a nonperturbative treatment of a quantum field theory. The δ-expansion approach can be applied to electrodynamics in such a way that local gauge invariance is preserved. In this paper it is shown that for electrodynamic processes involving only external photon lines and no external electron lines the δ expansion is equivalent to a fermion loop expansion. That is, the coefficient of δ n in the δ expansion is precisely the sum of all n-electron-loop Feynman diagrams in a conventional weak-coupling approximation. This equivalence does not extend to processes having external electron lines. When external electron lines are present, the δ expansion is truly nonperturbative and does not have a simple interpretation as a resummation of conventional Feynman diagrams. To illustrate the nonperturbative character of the δ expansion we perform a speculative calculation of the fermion condensate in the massive Schwinger model in the limit of large coupling constant

The noncoding-RNA landscape in cardiovascular health and disease

Directory of Open Access Journals (Sweden)

Vittoria Di Mauro

2018-03-01

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.

Novel Approach to Analyzing MFE of Noncoding RNA Sequences.

Science.gov (United States)

George, Tina P; Thomas, Tessamma

2016-01-01

Genomic studies have become noncoding RNA (ncRNA) centric after the study of different genomes provided enormous information on ncRNA over the past decades. The function of ncRNA is decided by its secondary structure, and across organisms, the secondary structure is more conserved than the sequence itself. In this study, the optimal secondary structure or the minimum free energy (MFE) structure of ncRNA was found based on the thermodynamic nearest neighbor model. MFE of over 2600 ncRNA sequences was analyzed in view of its signal properties. Mathematical models linking MFE to the signal properties were found for each of the four classes of ncRNA analyzed. MFE values computed with the proposed models were in concordance with those obtained with the standard web servers. A total of 95% of the sequences analyzed had deviation of MFE values within ±15% relative to those obtained from standard web servers.

Hysteresis of magnetostructural transitions: Repeatable and non-repeatable processes

Science.gov (United States)

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

2014-02-01

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.

Hysteresis of magnetostructural transitions: Repeatable and non-repeatable processes

International Nuclear Information System (INIS)

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

2014-01-01

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

Lnc2Catlas: an atlas of long noncoding RNAs associated with risk of cancers.

Science.gov (United States)

Ren, Chao; An, Gaole; Zhao, Chenghui; Ouyang, Zhangyi; Bo, Xiaochen; Shu, Wenjie

2018-01-30

Lnc2Catlas ( http://lnc2catlas.bioinfotech.org/ ) is an atlas of long noncoding RNAs (lncRNAs) associated with cancer risk. LncRNAs are a class of functional noncoding RNAs with lengths over 200 nt and play a vital role in diverse biological processes. Increasing evidence shows that lncRNA dysfunction is associated with many human cancers/diseases. It is therefore important to understand the underlying relationship between lncRNAs and cancers. To this end, we developed Lnc2Catlas to compile quantitative associations between lncRNAs and cancers using three computational methods, assessing secondary structure disruption, lncRNA-protein interactions, and co-expression networks. Lnc2Catlas was constructed based on 27,670 well-annotated lncRNAs, 31,749,216 SNPs, 1,473 cancer-associated proteins, and 10,539 expression profiles of 33 cancers from The Cancer Genome Atlas (TCGA). Lnc2Catlas contains 247,124 lncRNA-SNP pairs, over two millions lncRNA-protein interactions, and 6,902 co-expression clusters. We deposited Lnc2Catlas on Alibaba Cloud and developed interactive, mobile device-compatible, user-friendly interfaces to help users search and browse Lnc2Catlas with ultra-low latency. Lnc2Catlas can aid in the investigation of associations between lncRNAs and cancers and can provide candidate lncRNAs for further experimental validation. Lnc2Catlas will facilitate an understanding of the associations between lncRNAs and cancer and will help reveal the critical role of lncRNAs in cancer.

Revisiting the TALE repeat.

Science.gov (United States)

Deng, Dong; Yan, Chuangye; Wu, Jianping; Pan, Xiaojing; Yan, Nieng

2014-04-01

Transcription activator-like (TAL) effectors specifically bind to double stranded (ds) DNA through a central domain of tandem repeats. Each TAL effector (TALE) repeat comprises 33-35 amino acids and recognizes one specific DNA base through a highly variable residue at a fixed position in the repeat. Structural studies have revealed the molecular basis of DNA recognition by TALE repeats. Examination of the overall structure reveals that the basic building block of TALE protein, namely a helical hairpin, is one-helix shifted from the previously defined TALE motif. Here we wish to suggest a structure-based re-demarcation of the TALE repeat which starts with the residues that bind to the DNA backbone phosphate and concludes with the base-recognition hyper-variable residue. This new numbering system is consistent with the α-solenoid superfamily to which TALE belongs, and reflects the structural integrity of TAL effectors. In addition, it confers integral number of TALE repeats that matches the number of bound DNA bases. We then present fifteen crystal structures of engineered dHax3 variants in complex with target DNA molecules, which elucidate the structural basis for the recognition of bases adenine (A) and guanine (G) by reported or uncharacterized TALE codes. Finally, we analyzed the sequence-structure correlation of the amino acid residues within a TALE repeat. The structural analyses reported here may advance the mechanistic understanding of TALE proteins and facilitate the design of TALEN with improved affinity and specificity.

Decrease in the CGG{sub n} trinucleotide repeat mutation of the fragile X syndrome to normal size range during paternal transmission

Energy Technology Data Exchange (ETDEWEB)

Vaeisaenen, M.L.; Haataja, R.; Leisti, J. [Oulu Univ. Hospital (Finland)

1996-09-01

The fragile X syndrome, the most common inherited form of mental retardation, is caused by the expansion of a CGG{sub n} trinucleotide repeat in the FMR-1 gene. Although the repeat number usually increases during transmission, few cases with reduction of an expanded CGG{sub n} repeat back to the normal size range have been reported. We describe for the first time a family in which such reduction has occurred in the paternal transmission. The paternal premutation ({Delta} = 300 hp) was not detected in one of the five daughters or in the son of this daughter, although he had the grandpaternal RFLP haplotype. Instead, fragments indicating the normal CGG{sub n} repeat size were seen on a Southern blot probed with StB12.3. PCR analysis of the CGG{sub n} repeat confirmed this; in addition to a maternal allele of 30 repeats, an allele of 34 repeats was detected in the daughter and, further, in her son. Sequencing of this new allele revealed a pure CGG{sub n} repeat configuration without AGG interruptions. No evidence for a somatic mosaicism of a premutation allele in the daughter or a normal allele in her father was detected when investigating DNA derived from blood lymphocytes and skin fibroblasts. Another unusual finding in this family was lack of the PCR product of the microsatellite marker RS46 (DXS548) in one of the grandmaternal X chromosomes, detected as incompatible inheritance of RS46 alleles. The results suggest an intergenerational reduction in the CGG{sub n} repeat from premutation size to the normal size range and stable transmission of the contracted repeat to the next generation. However, paternal germ-line mosaicism could not be excluded as an alternative explanation for the reverse mutation. 37 refs., 4 figs.

The Population Origins and Expansion of Feral Cats in Australia

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Yurchenko, Andrey A.; David, Victor A.; Scott, Rachael; Koepfli, Klaus-Peter; Driscoll, Carlos; O’Brien, Stephen J.; Menotti-Raymond, Marilyn

2016-01-01

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

Long non-coding RNA expression profiles in hereditary haemorrhagic telangiectasia

DEFF Research Database (Denmark)

Tørring, Pernille M; Larsen, Martin Jakob; Kjeldsen, Anette D

2014-01-01

transcriptome, we wanted to assess whether lncRNAs play a role in the molecular pathogenesis of HHT manifestations. By microarray technology, we profiled lncRNA transcripts from HHT nasal telangiectasial and non-telangiectasial tissue using a paired design. The microarray probes were annotated using the GENCODE...... v.16 dataset, identifying 4,810 probes mapping to 2,811 lncRNAs. Comparing HHT telangiectasial tissue with HHT non-telangiectasial tissue, we identified 42 lncRNAs that are differentially expressed (qUsing GREAT, a tool that assumes cis-regulation, we showed that differently expressed lncRNAs...... to the TGF-β signalling pathway. The exact mechanism of how haploinsufficiency of ENG and ACVRL1 leads to HHT manifestations remains to be identified. As long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and constitute a sizable fraction of the human...

A Looking-Glass of Non-Coding RNAs in Oral Cancer

Science.gov (United States)

Irimie, Alexandra Iulia; Braicu, Cornelia; Sonea, Laura; Zimta, Alina Andreea; Diudea, Diana; Buduru, Smaranda; Berindan-Neagoe, Ioana

2017-01-01

Oral cancer is a multifactorial pathology and is characterized by the lack of efficient treatment and accurate diagnostic tools. This is mainly due the late diagnosis; therefore, reliable biomarkers for the timely detection of the disease and patient stratification are required. Non-coding RNAs (ncRNAs) are key elements in the physiological and pathological processes of various cancers, which is also reflected in oral cancer development and progression. A better understanding of their role could give a more thorough perspective on the future treatment options for this cancer type. This review offers a glimpse into the ncRNA involvement in oral cancer, which can help the medical community tap into the world of ncRNAs and lay the ground for more powerful diagnostic, prognostic and treatment tools for oral cancer that will ultimately help build a brighter future for these patients. PMID:29206174

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

LENUS (Irish Health Repository)

Whan, Vicki

2010-11-23

Abstract Background About forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation. Results The current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified

Regulation of Peripheral Myelination through Transcriptional Buffering of Egr2 by an Antisense Long Non-coding RNA

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Margot Martinez-Moreno

2017-08-01

Full Text Available Precise regulation of Egr2 transcription is fundamentally important to the control of peripheral myelination. Here, we describe a long non-coding RNA antisense to the promoter of Egr2 (Egr2-AS-RNA. During peripheral nerve injury, the expression of Egr2-AS-RNA is increased and correlates with decreased Egr2 transcript and protein levels. Ectopic expression of Egr2-AS-RNA in dorsal root ganglion (DRG cultures inhibits the expression of Egr2 mRNA and induces demyelination. In vivo inhibition of Egr2-AS-RNA using oligonucleotide GapMers released from a biodegradable hydrogel following sciatic nerve injury reverts the EGR2-mediated gene expression profile and significantly delays demyelination. Egr2-AS-RNA gradually recruits H3K27ME3, AGO1, AGO2, and EZH2 on the Egr2 promoter following sciatic nerve injury. Furthermore, expression of Egr2-AS-RNA is regulated through ERK1/2 signaling to YY1, while loss of Ser184 of YY1 regulates binding to Egr2-AS-RNA. In conclusion, we describe functional exploration of an antisense long non-coding RNA in peripheral nervous system (PNS biology.

All-photonic quantum repeaters

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

2015-01-01

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

Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder.

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Han, Yonghua; Liu, Yuchen; Gui, Yaoting; Cai, Zhiming

2013-04-01

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.

Accelerating the loop expansion

International Nuclear Information System (INIS)

Ingermanson, R.

1986-01-01

This thesis introduces a new non-perturbative technique into quantum field theory. To illustrate the method, I analyze the much-studied phi 4 theory in two dimensions. As a prelude, I first show that the Hartree approximation is easy to obtain from the calculation of the one-loop effective potential by a simple modification of the propagator that does not affect the perturbative renormalization procedure. A further modification then susggests itself, which has the same nice property, and which automatically yields a convex effective potential. I then show that both of these modifications extend naturally to higher orders in the derivative expansion of the effective action and to higher orders in the loop-expansion. The net effect is to re-sum the perturbation series for the effective action as a systematic ''accelerated'' non-perturbative expansion. Each term in the accelerated expansion corresponds to an infinite number of terms in the original series. Each term can be computed explicitly, albeit numerically. Many numerical graphs of the various approximations to the first two terms in the derivative expansion are given. I discuss the reliability of the results and the problem of spontaneous symmetry-breaking, as well as some potential applications to more interesting field theories. 40 refs

[[Length polymorphism of minisatellite repeat B2-VNTR of the bradykinin B2 receptor gene in healthy Russians and in patients with coronary heart disease].

Science.gov (United States)

Suchkova, I O; Pavlinova, L I; Larionova, E E; Alenina, N V; Solov'ev, K V; Baranova, T V; Belotserkovskaia, E V; Sasina, L K; Bader, M; Denisenko, A D; Mustafina, O E; Khusnutdinova, E K; Patkin, E L

2014-01-01

Bradykinin B2 receptor is involved in many processes, including the regulation of blood pressure and smooth muscle contraction, vasodilation, inflammation, edema, cell proliferation, pain. It is suggested that this receptor may be one of the factors that have cardioprotective and infarct-limiting effects. It is assumed that certain genetic variants in both coding and non-coding regions ofBDKRB2 gene may influence its expression. In the 3'-untranslated region of BDKRB2 exon 3 the minisatellite repeat B2-VNTR is located. B2-VNTR has previously been shown to affect the BDKRB2 mRNA stability. Therefore, it is important to perform the molecular genetic analysis of this minisatellite in patients with different forms of coronary heart disease in order to reveal possible associations between specific B2-VNTR alleles and certain clinical forms of coronary heart disease. In the present study, a comparative analysis of the allele and genotype frequencies of B2-VNTR was carried out in groups of healthy individuals and patients with two clinical forms of coronary heart disease (angina pectoris and myocardial infarction), ethnically Russian. The results of the B2-VNTR length polymorphism analysis indicate that this tandem repeat may be attributed to a class of low polymorphic and non-hypervariable minisatellite. In all analyzed groups we revealed three B2-VNTR alleles, consisting of 43, 38 and 33 repeat units. Alleles of 43 and 33 repeats were major in all investigated groups. No statistically significant differences were found in the B2-VNTR allele and genotype frequencies between men and women in control group, and also between healthy men and men with angina pectoris and myocardial infarction. Thus, B2-VNTR length polymorphism was not associated with these clinical forms of coronary heart disease in Russian men. However, we do not exclude the possibility of association between the B2-VNTR short alleles (38 and 33 repeats) and cardioprotective effects of bradykinin B2 receptor

Thermal expansion data

International Nuclear Information System (INIS)

Taylor, D.

1984-01-01

This paper gives regression data for a modified second order polynomial fitted to the expansion data of, and percentage expansions for dioxides with (a) the fluorite and antifluorite structure: AmO 2 , BkO 2 , CeO 2 , CmO 2 , HfO 2 , Li 2 O, NpO 2 , PrO 2 , PuO 2 , ThO 2 , UO 2 , ZrO 2 , and (b) the rutile structure: CrO 2 , GeO 2 , IrO 2 , MnO 2 , NbO 2 , PbO 2 , SiO 2 , SnO 2 , TeO 2 , TiO 2 and VO 2 . Reduced expansion curves for the dioxides showed only partial grouping into iso-electronic series for the fluorite structures and showed that the 'law of corresponding states' did not apply to the rutile structures. (author)

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.

1987-01-01

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

Combinatorial Control of mRNA Fates by RNA-Binding Proteins and Non-Coding RNAs

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Valentina Iadevaia

2015-09-01

Full Text Available Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs and small non-coding RNAs (e.g., microRNAs that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to determine the localisation, stability and translation of mRNAs in mammalian cells. From these studies, it is becoming increasingly apparent that dynamic rearrangements of RNA-protein complexes could have profound implications in human cancer, in synaptic plasticity, and in cellular differentiation.

Identification of the porcine homologous of human disease causing trinucleotide repeat sequences

DEFF Research Database (Denmark)

Madsen, Lone Bruhn; Thomsen, Bo; Sølvsten, Christina Ane Elisabeth

2007-01-01

in this paper the identification of porcine noncoding and polyglutamine-encoding TNR regions and the comparison to the homologous TNRs from human, chimpanzee, dog, opossum, rat, and mouse. Several of the porcine TNR regions are highly polymorphic both within and between different breeds. The TNR regions...

Convergence of mayer expansions

International Nuclear Information System (INIS)

Brydges, D.C.

1986-01-01

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

Long non-coding RNA expression profiling of mouse testis during postnatal development.

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Jin Sun

Full Text Available Mammalian testis development and spermatogenesis play critical roles in male fertility and continuation of a species. Previous research into the molecular mechanisms of testis development and spermatogenesis has largely focused on the role of protein-coding genes and small non-coding RNAs, such as microRNAs and piRNAs. Recently, it has become apparent that large numbers of long (>200 nt non-coding RNAs (lncRNAs are transcribed from mammalian genomes and that lncRNAs perform important regulatory functions in various developmental processes. However, the expression of lncRNAs and their biological functions in post-natal testis development remain unknown. In this study, we employed microarray technology to examine lncRNA expression profiles of neonatal (6-day-old and adult (8-week-old mouse testes. We found that 8,265 lncRNAs were expressed above background levels during post-natal testis development, of which 3,025 were differentially expressed. Candidate lncRNAs were identified for further characterization by an integrated examination of genomic context, gene ontology (GO enrichment of their associated protein-coding genes, promoter analysis for epigenetic modification, and evolutionary conservation of elements. Many lncRNAs overlapped or were adjacent to key transcription factors and other genes involved in spermatogenesis, such as Ovol1, Ovol2, Lhx1, Sox3, Sox9, Plzf, c-Kit, Wt1, Sycp2, Prm1 and Prm2. Most differentially expressed lncRNAs exhibited epigenetic modification marks similar to protein-coding genes and tend to be expressed in a tissue-specific manner. In addition, the majority of differentially expressed lncRNAs harbored evolutionary conserved elements. Taken together, our findings represent the first systematic investigation of lncRNA expression in the mammalian testis and provide a solid foundation for further research into the molecular mechanisms of lncRNAs function in mammalian testis development and spermatogenesis.

The prognostic potential and carcinogenesis of long non-coding RNA TUG1 in human cholangiocarcinoma

OpenAIRE

Xu, Yi; Leng, Kaiming; Li, Zhenglong; Zhang, Fumin; Zhong, Xiangyu; Kang, Pengcheng; Jiang, Xingming; Cui, Yunfu

2017-01-01

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...

Analysis of the giant genomes of Fritillaria (Liliaceae) indicates that a lack of DNA removal characterizes extreme expansions in genome size.

Science.gov (United States)

Kelly, Laura J; Renny-Byfield, Simon; Pellicer, Jaume; Macas, Jiří; Novák, Petr; Neumann, Pavel; Lysak, Martin A; Day, Peter D; Berger, Madeleine; Fay, Michael F; Nichols, Richard A; Leitch, Andrew R; Leitch, Ilia J

2015-10-01

Plants exhibit an extraordinary range of genome sizes, varying by > 2000-fold between the smallest and largest recorded values. In the absence of polyploidy, changes in the amount of repetitive DNA (transposable elements and tandem repeats) are primarily responsible for genome size differences between species. However, there is ongoing debate regarding the relative importance of amplification of repetitive DNA versus its deletion in governing genome size. Using data from 454 sequencing, we analysed the most repetitive fraction of some of the largest known genomes for diploid plant species, from members of Fritillaria. We revealed that genomic expansion has not resulted from the recent massive amplification of just a handful of repeat families, as shown in species with smaller genomes. Instead, the bulk of these immense genomes is composed of highly heterogeneous, relatively low-abundance repeat-derived DNA, supporting a scenario where amplified repeats continually accumulate due to infrequent DNA removal. Our results indicate that a lack of deletion and low turnover of repetitive DNA are major contributors to the evolution of extremely large genomes and show that their size cannot simply be accounted for by the activity of a small number of high-abundance repeat families. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Negative thermal expansion and magnetocaloric effect in Mn-Co-Ge-In thin films

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Liu, Y.; Qiao, K. M.; Zuo, S. L.; Zhang, H. R.; Kuang, H.; Wang, J.; Hu, F. X.; Sun, J. R.; Shen, B. G.

2018-01-01

MnCoGe-based alloys with magnetostructural transition show giant negative thermal expansion (NTE) behavior and magnetocaloric effects (MCEs) and thus have attracted a lot of attention. However, the drawback of bad mechanical behavior in these alloys obstructs their practical applications. Here, we report the growth of Mn-Co-Ge-In films with thickness of about 45 nm on (001)-LaAlO3, (001)-SrTiO3, and (001)-Al2O3 substrates. The films grown completely overcome the breakable nature of the alloy and promote its multifunctional applications. The deposited films have a textured structure and retain first-order magnetostructural transition. NTE and MCE behaviors associated with the magnetostructural transition have been studied. The films exhibit a completely repeatable NTE around room temperature. NTE coefficient α can be continuously tuned from the ultra-low expansion (α ˜ -2.0 × 10-7/K) to α ˜ -6.56 × 10-6/K, depending on the growth and particle size of the films on different substrates. Moreover, the films exhibit magnetic entropy changes comparable to the well-known metamagnetic films. All these demonstrate potential multifunctional applications of the present films.

The effect of SCHIP expansions on health insurance decisions by employers.

Science.gov (United States)

Buchmueller, Thomas; Cooper, Philip; Simon, Kosali; Vistnes, Jessica

2005-01-01

This study uses repeated cross-sectional data from the Medical Expenditure Panel Survey-Insurance Component (MEPS-IC), a large nationally representative survey of establishments, to investigate the effect of the State Children's Health Insurance Program (SCHIP) on health insurance decisions by employers. The data span the years 1997 to 2001, the period when states were implementing SCHIP. We exploit cross-state variation in the timing of SCHIP implementation and the extent to which the program increased eligibility for public insurance. We find evidence suggesting that employers whose workers were likely to have been affected by these expansions reacted by raising employee contributions for family coverage options, and that take-up of any coverage, generally, and family coverage, specifically, dropped in these establishments. We find no evidence that employers stopped offering single or family coverage outright.

Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.

Science.gov (United States)

Murray, Anna; Schoemaker, Minouk J; Bennett, Claire E; Ennis, Sarah; Macpherson, James N; Jones, Michael; Morris, Danielle H; Orr, Nick; Ashworth, Alan; Jacobs, Patricia A; Swerdlow, Anthony J

2014-01-01

Primary ovarian insufficiency before the age of 40 years affects 1% of the female population and is characterized by permanent cessation of menstruation. Genetic causes include FMR1 expansion mutations. Previous studies have estimated mutation prevalence in clinical referrals for primary ovarian insufficiency, but these are likely to be biased as compared with cases in the general population. The prevalence of FMR1 expansion mutations in early menopause (between the ages of 40 and 45 years) has not been published. We studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46 years. We determined the prevalence of premutation (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in women with primary ovarian insufficiency (n = 254) and early menopause (n = 1,881). The prevalence of the premutation was 2.0% in primary ovarian insufficiency, 0.7% in early menopause, and 0.4% in controls, corresponding to odds ratios of 5.4 (95% confidence interval = 1.7-17.4; P = 0.004) for primary ovarian insufficiency and 2.0 (95% confidence interval = 0.8-5.1; P = 0.12) for early menopause. Combining primary ovarian insufficiency and early menopause gave an odds ratio of 2.4 (95% confidence interval = 1.02-5.8; P = 0.04). Intermediate alleles were not significant risk factors for either early menopause or primary ovarian insufficiency. FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of primary ovarian insufficiency and early menopause.

CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC

Energy Technology Data Exchange (ETDEWEB)

Congrains, Ada; Kamide, Kei [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan); Katsuya, Tomohiro [Clinical Gene Therapy, Osaka University Graduate School of Medicine (Japan); Yasuda, Osamu [Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital (Japan); Oguro, Ryousuke; Yamamoto, Koichi [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan); Ohishi, Mitsuru, E-mail: ohishi@geriat.med.osaka-u.ac.jp [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan); Rakugi, Hiromi [Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (Japan)

2012-03-23

Highlights: Black-Right-Pointing-Pointer ANRIL maps in the strongest susceptibility locus for cardiovascular disease. Black-Right-Pointing-Pointer Silencing of ANRIL leads to altered expression of tissue remodeling-related genes. Black-Right-Pointing-Pointer The effects of ANRIL on gene expression are splicing variant specific. Black-Right-Pointing-Pointer ANRIL affects progression of cardiovascular disease by regulating proliferation and apoptosis pathways. -- Abstract: ANRIL is a newly discovered non-coding RNA lying on the strongest genetic susceptibility locus for cardiovascular disease (CVD) in the chromosome 9p21 region. Genome-wide association studies have been linking polymorphisms in this locus with CVD and several other major diseases such as diabetes and cancer. The role of this non-coding RNA in atherosclerosis progression is still poorly understood. In this study, we investigated the implication of ANRIL in the modulation of gene sets directly involved in atherosclerosis. We designed and tested siRNA sequences to selectively target two exons (exon 1 and exon 19) of the transcript and successfully knocked down expression of ANRIL in human aortic vascular smooth muscle cells (HuAoVSMC). We used a pathway-focused RT-PCR array to profile gene expression changes caused by ANRIL knock down. Notably, the genes affected by each of the siRNAs were different, suggesting that different splicing variants of ANRIL might have distinct roles in cell physiology. Our results suggest that ANRIL splicing variants play a role in coordinating tissue remodeling, by modulating the expression of genes involved in cell proliferation, apoptosis, extra-cellular matrix remodeling and inflammatory response to finally impact in the risk of cardiovascular disease and other pathologies.

Site-Directed Mutagenesis Study of an Antibiotic-Sensing Noncoding RNA Integrated into a One-Semester Project-Based Biochemistry Lab Course

Science.gov (United States)

Gerczei, Timea

2017-01-01

A laboratory sequence is described that is suitable for upper-level biochemistry or molecular biology laboratories that combines project-based and traditional laboratory experiments. In the project-based sequence, the individual laboratory experiments are thematically linked and aim to show how a bacterial antibiotic sensing noncoding RNA (the…

Bistability and oscillations in gene regulation mediated by small noncoding RNAs.

Directory of Open Access Journals (Sweden)

Dengyu Liu

Full Text Available The interplay of small noncoding RNAs (sRNAs, mRNAs, and proteins has been shown to play crucial roles in almost all cellular processes. As key post-transcriptional regulators of gene expression, the mechanisms and roles of sRNAs in various cellular processes still need to be fully understood. When participating in cellular processes, sRNAs mainly mediate mRNA degradation or translational repression. Here, we show how the dynamics of two minimal architectures is drastically affected by these two mechanisms. A comparison is also given to reveal the implication of the fundamental differences. This study may help us to analyze complex networks assembled by simple modules more easily. A better knowledge of the sRNA-mediated motifs is also of interest for bio-engineering and artificial control.

The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function

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Wahlestedt Claes

2007-03-01

Full Text Available Abstract Background Mutations in the PTEN induced putative kinase 1 (PINK1 are implicated in early-onset Parkinson's disease. PINK1 is expressed abundantly in mitochondria rich tissues, such as skeletal muscle, where it plays a critical role determining mitochondrial structural integrity in Drosophila. Results Herein we characterize a novel splice variant of PINK1 (svPINK1 that is homologous to the C-terminus regulatory domain of the protein kinase. Naturally occurring non-coding antisense provides sophisticated mechanisms for diversifying genomes and we describe a human specific non-coding antisense expressed at the PINK1 locus (naPINK1. We further demonstrate that PINK1 varies in vivo when human skeletal muscle mitochondrial content is enhanced, supporting the idea that PINK1 has a physiological role in mitochondrion. The observation of concordant regulation of svPINK1 and naPINK1 during in vivo mitochondrial biogenesis was confirmed using RNAi, where selective targeting of naPINK1 results in loss of the PINK1 splice variant in neuronal cell lines. Conclusion Our data presents the first direct observation that a mammalian non-coding antisense molecule can positively influence the abundance of a cis-transcribed mRNA under physiological abundance conditions. While our analysis implies a possible human specific and dsRNA-mediated mechanism for stabilizing the expression of svPINK1, it also points to a broader genomic strategy for regulating a human disease locus and increases the complexity through which alterations in the regulation of the PINK1 locus could occur.

Catalog of Differentially Expressed Long Non-Coding RNA following Activation of Human and Mouse Innate Immune Response

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Benoit T. Roux

2017-08-01

Full Text Available Despite increasing evidence to indicate that long non-coding RNAs (lncRNAs are novel regulators of immunity, there has been no systematic attempt to identify and characterize the lncRNAs whose expression is changed following the induction of the innate immune response. To address this issue, we have employed next-generation sequencing data to determine the changes in the lncRNA profile in four human (monocytes, macrophages, epithelium, and chondrocytes and four mouse cell types (RAW 264.7 macrophages, bone marrow-derived macrophages, peritoneal macrophages, and splenic dendritic cells following exposure to the pro-inflammatory mediators, lipopolysaccharides (LPS, or interleukin-1β. We show differential expression of 204 human and 210 mouse lncRNAs, with positional analysis demonstrating correlation with immune-related genes. These lncRNAs are predominantly cell-type specific, composed of large regions of repeat sequences, and show poor evolutionary conservation. Comparison within the human and mouse sequences showed less than 1% sequence conservation, although we identified multiple conserved motifs. Of the 204 human lncRNAs, 21 overlapped with syntenic mouse lncRNAs, of which five were differentially expressed in both species. Among these syntenic lncRNA was IL7-AS (antisense, which was induced in multiple cell types and shown to regulate the production of the pro-inflammatory mediator interleukin-6 in both human and mouse cells. In summary, we have identified and characterized those lncRNAs that are differentially expressed following activation of the human and mouse innate immune responses and believe that these catalogs will provide the foundation for the future analysis of the role of lncRNAs in immune and inflammatory responses.

Functions and mechanisms of long noncoding RNAs in lung cancer

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Peng ZZ

2016-07-01

Full Text Available Zhenzi Peng, Chunfang Zhang, Chaojun Duan Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, People’s Republic of China Abstract: Lung cancer is a heterogeneous disease, and there is a lack of adequate biomarkers for diagnosis. Long noncoding RNAs (lncRNAs are emerging as an important set of molecules because of their roles in various key pathophysiological pathways, including cell growth, apoptosis, and metastasis. We review the current knowledge of the lncRNAs in lung cancer. In-depth analyses of lncRNAs in lung cancer have increased the number of potential effective biomarkers, thus providing options to increase the therapeutic benefit. In this review, we summarize the functions, mechanisms, and regulatory networks of lncRNAs in lung cancer, providing a basis for further research in this field. Keywords: ncRNA, tumorigenesis, biomarker, network, proliferation, apoptosis 

A Looking-Glass of Non-Coding RNAs in Oral Cancer

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Alexandra Iulia Irimie

2017-12-01

Full Text Available Oral cancer is a multifactorial pathology and is characterized by the lack of efficient treatment and accurate diagnostic tools. This is mainly due the late diagnosis; therefore, reliable biomarkers for the timely detection of the disease and patient stratification are required. Non-coding RNAs (ncRNAs are key elements in the physiological and pathological processes of various cancers, which is also reflected in oral cancer development and progression. A better understanding of their role could give a more thorough perspective on the future treatment options for this cancer type. This review offers a glimpse into the ncRNA involvement in oral cancer, which can help the medical community tap into the world of ncRNAs and lay the ground for more powerful diagnostic, prognostic and treatment tools for oral cancer that will ultimately help build a brighter future for these patients.

Polyploidization of murine mesenchymal cells is associated with suppression of the long noncoding RNA H19 and reduced tumorigenicity.

Science.gov (United States)

Shoshani, Ofer; Massalha, Hassan; Shani, Nir; Kagan, Sivan; Ravid, Orly; Madar, Shalom; Trakhtenbrot, Luba; Leshkowitz, Dena; Rechavi, Gideon; Zipori, Dov

2012-12-15

Mesenchymal stromal cells (MSC) are used extensively in clinical trials; however, the possibility that MSCs have a potential for malignant transformation was raised. We examined the genomic stability versus the tumor-forming capacity of multiple mouse MSCs. Murine MSCs have been shown to be less stable and more prone to malignant transformation than their human counterparts. A large series of independently isolated MSC populations exhibited low tumorigenic potential under syngeneic conditions, which increased in immunocompromised animals. Unexpectedly, higher ploidy correlated with reduced tumor-forming capacity. Furthermore, in both cultured MSCs and primary hepatocytes, polyploidization was associated with a dramatic decrease in the expression of the long noncoding RNA H19. Direct knockdown of H19 expression in diploid cells resulted in acquisition of polyploid cell traits. Moreover, artificial tetraploidization of diploid cancer cells led to a reduction of H19 levels, as well as to an attenuation of the tumorigenic potential. Polyploidy might therefore serve as a protective mechanism aimed at reducing malignant transformation through the involvement of the H19 regulatory long noncoding RNA.

$\\delta$-Expansion at Finite Temperature

OpenAIRE

Ramos, Rudnei O.

1996-01-01

We apply the $\\delta$-expansion perturbation scheme to the $\\lambda \\phi^{4}$ self-interacting scalar field theory in 3+1 D at finite temperature. In the $\\delta$-expansion the interaction term is written as $\\lambda (\\phi^{2})^{ 1 + \\delta}$ and $\\delta$ is considered as the perturbation parameter. We compute within this perturbative approach the renormalized mass at finite temperature at a finite order in $\\delta$. The results are compared with the usual loop-expansion at finite temperature.

The Functional Characterization of Long Noncoding RNA SPRY4-IT1 in Human Melanoma Cells

OpenAIRE

Mazar, Joseph; Zhao, Wei; Khalil, Ahmad M.; Lee, Bongyong; Shelley, John; Govindarajan, Subramaniam S.; Yamamoto, Fumiko; Ratnam, Maya; Aftab, Muhammad Nauman; Collins, Sheila; Finck, Brian N.; Han, Xianlin; Mattick, John S.; Dinger, Marcel E.; Perera, Ranjan J.

2014-01-01

Expression of the long noncoding RNA (lncRNA) SPRY4-IT1 is low in normal human melanocytes but high in melanoma cells. siRNA knockdown of SPRY4-IT1 blocks melanoma cell invasion and proliferation, and increases apoptosis. To investigate its function further, we affinity purified SPRY4-IT1 from melanoma cells and used mass spectrometry to identify the protein lipin 2, an enzyme that converts phosphatidate to diacylglycerol (DAG), as a major binding partner. SPRY4-IT1 knockdown increases the ac...

Expansion of a globally pervasive grass occurs without substantial trait differences between home and away populations.

Science.gov (United States)

Leifso, A; MacDougall, A S; Husband, B; Hierro, J L; Köchy, M; Pärtel, M; Peltzer, D A

2012-12-01

The global expansion of species beyond their ancestral ranges can derive from mechanisms that are trait-based (e.g., post-establishment evolved differences compared to home populations) or circumstantial (e.g., propagule pressure, with no trait-based differences). These mechanisms can be difficult to distinguish following establishment, but each makes unique predictions regarding trait similarity between ancestral ('home') and introduced ('away') populations. Here, we tested for trait-based population differences across four continents for the globally distributed grass Dactylis glomerata, to assess the possible role of trait evolution in its worldwide expansion. We used a common-environment glasshouse experiment to quantify trait differences among home and away populations, and the potential relevance of these differences for competitive interactions. Few significant trait differences were found among continents, suggesting minimal change during global expansion. All populations were polyploids, with similar foliar carbon:nitrogen ratios (a proxy for defense), chlorophyll content, and biomass. Emergence time and growth rate favored home populations, resulting in their competitive superiority over away populations. Small but significant trait differences among away populations suggest different introductory histories or local adaptive responses following establishment. In summary, the worldwide distribution of this species appears to have arisen from its pre-adapted traits promoting growth, and its repeated introduction with cultivation and intense propagule pressure. Global expansion can thus occur without substantial shifts in growth, reproduction, or defense. Rather than focusing strictly on the invader, invasion success may also derive from the traits found (or lacking) in the recipient community and from environmental context including human disturbance.

78 FR 65594 - Vehicular Repeaters

Science.gov (United States)

2013-11-01

... coordinators estimate the effect on coordination fees? Does the supposed benefit that mobile repeater stations... allow the licensing and operation of vehicular repeater systems and other mobile repeaters by public... email: [email protected] or phone: 202-418- 0530 or TTY: 202-418-0432. For detailed instructions for...

Electrical Resistance Alloys and Low-Expansion Alloys

DEFF Research Database (Denmark)

Kjer, Torben

1996-01-01

The article gives an overview of electrical resistance alloys and alloys with low thermal expansion. The electrical resistance alloys comprise resistance alloys, heating alloys and thermostat alloys. The low expansion alloys comprise alloys with very low expansion coefficients, alloys with very low...... thermoelastic coefficients and age hardenable low expansion alloys....

Tevatron serial data repeater system

International Nuclear Information System (INIS)

Ducar, R.J.

1981-01-01

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

Disjoint sum expansion method in FTA

International Nuclear Information System (INIS)

Ruan Keqiang

1987-01-01

An expansion formula for transforming boolean algebraic expressions into disjoint form was proved. Based on this expansion formula, a method for transforming system failure function into disjoint form was devised. The fact that the expansion can be done for several elements simulatneously makes the method flexible and fast. Some examples from fault tree analysis (FTA) and network analysis were examined by the new method to show its algorithm and its merit. Besides, by means of the proved expansion formula some boolean algebraic relations can proved very easily

Study on peripheral expansion of bone marrow in hematologic patients and its clinical application

International Nuclear Information System (INIS)

Liu Yong; Liu Dai; Kang Fu

1995-01-01

It is found previously that the changing patterns of bone marrow scintigraphy resulting from hematologic disorders were various. This study focused on discussing the imaging features and regularity of expanded peripheral bone marrow (PBM) in some blood diseases as well as their clinical usefulness. Bone marrow scintigraphy with 99m Tc-sulfur colloid 370∼550 MBq was performed in 130 cases with different types of blood diseases (iron-deficiency anemia 17 cases, chronic hemolytic 13 cases, aplastic 41 cases; leukemia 37 cases, marrow dyshyperplasia syndrome 22 cases) and various stages of the disease (19 cases). The aspiration in PBM comparing with central bone marrow (CBM) was made in 12 aplastic anemia and 10 leukemia patients. The expansion rate of PBM was 58.5% and the various blood diseases had different expansion regions. Repeated imaging showed that the expanded PBM tended to retract during clinical recovery. Aspiration from the expanding PBM defined more active hematopoiesis and higher count of leukemia blast cells than that from iliac crest. The results indicated the presence of 'focal residual leukemia' (FRL) in PBM of complete remission leukemia patient. The result of this study suggested that the expansion patterns of PBM in various hematologic disorders have definite features, which are helpful for the differential diagnosis, valuable for evaluation of the reserved capability of active marrow and prognosis of the patients according to the further analysis of the PBM state. The bone marrow imaging is also an indispensable technique for finding FRL

Maxwell superalgebras and Abelian semigroup expansion

Directory of Open Access Journals (Sweden)

P.K. Concha

2014-09-01

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.

Maxwell superalgebras and Abelian semigroup expansion

Energy Technology Data Exchange (ETDEWEB)

Concha, P.K.; Rodríguez, E.K. [Departamento de Física, Universidad de Concepción, Casilla 160-C, Concepción (Chile); Dipartimento di Scienza Applicata e Tecnologia (DISAT), Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino (Italy); Istituto Nazionale di Fisica Nucleare (INFN), Sezione di Torino, Via Pietro Giuria, 1, 10125 Torino (Italy)

2014-09-15

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{sup (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 sM{sub m+2} and their N-extended generalization can be obtained using the S-expansion procedure.

Repeat Customer Success in Extension

Science.gov (United States)

Bess, Melissa M.; Traub, Sarah M.

2013-01-01

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…

Film repeats in radiology department

International Nuclear Information System (INIS)

Suwan, A. Z.; Al-Shakharah, A. I

1997-01-01

During a one year period, 4910 radiographs of 55780 films were repeated. The objective of our study was to analyse and to classify the causes in order to minimize the repeats, cut the expenses and to provide optimal radiographs for accurate diagnosis. Analysis of the different factors revealed that, 43.6% of film repeats in our service were due to faults in exposure factors, centering comprises 15.9% of the repeats, while too much collimation was responsible for 7.6% of these repeats. All of which can be decreased by awareness and programmed training of technicians. Film blurring caused by patient motion was also responsible for 4.9% for radiographs reexamination, which can be minimized by detailed explanation to the patient and providing the necessary privacy. Fogging of X-Ray films by improper storage or inadequate handling or processing faults were responsible for 14.5% in repeats in our study. Methods and criteria for proper storage and handling of films were discussed. Recommendation for using modern day-light and laser processor has been high lighted. Artefacts are noticeably high in our cases, due to spinal dresses and frequent usage of precious metals for c osmotic purposes in this part of the world. The repeated films comprise 8.8% of all films We conclude that, the main factor responsible for repeats of up to 81.6% of cases was the technologists, thus emphasizing the importance of adequate training of the technologists. (authors). 15 refs., 9 figs., 1 table

An internal duplication in the 5' noncoding region of strain H: a bovine viral diarrhoea virus (BVDV) isolated from pigs

NARCIS (Netherlands)

Gennip, van H.G.P.; Widjojoatmodjo, M.N.; Smit, de A.J.; Moormann, R.J.M.

1999-01-01

A pig pestivirus isolate, strain H, was characterized by using reverse transcription-PCR (RT-PCR) and direct sequencing of the amplicons. A duplication of 74 nucleotides was found at the 5' terminus of the 5' noncoding (NC) region, which was also found in RNA isolates from tonsils from two other

Uniform gradient expansions

CERN Document Server

Giovannini, Massimo

2015-01-01

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.

Prediction of myotonic dystrophy clinical severity based on the number of intragenic [CTG]{sub n} trinucleotide repeats

Energy Technology Data Exchange (ETDEWEB)

Gennarelli, M.; Dallapiccola, B. [Universita Tor Vergata, Rome (Italy); Novelli, G. [Universita Cattolica del Sacro Cuore, Rome (Italy)] [and others

1996-11-11

We carried out a genotype-phenotype correlation study, based on clinical findings in 465 patients with myotonic dystrophy (DM), in order to assess [CTG] repeat number as a predictive test of disease severity. Our analysis showed that the DM subtypes defined by strict clinical criteria fall into three different classes with a log-normal distribution. This distribution is useful in predicting the probability of specific DM phenotypes based on triplet [CTG] number. This study demonstrates that measurement of triplet expansions in patients` lymphocyte DNA is highly valuable and accurate for prognostic assessment. 45 refs., 1 fig., 2 tabs.

Repeat migration and disappointment.

Science.gov (United States)

Grant, E K; Vanderkamp, J

1986-01-01

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.

Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element

Directory of Open Access Journals (Sweden)

Wilson Leung

2017-08-01

Full Text Available The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb in D. ananassae. To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons are major contributors to this expansion (78.6%, while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%. Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias, but these differences are exaggerated in D. ananassae. Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5′ ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2, while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains.

Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element

Science.gov (United States)

Shaffer, Christopher D.; Chen, Elizabeth J.; Quisenberry, Thomas J.; Ko, Kevin; Braverman, John M.; Giarla, Thomas C.; Mortimer, Nathan T.; Reed, Laura K.; Smith, Sheryl T.; Robic, Srebrenka; McCartha, Shannon R.; Perry, Danielle R.; Prescod, Lindsay M.; Sheppard, Zenyth A.; Saville, Ken J.; McClish, Allison; Morlock, Emily A.; Sochor, Victoria R.; Stanton, Brittney; Veysey-White, Isaac C.; Revie, Dennis; Jimenez, Luis A.; Palomino, Jennifer J.; Patao, Melissa D.; Patao, Shane M.; Himelblau, Edward T.; Campbell, Jaclyn D.; Hertz, Alexandra L.; McEvilly, Maddison F.; Wagner, Allison R.; Youngblom, James; Bedi, Baljit; Bettincourt, Jeffery; Duso, Erin; Her, Maiye; Hilton, William; House, Samantha; Karimi, Masud; Kumimoto, Kevin; Lee, Rebekah; Lopez, Darryl; Odisho, George; Prasad, Ricky; Robbins, Holly Lyn; Sandhu, Tanveer; Selfridge, Tracy; Tsukashima, Kara; Yosif, Hani; Kokan, Nighat P.; Britt, Latia; Zoellner, Alycia; Spana, Eric P.; Chlebina, Ben T.; Chong, Insun; Friedman, Harrison; Mammo, Danny A.; Ng, Chun L.; Nikam, Vinayak S.; Schwartz, Nicholas U.; Xu, Thomas Q.; Burg, Martin G.; Batten, Spencer M.; Corbeill, Lindsay M.; Enoch, Erica; Ensign, Jesse J.; Franks, Mary E.; Haiker, Breanna; Ingles, Judith A.; Kirkland, Lyndsay D.; Lorenz-Guertin, Joshua M.; Matthews, Jordan; Mittig, Cody M.; Monsma, Nicholaus; Olson, Katherine J.; Perez-Aragon, Guillermo; Ramic, Alen; Ramirez, Jordan R.; Scheiber, Christopher; Schneider, Patrick A.; Schultz, Devon E.; Simon, Matthew; Spencer, Eric; Wernette, Adam C.; Wykle, Maxine E.; Zavala-Arellano, Elizabeth; McDonald, Mitchell J.; Ostby, Kristine; Wendland, Peter; DiAngelo, Justin R.; Ceasrine, Alexis M.; Cox, Amanda H.; Docherty, James E.B.; Gingras, Robert M.; Grieb, Stephanie M.; Pavia, Michael J.; Personius, Casey L.; Polak, Grzegorz L.; Beach, Dale L.; Cerritos, Heaven L.; Horansky, Edward A.; Sharif, Karim A.; Moran, Ryan; Parrish, Susan; Bickford, Kirsten; Bland, Jennifer; Broussard, Juliana; Campbell, Kerry; Deibel, Katelynn E.; Forka, Richard; Lemke, Monika C.; Nelson, Marlee B.; O'Keeffe, Catherine; Ramey, S. Mariel; Schmidt, Luke; Villegas, Paola; Jones, Christopher J.; Christ, Stephanie L.; Mamari, Sami; Rinaldi, Adam S.; Stity, Ghazal; Hark, Amy T.; Scheuerman, Mark; Silver Key, S. Catherine; McRae, Briana D.; Haberman, Adam S.; Asinof, Sam; Carrington, Harriette; Drumm, Kelly; Embry, Terrance; McGuire, Richard; Miller-Foreman, Drew; Rosen, Stella; Safa, Nadia; Schultz, Darrin; Segal, Matt; Shevin, Yakov; Svoronos, Petros; Vuong, Tam; Skuse, Gary; Paetkau, Don W.; Bridgman, Rachael K.; Brown, Charlotte M.; Carroll, Alicia R.; Gifford, Francesca M.; Gillespie, Julie Beth; Herman, Susan E.; Holtcamp, Krystal L.; Host, Misha A.; Hussey, Gabrielle; Kramer, Danielle M.; Lawrence, Joan Q.; Martin, Madeline M.; Niemiec, Ellen N.; O'Reilly, Ashleigh P.; Pahl, Olivia A.; Quintana, Guadalupe; Rettie, Elizabeth A.S.; Richardson, Torie L.; Rodriguez, Arianne E.; Rodriguez, Mona O.; Schiraldi, Laura; Smith, Joanna J.; Sugrue, Kelsey F.; Suriano, Lindsey J.; Takach, Kaitlyn E.; Vasquez, Arielle M.; Velez, Ximena; Villafuerte, Elizabeth J.; Vives, Laura T.; Zellmer, Victoria R.; Hauke, Jeanette; Hauser, Charles R.; Barker, Karolyn; Cannon, Laurie; Parsamian, Perouza; Parsons, Samantha; Wichman, Zachariah; Bazinet, Christopher W.; Johnson, Diana E.; Bangura, Abubakarr; Black, Jordan A.; Chevee, Victoria; Einsteen, Sarah A.; Hilton, Sarah K.; Kollmer, Max; Nadendla, Rahul; Stamm, Joyce; Fafara-Thompson, Antoinette E.; Gygi, Amber M.; Ogawa, Emmy E.; Van Camp, Matt; Kocsisova, Zuzana; Leatherman, Judith L.; Modahl, Cassie M.; Rubin, Michael R.; Apiz-Saab, Susana S.; Arias-Mejias, Suzette M.; Carrion-Ortiz, Carlos F.; Claudio-Vazquez, Patricia N.; Espada-Green, Debbie M.; Feliciano-Camacho, Marium; Gonzalez-Bonilla, Karina M.; Taboas-Arroyo, Mariela; Vargas-Franco, Dorianmarie; Montañez-Gonzalez, Raquel; Perez-Otero, Joseph; Rivera-Burgos, Myrielis; Rivera-Rosario, Francisco J.; Eisler, Heather L.; Alexander, Jackie; Begley, Samatha K.; Gabbard, Deana; Allen, Robert J.; Aung, Wint Yan; Barshop, William D.; Boozalis, Amanda; Chu, Vanessa P.; Davis, Jeremy S.; Duggal, Ryan N.; Franklin, Robert; Gavinski, Katherine; Gebreyesus, Heran; Gong, Henry Z.; Greenstein, Rachel A.; Guo, Averill D.; Hanson, Casey; Homa, Kaitlin E.; Hsu, Simon C.; Huang, Yi; Huo, Lucy; Jacobs, Sarah; Jia, Sasha; Jung, Kyle L.; Wai-Chee Kong, Sarah; Kroll, Matthew R.; Lee, Brandon M.; Lee, Paul F.; Levine, Kevin M.; Li, Amy S.; Liu, Chengyu; Liu, Max Mian; Lousararian, Adam P.; Lowery, Peter B.; Mallya, Allyson P.; Marcus, Joseph E.; Ng, Patrick C.; Nguyen, Hien P.; Patel, Ruchik; Precht, Hashini; Rastogi, Suchita; Sarezky, Jonathan M.; Schefkind, Adam; Schultz, Michael B.; Shen, Delia; Skorupa, Tara; Spies, Nicholas C.; Stancu, Gabriel; Vivian Tsang, Hiu Man; Turski, Alice L.; Venkat, Rohit; Waldman, Leah E.; Wang, Kaidi; Wang, Tracy; Wei, Jeffrey W.; Wu, Dennis Y.; Xiong, David D.; Yu, Jack; Zhou, Karen; McNeil, Gerard P.; Fernandez, Robert W.; Menzies, Patrick Gomez; Gu, Tingting; Buhler, Jeremy; Mardis, Elaine R.; Elgin, Sarah C.R.

2017-01-01

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb) in D. ananassae. To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae. Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5′ ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains. PMID:28667019

Quantum repeated games revisited

International Nuclear Information System (INIS)

Frąckiewicz, Piotr

2012-01-01

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)

Threats from urban expansion, agricultural transformation and forest loss on global conservation priority areas

Science.gov (United States)

Moilanen, Atte; Di Minin, Enrico

2017-01-01

Including threats in spatial conservation prioritization helps identify areas for conservation actions where biodiversity is at imminent risk of extinction. At the global level, an important limitation when identifying spatial priorities for conservation actions is the lack of information on the spatial distribution of threats. Here, we identify spatial conservation priorities under three prominent threats to biodiversity (residential and commercial development, agricultural expansion, and forest loss), which are primary drivers of habitat loss and threaten the persistence of the highest number of species in the International Union for the Conservation of Nature (IUCN) Red List, and for which spatial data is available. We first explore how global priority areas for the conservation of vertebrate (mammals, birds, and amphibians) species coded in the Red List as vulnerable to each threat differ spatially. We then identify spatial conservation priorities for all species vulnerable to all threats. Finally, we identify the potentially most threatened areas by overlapping the identified priority areas for conservation with maps for each threat. We repeat the same with four other well-known global conservation priority area schemes, namely Key Biodiversity Areas, Biodiversity Hotspots, the global Protected Area Network, and Wilderness Areas. We find that residential and commercial development directly threatens only about 4% of the global top 17% priority areas for species vulnerable under this threat. However, 50% of the high priority areas for species vulnerable to forest loss overlap with areas that have already experienced some forest loss. Agricultural expansion overlapped with ~20% of high priority areas. Biodiversity Hotspots had the greatest proportion of their total area under direct threat from all threats, while expansion of low intensity agriculture was found to pose an imminent threat to Wilderness Areas under future agricultural expansion. Our results

Integrated Analysis of Long Noncoding RNA and Coding RNA Expression in Esophageal Squamous Cell Carcinoma

Directory of Open Access Journals (Sweden)

Wei Cao

2013-01-01

Full Text Available Tumorigenesis is a complex dynamic biological process that includes multiple steps of genetic and epigenetic alterations, aberrant expression of noncoding RNA, and changes in the expression profiles of coding genes. We call the collection of those perturbations in genome space the “cancer initiatome.” Long noncoding RNAs (lncRNAs are pervasively transcribed in the genome and they have key regulatory functions in chromatin remodeling and gene expression. Spatiotemporal variation in the expression of lncRNAs has been observed in development and disease states, including cancer. A few dysregulated lncRNAs have been studied in cancers, but the role of lncRNAs in the cancer initiatome remains largely unknown, especially in esophageal squamous cell carcinoma (ESCC. We conducted a genome-wide screen of the expression of lncRNAs and coding RNAs from ESCC and matched adjacent nonneoplastic normal tissues. We identified differentially expressed lncRNAs and coding RNAs in ESCC relative to their matched normal tissue counterparts and validated the result using polymerase chain reaction analysis. Furthermore, we identified differentially expressed lncRNAs that are co-located and co-expressed with differentially expressed coding RNAs in ESCC and the results point to a potential interaction between lncRNAs and neighboring coding genes that affect ether lipid metabolism, and the interaction may contribute to the development of ESCC. These data provide compelling evidence for a potential novel genomic biomarker of esophageal squamous cell cancer.

Thin foil expansion into a vacuum

International Nuclear Information System (INIS)

Mora, P.

2005-01-01

Plasma expansion into a vacuum is an old problem which has been renewed recently in various contexts: expansion of ultra-cold plasmas, cluster expansion, of dust grains, expansion of thin foils. In this presentation I will first discuss the physics of the expansion of a thin foil irradiated by an ultra-short ultra-intense laser pulse. The expansion results in the formation of high energy ions. For an infinitely steep plasma-vacuum interface the fastest ions are located in the outer part of the expansion and their velocity is given by ν m ax∼ 2 C s (In ω p it) where c s (Zk B T e /m i )''1/2 is the ion-acoustic velocity ω p i=(n e 0Ze''2/m i e 0 )''1/2 is the ion plasma frequency, n e 0 is the electron density in the unperturbed plasma, Z is the ion charge number. In the above expression, t is either the pulse duration or the effective acceleration time (in particular t∼L/2c s , where L is the width of the foil, when the electron cooling is taken into account). A salient characteristic of the expansion is the occurrence of a double layer structure and a peak of the accelerating electric field at the ion front. I will explain the origin of the peak and predict its temporal behavior. This peak has been diagnosed in recent experiments. I will also discuss the effect of a 2-temperatures electron distribution function on the expansion, showing the dominant role of the hot electron component. Finally I will discuss the occurrence of ion spikes in the expansion when the initial density profile is smooth. The ion spike is due to a wave breaking which cannot be handled in a satisfactory way by a fluid code and requires a kinetic description. A. simple collisionless particle code has been used to treat the evolution of the spike after the wave breaking and the results will be shown. (Author)

JUNCTOPHILIN 3 (JPH3) EXPANSION MUTATIONS CAUSING HUNTINGTON DISEASE LIKE 2 (HDL2) ARE COMMON IN SOUTH AFRICAN PATIENTS WITH AFRICAN ANCESTRY AND A HUNTINGTON DISEASE PHENOTYPE

Science.gov (United States)

Krause, A; Mitchell, CL; Essop, F; Tager, S; Temlett, J; Stevanin, G; Ross, CA; Rudnicki, DD; Margolis, RL

2015-01-01

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

Rethinking the central dogma: noncoding RNAs are biologically relevant.

Science.gov (United States)

Robinson, Victoria L

2009-01-01

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.

DNA watermarks in non-coding regulatory sequences

Directory of Open Access Journals (Sweden)

Pyka Martin

2009-07-01

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.

The functional role of long non-coding RNA in digestive system carcinomas.

Science.gov (United States)

Wang, Guang-Yu; Zhu, Yuan-Yuan; Zhang, Yan-Qiao

2014-09-01

In recent years, long non-coding RNAs (lncRNAs) are emerging as either oncogenes or tumor suppressor genes. Recent evidences suggest that lncRNAs play a very important role in digestive system carcinomas. However, the biological function of lncRNAs in the vast majority of digestive system carcinomas remains unclear. Recently, increasing studies has begun to explore their molecular mechanisms and regulatory networks that they are implicated in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in digestive system carcinomas. It is becoming clear that lncRNAs will be exciting and potentially useful for diagnosis and treatment of digestive system carcinomas, some of these lncRNAs might function as both diagnostic markers and the treatment targets of digestive system carcinomas.

The Population Origins and Expansion of Feral Cats in Australia.

Science.gov (United States)

Spencer, Peter B S; Yurchenko, Andrey A; David, Victor A; Scott, Rachael; Koepfli, Klaus-Peter; Driscoll, Carlos; O'Brien, Stephen J; Menotti-Raymond, Marilyn

2016-03-01

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). © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Thermal Expansion Of Feldspars

Science.gov (United States)

Hovis, G. L.; Medford, A.; Conlon, M.

2009-12-01

Hovis and others (1) investigated the thermal expansion of natural and synthetic AlSi3 feldspars and demonstrated that the coefficient of thermal expansion (α) decreases significantly, and linearly, with increasing room-temperature volume (VRT). In all such feldspars, therefore, chemical expansion limits thermal expansion. The scope of this work now has been broadened to include plagioclase and Ba-K feldspar crystalline solutions. X-ray powder diffraction data have been collected between room temperature and 925 °C on six plagioclase specimens ranging in composition from anorthite to oligoclase. When combined with thermal expansion data for albite (2,3,4) a steep linear trend of α as a function of VRT emerges, reflecting how small changes in composition dramatically affect expansion behavior. The thermal expansion data for five synthetic Ba-K feldspars ranging in composition from 20 to 100 mole percent celsian, combined with data for pure K-feldspar (3,4), show α-VRT relationships similar in nature to the plagioclase series, but with a slope and intercept different from the latter. Taken as a group all Al2Si2 feldspars, including anorthite and celsian from the present study along with Sr- (5) and Pb-feldspar (6) from other workers, show very limited thermal expansion that, unlike AlSi3 feldspars, has little dependence on the divalent-ion (or M-) site occupant. This apparently is due to the necessitated alternation of Al and Si in the tetrahedral sites of these minerals (7), which in turn locks the tetrahedral framework and makes the M-site occupant nearly irrelevant to expansion behavior. Indeed, in feldspar series with coupled chemical substitution it is the change away from a 1:1 Al:Si ratio that gives feldspars greater freedom to expand. Overall, the relationships among α, chemical composition, and room-temperature volume provide useful predictive tools for estimating feldspar thermal expansion and give insight into the controls of expansion behavior in

Always look on both sides: phylogenetic information conveyed by simple sequence repeat allele sequences.

Directory of Open Access Journals (Sweden)

Stéphanie Barthe

Full Text Available Simple sequence repeat (SSR markers are widely used tools for inferences about genetic diversity, phylogeography and spatial genetic structure. Their applications assume that variation among alleles is essentially caused by an expansion or contraction of the number of repeats and that, accessorily, mutations in the target sequences follow the stepwise mutation model (SMM. Generally speaking, PCR amplicon sizes are used as direct indicators of the number of SSR repeats composing an allele with the data analysis either ignoring the extent of allele size differences or assuming that there is a direct correlation between differences in amplicon size and evolutionary distance. However, without precisely knowing the kind and distribution of polymorphism within an allele (SSR and the associated flanking region (FR sequences, it is hard to say what kind of evolutionary message is conveyed by such a synthetic descriptor of polymorphism as DNA amplicon size. In this study, we sequenced several SSR alleles in multiple populations of three divergent tree genera and disentangled the types of polymorphisms contained in each portion of the DNA amplicon containing an SSR. The patterns of diversity provided by amplicon size variation, SSR variation itself, insertions/deletions (indels, and single nucleotide polymorphisms (SNPs observed in the FRs were compared. Amplicon size variation largely reflected SSR repeat number. The amount of variation was as large in FRs as in the SSR itself. The former contributed significantly to the phylogenetic information and sometimes was the main source of differentiation among individuals and populations contained by FR and SSR regions of SSR markers. The presence of mutations occurring at different rates within a marker's sequence offers the opportunity to analyse evolutionary events occurring on various timescales, but at the same time calls for caution in the interpretation of SSR marker data when the distribution of within

The mitochondrial and plastid genomes of Volvox carteri: bloated molecules rich in repetitive DNA

Directory of Open Access Journals (Sweden)

Lee Robert W

2009-03-01

Full Text Available Abstract Background The magnitude of noncoding DNA in organelle genomes can vary significantly; it is argued that much of this variation is attributable to the dissemination of selfish DNA. The results of a previous study indicate that the mitochondrial DNA (mtDNA of the green alga Volvox carteri abounds with palindromic repeats, which appear to be selfish elements. We became interested in the evolution and distribution of these repeats when, during a cursory exploration of the V. carteri nuclear DNA (nucDNA and plastid DNA (ptDNA sequences, we found palindromic repeats with similar structural features to those of the mtDNA. Upon this discovery, we decided to investigate the diversity and evolutionary implications of these palindromic elements by sequencing and characterizing large portions of mtDNA and ptDNA and then comparing these data to the V. carteri draft nuclear genome sequence. Results We sequenced 30 and 420 kilobases (kb of the mitochondrial and plastid genomes of V. carteri, respectively – resulting in partial assemblies of these genomes. The mitochondrial genome is the most bloated green-algal mtDNA observed to date: ~61% of the sequence is noncoding, most of which is comprised of short palindromic repeats spread throughout the intergenic and intronic regions. The plastid genome is the largest (>420 kb and most expanded (>80% noncoding ptDNA sequence yet discovered, with a myriad of palindromic repeats in the noncoding regions, which have a similar size and secondary structure to those of the mtDNA. We found that 15 kb (~0.01% of the nuclear genome are homologous to the palindromic elements of the mtDNA, and 50 kb (~0.05% are homologous to those of the ptDNA. Conclusion Selfish elements in the form of short palindromic repeats have propagated in the V. carteri mtDNA and ptDNA, resulting in the distension of these genomes. Copies of these same repeats are also found in a small fraction of the nucDNA, but appear to be inert in this

ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data.

Science.gov (United States)

Yang, Jian-Hua; Li, Jun-Hao; Jiang, Shan; Zhou, Hui; Qu, Liang-Hu

2013-01-01

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) represent two classes of important non-coding RNAs in eukaryotes. Although these non-coding RNAs have been implicated in organismal development and in various human diseases, surprisingly little is known about their transcriptional regulation. Recent advances in chromatin immunoprecipitation with next-generation DNA sequencing (ChIP-Seq) have provided methods of detecting transcription factor binding sites (TFBSs) with unprecedented sensitivity. In this study, we describe ChIPBase (http://deepbase.sysu.edu.cn/chipbase/), a novel database that we have developed to facilitate the comprehensive annotation and discovery of transcription factor binding maps and transcriptional regulatory relationships of lncRNAs and miRNAs from ChIP-Seq data. The current release of ChIPBase includes high-throughput sequencing data that were generated by 543 ChIP-Seq experiments in diverse tissues and cell lines from six organisms. By analysing millions of TFBSs, we identified tens of thousands of TF-lncRNA and TF-miRNA regulatory relationships. Furthermore, two web-based servers were developed to annotate and discover transcriptional regulatory relationships of lncRNAs and miRNAs from ChIP-Seq data. In addition, we developed two genome browsers, deepView and genomeView, to provide integrated views of multidimensional data. Moreover, our web implementation supports diverse query types and the exploration of TFs, lncRNAs, miRNAs, gene ontologies and pathways.

Thermal expansion of L-ascorbic acid

Science.gov (United States)

Nicolaï, B.; Barrio, M.; Tamarit, J.-Ll.; Céolin, R.; Rietveld, I. B.

2017-04-01

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.

Chemical graph-theoretic cluster expansions

International Nuclear Information System (INIS)

Klein, D.J.

1986-01-01

A general computationally amenable chemico-graph-theoretic cluster expansion method is suggested as a paradigm for incorporation of chemical structure concepts in a systematic manner. The cluster expansion approach is presented in a formalism general enough to cover a variety of empirical, semiempirical, and even ab initio applications. Formally such approaches for the utilization of chemical structure-related concepts may be viewed as discrete analogues of Taylor series expansions. The efficacy of the chemical structure concepts then is simply bound up in the rate of convergence of the cluster expansions. In many empirical applications, e.g., boiling points, chromatographic separation coefficients, and biological activities, this rate of convergence has been observed to be quite rapid. More note will be made here of quantum chemical applications. Relations to questions concerning size extensivity of energies and size consistency of wave functions are addressed

Defining chemical expansion: the choice of units for the stoichiometric expansion coefficient

DEFF Research Database (Denmark)

Marrocchelli, Dario; Chatzichristodoulou, Christodoulos; Bishop, Sean R.

2014-01-01

Chemical expansion refers to the spatial dilation of a material that occurs upon changes in its composition. When this dilation is caused by a gradual, iso-structural increase in the lattice parameter with composition, it is related to the composition change by the stoichiometric expansion coeffi...... are provided for changes in oxygen content in fluorite, perovskite, and Ruddlesden-Popper (K2NiF4) phase materials used in solid oxide fuel cells....

Long non-coding RNAs as regulators of the endocrine system.

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Knoll, Marko; Lodish, Harvey F; Sun, Lei

2015-03-01

Long non-coding RNAs (lncRNAs) are a large and diverse group of RNAs that are often lineage-specific and that regulate multiple biological functions. Many are nuclear and are essential parts of ribonucleoprotein complexes that modify chromatin segments and establish active or repressive chromatin states; others are cytosolic and regulate the stability of mRNA or act as microRNA sponges. This Review summarizes the current knowledge of lncRNAs as regulators of the endocrine system, with a focus on the identification and mode of action of several endocrine-important lncRNAs. We highlight lncRNAs that have a role in the development and function of pancreatic β cells, white and brown adipose tissue, and other endocrine organs, and discuss the involvement of these molecules in endocrine dysfunction (for example, diabetes mellitus). We also address the associations of lncRNAs with nuclear receptors involved in major hormonal signalling pathways, such as estrogen and androgen receptors, and the relevance of these associations in certain endocrine cancers.

Quantitative Profiling of Peptides from RNAs classified as non-coding

Science.gov (United States)

Prabakaran, Sudhakaran; Hemberg, Martin; Chauhan, Ruchi; Winter, Dominic; Tweedie-Cullen, Ry Y.; Dittrich, Christian; Hong, Elizabeth; Gunawardena, Jeremy; Steen, Hanno; Kreiman, Gabriel; Steen, Judith A.

2014-01-01

Only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into proteins, and it is generally assumed that a large portion of transcribed sequences - including introns and several classes of non-coding RNAs (ncRNAs) do not give rise to peptide products. A systematic examination of translation and physiological regulation of ncRNAs has not been conducted. Here, we use computational methods to identify the products of non-canonical translation in mouse neurons by analyzing unannotated transcripts in combination with proteomic data. This study supports the existence of non-canonical translation products from both intragenic and extragenic genomic regions, including peptides derived from anti-sense transcripts and introns. Moreover, the studied novel translation products exhibit temporal regulation similar to that of proteins known to be involved in neuronal activity processes. These observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential. PMID:25403355

Human Long Noncoding RNA Regulation of Stem Cell Potency and Differentiation

Directory of Open Access Journals (Sweden)

Seahyoung Lee

2017-01-01

Full Text Available Because of their capability of differentiation into lineage-specific cells, stem cells are an attractive therapeutic modality in regenerative medicine. To develop an effective stem cell-based therapeutic strategy with predictable results, deeper understanding of the underlying molecular mechanisms of stem cell differentiation and/or pluripotency maintenance is required. Thus, reviewing the key factors involved in the transcriptional and epigenetic regulation of stem cell differentiation and maintenance is important. Accumulating data indicate that long noncoding RNAs (lncRNAs mediate numerous biological processes, including stem cell differentiation and maintenance. Here, we review recent findings on the human lncRNA regulation of stem cell potency and differentiation. Although the clinical implication of these lncRNAs is only beginning to be elucidated, it is anticipated that lncRNAs will become important therapeutic targets in the near future.

The non-coding RNAs of the H19-IGF2 imprinted loci: a focus on biological roles and therapeutic potential in Lung Cancer.

Science.gov (United States)

Matouk, Imad J; Halle, David; Gilon, Michal; Hochberg, Abraham

2015-04-09

Since it was first described, the imprinted cluster 11p15.5 has been reported to be deregulated in a variety of pediatric and adult cancers including that of the lung. Both protein coding and non-coding genes functioning as oncogenes or as tumor suppressor genes reside within this cluster. Oncomirs that can function as oncogenes or as tumor suppressors have also been reported. While a complete account of the role played by the 11p15.5 imprinted cluster in lung cancer is beyond the scope of this review, we will focus on the role of the non-coding RNAs processed from the H19-IGF2 loci. A special emphasis will be given to the H19/miR-675 gene locus. Their potential diagnostic and therapeutic use in lung cancer will be described.

Edgeworth expansion for functionals of continuous diffusion processes

DEFF Research Database (Denmark)

Podolskij, Mark; Yoshida, Nakahiro

This paper presents new results on the Edgeworth expansion for high frequency functionals of continuous diffusion processes. We derive asymptotic expansions for weighted functionals of the Brownian motion and apply them to provide the Edgeworth expansion for power variation of diffusion processes....... Our methodology relies on martingale embedding, Malliavin calculus and stable central limit theorems for semimartingales. Finally, we demonstrate the density expansion for studentized statistics of power variations.......This paper presents new results on the Edgeworth expansion for high frequency functionals of continuous diffusion processes. We derive asymptotic expansions for weighted functionals of the Brownian motion and apply them to provide the Edgeworth expansion for power variation of diffusion processes...

MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

Science.gov (United States)

Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei; Taylor, Patricia A; Efebera, Yvonne A; Devine, Steven M; Blazar, Bruce R; Garzon, Ramiro; Ranganathan, Parvathi

2018-06-15

MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155 -/- ) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 + T cells and conventional CD4 + CD25 - T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 + donor T cells and promoting exhaustion in donor CD4 + T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 -/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. Copyright © 2018 by The American Association of Immunologists, Inc.

Expansion lyre-shaped tube

International Nuclear Information System (INIS)

Andro, Jean.

1973-01-01

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

Repeatability of visual acuity measurement.

Science.gov (United States)

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

1998-05-01

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.

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.

Artificial Intelligence, DNA Mimicry, and Human Health.

Science.gov (United States)

Stefano, George B; Kream, Richard M

2017-08-14

The molecular evolution of genomic DNA across diverse plant and animal phyla involved dynamic registrations of sequence modifications to maintain existential homeostasis to increasingly complex patterns of environmental stressors. As an essential corollary, driver effects of positive evolutionary pressure are hypothesized to effect concerted modifications of genomic DNA sequences to meet expanded platforms of regulatory controls for successful implementation of advanced physiological requirements. It is also clearly apparent that preservation of updated registries of advantageous modifications of genomic DNA sequences requires coordinate expansion of convergent cellular proofreading/error correction mechanisms that are encoded by reciprocally modified genomic DNA. Computational expansion of operationally defined DNA memory extends to coordinate modification of coding and previously under-emphasized noncoding regions that now appear to represent essential reservoirs of untapped genetic information amenable to evolutionary driven recruitment into the realm of biologically active domains. Additionally, expansion of DNA memory potential via chemical modification and activation of noncoding sequences is targeted to vertical augmentation and integration of an expanded cadre of transcriptional and epigenetic regulatory factors affecting linear coding of protein amino acid sequences within open reading frames.

Complex organisation and structure of the ghrelin antisense strand gene GHRLOS, a candidate non-coding RNA gene

Directory of Open Access Journals (Sweden)

Herington Adrian C

2008-10-01

Full Text Available Abstract Background The peptide hormone ghrelin has many important physiological and pathophysiological roles, including the stimulation of growth hormone (GH release, appetite regulation, gut motility and proliferation of cancer cells. We previously identified a gene on the opposite strand of the ghrelin gene, ghrelinOS (GHRLOS, which spans the promoter and untranslated regions of the ghrelin gene (GHRL. Here we further characterise GHRLOS. Results We have described GHRLOS mRNA isoforms that extend over 1.4 kb of the promoter region and 106 nucleotides of exon 4 of the ghrelin gene, GHRL. These GHRLOS transcripts initiate 4.8 kb downstream of the terminal exon 4 of GHRL and are present in the 3' untranslated exon of the adjacent gene TATDN2 (TatD DNase domain containing 2. Interestingly, we have also identified a putative non-coding TATDN2-GHRLOS chimaeric transcript, indicating that GHRLOS RNA biogenesis is extremely complex. Moreover, we have discovered that the 3' region of GHRLOS is also antisense, in a tail-to-tail fashion to a novel terminal exon of the neighbouring SEC13 gene, which is important in protein transport. Sequence analyses revealed that GHRLOS is riddled with stop codons, and that there is little nucleotide and amino-acid sequence conservation of the GHRLOS gene between vertebrates. The gene spans 44 kb on 3p25.3, is extensively spliced and harbours multiple variable exons. We have also investigated the expression of GHRLOS and found evidence of differential tissue expression. It is highly expressed in tissues which are emerging as major sites of non-coding RNA expression (the thymus, brain, and testis, as well as in the ovary and uterus. In contrast, very low levels were found in the stomach where sense, GHRL derived RNAs are highly expressed. Conclusion GHRLOS RNA transcripts display several distinctive features of non-coding (ncRNA genes, including 5' capping, polyadenylation, extensive splicing and short open reading

Simulation and Experimental Study of Arc Column Expansion After Ignition in Low-Voltage Circuit Breakers

Institute of Scientific and Technical Information of China (English)

MA Qiang; RONG Mingzhe; WU Yi; XU Tiejun; SUN Zhiqiang

2008-01-01

The dynamicprocess of arc pressure and corresponding arc column expansion, which is the main feature after arc ignition and has a significant effect on the breaking behaviour of low -voltage circuit breakers, is studied. By constructing a three dimensional mathematical model of air arc plasma and adopting the Control Volume Method, the parameters of arc plasma including temperature and pressure axe obtained. The variations of pressure field and temperature field with time are simulated. The result indicates that there are six stages for the process of arc column expansion according to the variation of pressure in arc chamber. In the first stage, the maximal pressure locates in the region close to cathode, and in the second stage the maximal pressure shifts to the region close to the anode. In the third stage, the pressure difference between the middle of arc column and the ambient gas is very large, so the arc column begins to expand apparently. In the fourth stage, the pressure wave propagates towards both ends and the maximal pressure appears at the two ends when the pressure wave reaches both sidewalls. In the fifth stage, the pressure wave is reflected and collides in the middle of the arc chamber. In the last stage, the propagation and reflection of pressure wave will repeat several times until a steady burning state is reached. In addition, the experimental results of arc column expansion, corresponding to the arc pressure variation, are presented to verify the simulation results.

A Simple, High-Throughput Assay for Fragile X Expanded Alleles Using Triple Repeat Primed PCR and Capillary Electrophoresis

Science.gov (United States)

Lyon, Elaine; Laver, Thomas; Yu, Ping; Jama, Mohamed; Young, Keith; Zoccoli, Michael; Marlowe, Natalia

2010-01-01

Population screening has been proposed for Fragile X syndrome to identify premutation carrier females and affected newborns. We developed a PCR-based assay capable of quickly detecting the presence or absence of an expanded FMR1 allele with high sensitivity and specificity. This assay combines a triplet repeat primed PCR with high-throughput automated capillary electrophoresis. We evaluated assay performance using archived samples sent for Fragile X diagnostic testing representing a range of Fragile X CGG-repeat expansions. Two hundred five previously genotyped samples were tested with the new assay. Data were analyzed for the presence of a trinucleotide “ladder” extending beyond 55 repeats, which was set as a cut-off to identify expanded FMR1 alleles. We identified expanded FMR1 alleles in 132 samples (59 premutation, 71 full mutation, 2 mosaics) and normal FMR1 alleles in 73 samples. We found 100% concordance with previous results from PCR and Southern blot analyses. In addition, we show feasibility of using this assay with DNA extracted from dried-blood spots. Using a single PCR combined with high-throughput fragment analysis on the automated capillary electrophoresis instrument, we developed a rapid and reproducible PCR-based laboratory assay that meets many of the requirements for a first-tier test for population screening. PMID:20431035

Plasma expansion: fundamentals and applications

International Nuclear Information System (INIS)

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

2002-01-01

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

Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions

DEFF Research Database (Denmark)

Lavstsen, Thomas; Salanti, Ali; Jensen, Anja T R

2003-01-01

and organization of the 3D7 PfEMP1 repertoire was investigated on the basis of the complete genome sequence. METHODS: Using two tree-building methods we analysed the coding and non-coding sequences of 3D7 var and rif genes as well as var genes of other parasite strains. RESULTS: var genes can be sub...

On genus expansion of superpolynomials

Energy Technology Data Exchange (ETDEWEB)

Mironov, Andrei, E-mail: mironov@itep.ru [Lebedev Physics Institute, Moscow 119991 (Russian Federation); ITEP, Moscow 117218 (Russian Federation); National Research Nuclear University MEPhI, Moscow 115409 (Russian Federation); Morozov, Alexei, E-mail: morozov@itep.ru [ITEP, Moscow 117218 (Russian Federation); National Research Nuclear University MEPhI, Moscow 115409 (Russian Federation); Sleptsov, Alexei, E-mail: sleptsov@itep.ru [ITEP, Moscow 117218 (Russian Federation); Laboratory of Quantum Topology, Chelyabinsk State University, Chelyabinsk 454001 (Russian Federation); KdVI, University of Amsterdam (Netherlands); Smirnov, Andrey, E-mail: asmirnov@math.columbia.edu [ITEP, Moscow 117218 (Russian Federation); Columbia University, Department of Mathematics, New York (United States)

2014-12-15

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.

A Positive Regulatory Loop between a Wnt-Regulated Non-coding RNA and ASCL2 Controls Intestinal Stem Cell Fate.

Science.gov (United States)

Giakountis, Antonis; Moulos, Panagiotis; Zarkou, Vasiliki; Oikonomou, Christina; Harokopos, Vaggelis; Hatzigeorgiou, Artemis G; Reczko, Martin; Hatzis, Pantelis

2016-06-21

The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation, and proliferation in the intestinal epithelium. Constitutive, aberrant activity of the TCF4/β-catenin transcriptional complex is the primary transforming factor in colorectal cancer. We identify a nuclear long non-coding RNA, termed WiNTRLINC1, as a direct target of TCF4/β-catenin in colorectal cancer cells. WiNTRLINC1 positively regulates the expression of its genomic neighbor ASCL2, a transcription factor that controls intestinal stem cell fate. WiNTRLINC1 interacts with TCF4/β-catenin to mediate the juxtaposition of its promoter with the regulatory regions of ASCL2. ASCL2, in turn, regulates WiNTRLINC1 transcriptionally, closing a feedforward regulatory loop that controls stem cell-related gene expression. This regulatory circuitry is highly amplified in colorectal cancer and correlates with increased metastatic potential and decreased patient survival. Our results uncover the interplay between non-coding RNA-mediated regulation and Wnt signaling and point to the diagnostic and therapeutic potential of WiNTRLINC1. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Noncoding Subgenomic Flavivirus RNA Is Processed by the Mosquito RNA Interference Machinery and Determines West Nile Virus Transmission by Culex pipiens Mosquitoes

NARCIS (Netherlands)

Goertz, G.P.; Fros, J.J.; Miesen, P.; Vogels, C.B.F.; Bent, M.L. van der; Geertsema, C.; Koenraadt, C.J.M.; Rij, R.P. van; Oers, M.M. van; Pijlman, G.P.

2016-01-01

Flaviviruses, such as Zika virus, yellow fever virus, dengue virus, and West Nile virus (WNV), are a serious concern for human health. Flaviviruses produce an abundant noncoding subgenomic flavivirus RNA (sfRNA) in infected cells. sfRNA results from stalling of the host 5'-3' exoribonuclease

On summation of perturbation expansions

International Nuclear Information System (INIS)

Horzela, A.

1985-04-01

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)

OPEC future capacity expansions

International Nuclear Information System (INIS)

Sandrea, I.

2005-01-01

This conference presentation examined OPEC future capacity expansions including highlights from 2000-2004 from the supply perspective and actions by OPEC; OPEC spare capacity in 2005/2006; medium-term capacity expansion and investments; long-term scenarios, challenges and opportunities; and upstream policies in member countries. Highlights from the supply perspective included worst than expected non-OPEC supply response; non-OPEC supply affected by a number of accidents and strikes; geopolitical tensions; and higher than expected demand for OPEC crude. OPEC's actions included closer relationship with other producers and consumers; capacity expansions in 2004 and 2005/2006; and OPEC kept the market well supplied with crude in 2004. The presentation also provided data using graphical charts on OPEC net capacity additions until 2005/2006; OPEC production versus spare capacity from 2003 to 2005; OPEC production and capacity to 2010; and change in required OPEC production from 2005-2020. Medium term expansion to 2010 includes over 60 projects. Medium-term risks such as project execution, financing, costs, demand, reserves, depletion, integration of Iraq, and geopolitical tensions were also discussed. The presentation concluded that in the long term, large uncertainties remain; the peak of world supply is not imminent; and continued and enhanced cooperation is essential to market stability. tabs., figs

On Learning Ring-Sum-Expansions

DEFF Research Database (Denmark)

Fischer, Paul; Simon, H. -U.

1992-01-01

The problem of learning ring-sum-expansions from examples is studied. Ring-sum-expansions (RSE) are representations of Boolean functions over the base {#123;small infinum, (+), 1}#125;, which reflect arithmetic operations in GF(2). k-RSE is the class of ring-sum-expansions containing only monomials...... of length at most k:. term-RSE is the class of ring-sum-expansions having at most I: monomials. It is shown that k-RSE, k>or=1, is learnable while k-term-RSE, k>2, is not learnable if RPnot=NP. Without using a complexity-theoretical hypothesis, it is proven that k-RSE, k>or=1, and k-term-RSE, k>or=2 cannot...... be learned from positive (negative) examples alone. However, if the restriction that the hypothesis which is output by the learning algorithm is also a k-RSE is suspended, then k-RSE is learnable from positive (negative) examples only. Moreover, it is proved that 2-term-RSE is learnable by a conjunction...

The bootstrap and edgeworth expansion

CERN Document Server

Hall, Peter

1992-01-01

This monograph addresses two quite different topics, in the belief that each can shed light on the other. Firstly, it lays the foundation for a particular view of the bootstrap. Secondly, it gives an account of Edgeworth expansion. Chapter 1 is about the bootstrap, witih almost no mention of Edgeworth expansion; Chapter 2 is about Edgeworth expansion, with scarcely a word about the bootstrap; and Chapters 3 and 4 bring these two themes together, using Edgeworth expansion to explore and develop the properites of the bootstrap. The book is aimed a a graduate level audience who has some exposure to the methods of theoretical statistics. However, technical details are delayed until the last chapter (entitled "Details of Mathematical Rogour"), and so a mathematically able reader without knowledge of the rigorous theory of probability will have no trouble understanding the first four-fifths of the book. The book simultaneously fills two gaps in the literature; it provides a very readable graduate level account of t...

Fostering repeat donations in Ghana.

Science.gov (United States)

Owusu-Ofori, S; Asenso-Mensah, K; Boateng, P; Sarkodie, F; Allain, J-P

2010-01-01

Most African countries are challenged in recruiting and retaining voluntary blood donors by cost and other complexities and in establishing and implementing national blood policies. The availability of replacement donors who are a cheaper source of blood has not enhanced repeat voluntary donor initiatives. An overview of activities for recruiting and retaining voluntary blood donors was carried out. Donor records from mobile sessions were reviewed from 2002 to 2008. A total of 71,701 blood donations; 45,515 (63.5%) being voluntary donations with 11,680 (25%) repeat donations were collected during the study period. Donations from schools and colleges contributed a steady 60% of total voluntary whilst radio station blood drives increased contribution from 10 to 27%. Though Muslim population is less than 20%, blood collection was above the 30-donation cost-effectiveness threshold with a repeat donation trend reaching 60%. In contrast Christian worshippers provided donations. Repeat donation trends amongst school donors and radio blood drives were 20% and 70% respectively. Repeat donations rates have been variable amongst different blood donor groups in Kumasi, Ghana. The impact of community leaders in propagating altruism cannot be overemphasized. Programs aiming at motivating replacement donors to be repeat donors should be developed and assessed. Copyright 2009 The International Association for Biologicals. All rights reserved.

The long noncoding RNA Tug1 connects metabolic changes with kidney disease in podocytes.

Science.gov (United States)

Li, Szu Yuan; Susztak, Katalin

2016-11-01

An increasing amount of evidence suggests that metabolic alterations play a key role in chronic kidney disease (CKD) pathogenesis. In this issue of the JCI, Long et al. report that the long noncoding RNA (lncRNA) taurine-upregulated 1 (Tug1) contributes to CKD development. The authors show that Tug1 regulates mitochondrial function in podocytes by epigenetic targeting of expression of the transcription factor PPARγ coactivator 1α (PGC-1α, encoded by Ppargc1a). Transgenic overexpression of Tug1 specifically in podocytes ameliorated diabetes-induced CKD in mice. Together, these results highlight an important connection between lncRNA-mediated metabolic alterations in podocytes and kidney disease development.

Numerical studies of QCD renormalons in high-order perturbative expansions

International Nuclear Information System (INIS)

Bauer, Clemens

2013-01-01

Perturbative expansions in four-dimensional non-Abelian gauge theories such as Quantum Chromodynamics (QCD) are expected to be divergent, at best asymptotic. One reason is that it is impossible to strictly exclude from the relevant Feynman diagrams those energy regions in which a perturbative treatment is inapplicable. The divergent nature of the series is then signaled by a rapid (factorial) growth of the perturbative expansion coefficients, commonly referred to as a renormalon. In QCD, the most severe divergences occur in the infrared (IR) limit and therefore they are classified as IR renormalons. Their appearance can be understood within the well-accepted Operator Product Expansion (OPE) framework. According to the OPE, the perturbative calculation of a physical observable must be amended by non-perturbative power corrections that come in the form of condensates, universal characteristics of the rich QCD vacuum structure. Adding up perturbative and non-perturbative contributions, the ambiguity due to the renormalon cancels and the physical observable is well-defined. Although the field has made considerable progress in the last twenty years, a proof of renormalon existence is still pending. It has only been tested assuming strong simplifications or in toy models. The aim of this thesis is to provide the first numerical evidence for renormalon existence in the gauge sector of QCD. We use Numerical Stochastic Perturbation Theory (NSPT) to directly obtain perturbative coefficients within lattice regularization, a means to replace continuum spacetime by a four-dimensional hypercubic lattice. A peculiar feature of NSPT are comparatively low simulation costs when reaching high expansion orders. We examine two distinct observables: the static self-energy of an isolated quark and the elementary plaquette. Following the OPE classification, the static quark self-energy is ideally suited for a renormalon study. Taking into account peculiarities of the lattice approach such

Association of ECRG2 TCA short tandem repeat polymorphism with the risk of oesophageal cancer in a North Indian population.

Science.gov (United States)

Jain, Meenu; Kumar, Shaleen; Ghoshal, Uday C; Mittal, Balraj

2008-06-01

Oesophageal cancer-related gene (ECRG2) is a tumour suppressor gene and it has been suggested that a triplet TCA short tandem repeat (STR) in the noncoding region of exon 4 plays a role in genetic susceptibility to oesophageal cancer. In the present study, ECRG2 STR polymorphism was studied in 134 patients with oesophageal cancer and 194 controls, using PCR and polyacrylamide gel electrophoresis. The results showed a higher frequency of the ECRG2 TCA (3)/TCA (4) genotype in cancer patients than in controls (odds ratio 2.6, 95% CI 1.0-6.4, p = 0.03). The association of the ECRG2 TCA (3)/TCA (4) genotype with clinical characteristics showed an increased risk for squamous cell histology (2.8, 95% CI 1.1-7.1, p = 0.03), while no association with tumor location or lymph node involvement was observed. Interaction of tobacco, alcohol and occupational exposure with the ECRG2 genotypes did not show modulation of risk. In conclusion, the ECRG2 TCA (3)/TCA (4) genotype is associated with the risk of oesophageal carcinoma in a North Indian population.

Fuel Thermal Expansion (FTHEXP)

International Nuclear Information System (INIS)

Reymann, G.A.

1978-07-01

A model is presented which deals with dimensional changes in LWR fuel pellets caused by changes in temperature. It is capable of dealing with any combination of UO 2 and PuO 2 in solid, liquid or mixed phase states, and includes expansion due to the solid-liquid phase change. The function FTHEXP models fuel thermal expansion as a function of temperature, fraction of PuO 2 , and the fraction of fuel which is molten