Deciphering RNA Regulatory Elements Involved in the Developmental and Environmental Gene Regulation of Trypanosoma brucei.

Science.gov (United States)

Gazestani, Vahid H; Salavati, Reza

2015-01-01

Trypanosoma brucei is a vector-borne parasite with intricate life cycle that can cause serious diseases in humans and animals. This pathogen relies on fine regulation of gene expression to respond and adapt to variable environments, with implications in transmission and infectivity. However, the involved regulatory elements and their mechanisms of actions are largely unknown. Here, benefiting from a new graph-based approach for finding functional regulatory elements in RNA (GRAFFER), we have predicted 88 new RNA regulatory elements that are potentially involved in the gene regulatory network of T. brucei. We show that many of these newly predicted elements are responsive to both transcriptomic and proteomic changes during the life cycle of the parasite. Moreover, we found that 11 of predicted elements strikingly resemble previously identified regulatory elements for the parasite. Additionally, comparison with previously predicted motifs on T. brucei suggested the superior performance of our approach based on the current limited knowledge of regulatory elements in T. brucei.

Close Sequence Comparisons are Sufficient to Identify Humancis-Regulatory Elements

Energy Technology Data Exchange (ETDEWEB)

Prabhakar, Shyam; Poulin, Francis; Shoukry, Malak; Afzal, Veena; Rubin, Edward M.; Couronne, Olivier; Pennacchio, Len A.

2005-12-01

Cross-species DNA sequence comparison is the primary method used to identify functional noncoding elements in human and other large genomes. However, little is known about the relative merits of evolutionarily close and distant sequence comparisons, due to the lack of a universal metric for sequence conservation, and also the paucity of empirically defined benchmark sets of cis-regulatory elements. To address this problem, we developed a general-purpose algorithm (Gumby) that detects slowly-evolving regions in primate, mammalian and more distant comparisons without requiring adjustment of parameters, and ranks conserved elements by P-value using Karlin-Altschul statistics. We benchmarked Gumby predictions against previously identified cis-regulatory elements at diverse genomic loci, and also tested numerous extremely conserved human-rodent sequences for transcriptional enhancer activity using reporter-gene assays in transgenic mice. Human regulatory elements were identified with acceptable sensitivity and specificity by comparison with 1-5 other eutherian mammals or 6 other simian primates. More distant comparisons (marsupial, avian, amphibian and fish) failed to identify many of the empirically defined functional noncoding elements. We derived an intuitive relationship between ancient and recent noncoding sequence conservation from whole genome comparative analysis, which explains some of these findings. Lastly, we determined that, in addition to strength of conservation, genomic location and/or density of surrounding conserved elements must also be considered in selecting candidate enhancers for testing at embryonic time points.

Discovery of regulatory elements is improved by a discriminatory approach

DEFF Research Database (Denmark)

Valen, Eivind; Sandelin, Albin; Winther, Ole

2009-01-01

, but contemporary methods are challenged by the size and diversity of regulatory regions in higher metazoans. Two key issues are the small amount of information contained in a pattern compared to the large promoter regions and the repetitive characteristics of genomic DNA, which both lead to "pattern drowning''. We...... demonstrate higher accuracy than the best of contemporary methods, high robustness when extending the length of the input sequences and a strong correlation between our objective function and the correct solution. Using a large background set of real promoters instead of a simplified model leads to higher...

In silico analysis of cis-acting regulatory elements in 5' regulatory regions of sucrose transporter gene families in rice (Oryza sativa Japonica) and Arabidopsis thaliana.

Science.gov (United States)

Ibraheem, Omodele; Botha, Christiaan E J; Bradley, Graeme

2010-12-01

The regulation of gene expression involves a multifarious regulatory system. Each gene contains a unique combination of cis-acting regulatory sequence elements in the 5' regulatory region that determines its temporal and spatial expression. Cis-acting regulatory elements are essential transcriptional gene regulatory units; they control many biological processes and stress responses. Thus a full understanding of the transcriptional gene regulation system will depend on successful functional analyses of cis-acting elements. Cis-acting regulatory elements present within the 5' regulatory region of the sucrose transporter gene families in rice (Oryza sativa Japonica cultivar-group) and Arabidopsis thaliana, were identified using a bioinformatics approach. The possible cis-acting regulatory elements were predicted by scanning 1.5kbp of 5' regulatory regions of the sucrose transporter genes translational start sites, using Plant CARE, PLACE and Genomatix Matinspector professional databases. Several cis-acting regulatory elements that are associated with plant development, plant hormonal regulation and stress response were identified, and were present in varying frequencies within the 1.5kbp of 5' regulatory region, among which are; A-box, RY, CAT, Pyrimidine-box, Sucrose-box, ABRE, ARF, ERE, GARE, Me-JA, ARE, DRE, GA-motif, GATA, GT-1, MYC, MYB, W-box, and I-box. This result reveals the probable cis-acting regulatory elements that possibly are involved in the expression and regulation of sucrose transporter gene families in rice and Arabidopsis thaliana during cellular development or environmental stress conditions. Copyright © 2010 Elsevier Ltd. All rights reserved.

Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures

DEFF Research Database (Denmark)

Stark, Alexander; Lin, Michael F; Kheradpour, Pouya

2007-01-01

Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional e...... individual motif instances with high confidence. We also study how discovery power scales with the divergence and number of species compared, and we provide general guidelines for comparative studies....

A HLA class I cis-regulatory element whose activity can be modulated by hormones.

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Sim, B C; Hui, K M

1994-12-01

To elucidate the basis of the down-regulation in major histocompatibility complex (MHC) class I gene expression and to identify possible DNA-binding regulatory elements that have the potential to interact with class I MHC genes, we have studied the transcriptional regulation of class I HLA genes in human breast carcinoma cells. A 9 base pair (bp) negative cis-regulatory element (NRE) has been identified using band-shift assays employing DNA sequences derived from the 5'-flanking region of HLA class I genes. This 9-bp element, GTCATGGCG, located within exon I of the HLA class I gene, can potently inhibit the expression of a heterologous thymidine kinase (TK) gene promoter and the HLA enhancer element. Furthermore, this regulatory element can exert its suppressive function in either the sense or anti-sense orientation. More interestingly, NRE can suppress dexamethasone-mediated gene activation in the context of the reported glucocorticoid-responsive element (GRE) in MCF-7 cells but has no influence on the estrogen-mediated transcriptional activation of MCF-7 cells in the context of the reported estrogen-responsive element (ERE). Furthermore, the presence of such a regulatory element within the HLA class I gene whose activity can be modulated by hormones correlates well with our observation that the level of HLA class I gene expression can be down-regulated by hormones in human breast carcinoma cells. Such interactions between negative regulatory elements and specific hormone trans-activators are novel and suggest a versatile form of transcriptional control.

Implications of duplicated cis-regulatory elements in the evolution of metazoans: the DDI model or how simplicity begets novelty.

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Jiménez-Delgado, Senda; Pascual-Anaya, Juan; Garcia-Fernàndez, Jordi

2009-07-01

The discovery that most regulatory genes were conserved among animals from distant phyla challenged the ideas that gene duplication and divergence of homologous coding sequences were the basis for major morphological changes in metazoan evolution. In recent years, however, the interest for the roles, conservation and changes of non-coding sequences grew-up in parallel with genome sequencing projects. Presently, many independent studies are highlighting the importance that subtle changes in cis-regulatory regions had in the evolution of morphology trough the Animal Kingdom. Here we will show and discuss some of these studies, and underscore the future of cis-Evo-Devo research. Nevertheless, we would also explore how gene duplication, which includes duplication of regulatory regions, may have been critical for spatial or temporal co-option of new regulatory networks, causing the deployment of new transcriptome scenarios, and how these induced morphological changes were critical for the evolution of new forms. Forty years after Susumu Ohno famous sentence 'natural selection merely modifies, while redundancy creates', we suggest the alternative: 'natural selection modifies, while redundancy of cis-regulatory elements innovates', and propose the Duplication-Degeneration-Innovation model to explain the increased evolvability of duplicated cis-regulatory regions. Paradoxically, making regulation simpler by subfunctionalization paved the path for future complexity or, in other words, 'to make it simple to make it complex'.

CRISPR-Cas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome.

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Klann, Tyler S; Black, Joshua B; Chellappan, Malathi; Safi, Alexias; Song, Lingyun; Hilton, Isaac B; Crawford, Gregory E; Reddy, Timothy E; Gersbach, Charles A

2017-06-01

Large genome-mapping consortia and thousands of genome-wide association studies have identified non-protein-coding elements in the genome as having a central role in various biological processes. However, decoding the functions of the millions of putative regulatory elements discovered in these studies remains challenging. CRISPR-Cas9-based epigenome editing technologies have enabled precise perturbation of the activity of specific regulatory elements. Here we describe CRISPR-Cas9-based epigenomic regulatory element screening (CERES) for improved high-throughput screening of regulatory element activity in the native genomic context. Using dCas9 KRAB repressor and dCas9 p300 activator constructs and lentiviral single guide RNA libraries to target DNase I hypersensitive sites surrounding a gene of interest, we carried out both loss- and gain-of-function screens to identify regulatory elements for the β-globin and HER2 loci in human cells. CERES readily identified known and previously unidentified regulatory elements, some of which were dependent on cell type or direction of perturbation. This technology allows the high-throughput functional annotation of putative regulatory elements in their native chromosomal context.

Discovery of rare, diagnostic AluYb8/9 elements in diverse human populations.

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Feusier, Julie; Witherspoon, David J; Scott Watkins, W; Goubert, Clément; Sasani, Thomas A; Jorde, Lynn B

2017-01-01

Polymorphic human Alu elements are excellent tools for assessing population structure, and new retrotransposition events can contribute to disease. Next-generation sequencing has greatly increased the potential to discover Alu elements in human populations, and various sequencing and bioinformatics methods have been designed to tackle the problem of detecting these highly repetitive elements. However, current techniques for Alu discovery may miss rare, polymorphic Alu elements. Combining multiple discovery approaches may provide a better profile of the polymorphic Alu mobilome. Alu Yb8/9 elements have been a focus of our recent studies as they are young subfamilies (~2.3 million years old) that contribute ~30% of recent polymorphic Alu retrotransposition events. Here, we update our ME-Scan methods for detecting Alu elements and apply these methods to discover new insertions in a large set of individuals with diverse ancestral backgrounds. We identified 5,288 putative Alu insertion events, including several hundred novel Alu Yb8/9 elements from 213 individuals from 18 diverse human populations. Hundreds of these loci were specific to continental populations, and 23 non-reference population-specific loci were validated by PCR. We provide high-quality sequence information for 68 rare Alu Yb8/9 elements, of which 11 have hallmarks of an active source element. Our subfamily distribution of rare Alu Yb8/9 elements is consistent with previous datasets, and may be representative of rare loci. We also find that while ME-Scan and low-coverage, whole-genome sequencing (WGS) detect different Alu elements in 41 1000 Genomes individuals, the two methods yield similar population structure results. Current in-silico methods for Alu discovery may miss rare, polymorphic Alu elements. Therefore, using multiple techniques can provide a more accurate profile of Alu elements in individuals and populations. We improved our false-negative rate as an indicator of sample quality for future

Identification of germline transcriptional regulatory elements in Aedes aegypti

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Akbari, Omar S.; Papathanos, Philippos A.; Sandler, Jeremy E.; Kennedy, Katie; Hay, Bruce A.

2014-02-01

The mosquito Aedes aegypti is the principal vector for the yellow fever and dengue viruses, and is also responsible for recent outbreaks of the alphavirus chikungunya. Vector control strategies utilizing engineered gene drive systems are being developed as a means of replacing wild, pathogen transmitting mosquitoes with individuals refractory to disease transmission, or bringing about population suppression. Several of these systems, including Medea, UDMEL, and site-specific nucleases, which can be used to drive genes into populations or bring about population suppression, utilize transcriptional regulatory elements that drive germline-specific expression. Here we report the identification of multiple regulatory elements able to drive gene expression specifically in the female germline, or in the male and female germline, in the mosquito Aedes aegypti. These elements can also be used as tools with which to probe the roles of specific genes in germline function and in the early embryo, through overexpression or RNA interference.

Cis-regulatory RNA elements that regulate specialized ribosome activity.

Science.gov (United States)

Xue, Shifeng; Barna, Maria

2015-01-01

Recent evidence has shown that the ribosome itself can play a highly regulatory role in the specialized translation of specific subpools of mRNAs, in particular at the level of ribosomal proteins (RP). However, the mechanism(s) by which this selection takes place has remained poorly understood. In our recent study, we discovered a combination of unique RNA elements in the 5'UTRs of mRNAs that allows for such control by the ribosome. These mRNAs contain a Translation Inhibitory Element (TIE) that inhibits general cap-dependent translation, and an Internal Ribosome Entry Site (IRES) that relies on a specific RP for activation. The unique combination of an inhibitor of general translation and an activator of specialized translation is key to ribosome-mediated control of gene expression. Here we discuss how these RNA regulatory elements provide a new level of control to protein expression and their implications for gene expression, organismal development and evolution.

Gene set-based module discovery in the breast cancer transcriptome

Directory of Open Access Journals (Sweden)

Zhang Michael Q

2009-02-01

Full Text Available Abstract Background Although microarray-based studies have revealed global view of gene expression in cancer cells, we still have little knowledge about regulatory mechanisms underlying the transcriptome. Several computational methods applied to yeast data have recently succeeded in identifying expression modules, which is defined as co-expressed gene sets under common regulatory mechanisms. However, such module discovery methods are not applied cancer transcriptome data. Results In order to decode oncogenic regulatory programs in cancer cells, we developed a novel module discovery method termed EEM by extending a previously reported module discovery method, and applied it to breast cancer expression data. Starting from seed gene sets prepared based on cis-regulatory elements, ChIP-chip data, and gene locus information, EEM identified 10 principal expression modules in breast cancer based on their expression coherence. Moreover, EEM depicted their activity profiles, which predict regulatory programs in each subtypes of breast tumors. For example, our analysis revealed that the expression module regulated by the Polycomb repressive complex 2 (PRC2 is downregulated in triple negative breast cancers, suggesting similarity of transcriptional programs between stem cells and aggressive breast cancer cells. We also found that the activity of the PRC2 expression module is negatively correlated to the expression of EZH2, a component of PRC2 which belongs to the E2F expression module. E2F-driven EZH2 overexpression may be responsible for the repression of the PRC2 expression modules in triple negative tumors. Furthermore, our network analysis predicts regulatory circuits in breast cancer cells. Conclusion These results demonstrate that the gene set-based module discovery approach is a powerful tool to decode regulatory programs in cancer cells.

Prediction of transcriptional regulatory elements for plant hormone responses based on microarray data

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Yamaguchi-Shinozaki Kazuko

2011-02-01

Full Text Available Abstract Background Phytohormones organize plant development and environmental adaptation through cell-to-cell signal transduction, and their action involves transcriptional activation. Recent international efforts to establish and maintain public databases of Arabidopsis microarray data have enabled the utilization of this data in the analysis of various phytohormone responses, providing genome-wide identification of promoters targeted by phytohormones. Results We utilized such microarray data for prediction of cis-regulatory elements with an octamer-based approach. Our test prediction of a drought-responsive RD29A promoter with the aid of microarray data for response to drought, ABA and overexpression of DREB1A, a key regulator of cold and drought response, provided reasonable results that fit with the experimentally identified regulatory elements. With this succession, we expanded the prediction to various phytohormone responses, including those for abscisic acid, auxin, cytokinin, ethylene, brassinosteroid, jasmonic acid, and salicylic acid, as well as for hydrogen peroxide, drought and DREB1A overexpression. Totally 622 promoters that are activated by phytohormones were subjected to the prediction. In addition, we have assigned putative functions to 53 octamers of the Regulatory Element Group (REG that have been extracted as position-dependent cis-regulatory elements with the aid of their feature of preferential appearance in the promoter region. Conclusions Our prediction of Arabidopsis cis-regulatory elements for phytohormone responses provides guidance for experimental analysis of promoters to reveal the basis of the transcriptional network of phytohormone responses.

Dynamic SPR monitoring of yeast nuclear protein binding to a cis-regulatory element

International Nuclear Information System (INIS)

Mao, Grace; Brody, James P.

2007-01-01

Gene expression is controlled by protein complexes binding to short specific sequences of DNA, called cis-regulatory elements. Expression of most eukaryotic genes is controlled by dozens of these elements. Comprehensive identification and monitoring of these elements is a major goal of genomics. In pursuit of this goal, we are developing a surface plasmon resonance (SPR) based assay to identify and monitor cis-regulatory elements. To test whether we could reliably monitor protein binding to a regulatory element, we immobilized a 16 bp region of Saccharomyces cerevisiae chromosome 5 onto a gold surface. This 16 bp region of DNA is known to bind several proteins and thought to control expression of the gene RNR1, which varies through the cell cycle. We synchronized yeast cell cultures, and then sampled these cultures at a regular interval. These samples were processed to purify nuclear lysate, which was then exposed to the sensor. We found that nuclear protein binds this particular element of DNA at a significantly higher rate (as compared to unsynchronized cells) during G1 phase. Other time points show levels of DNA-nuclear protein binding similar to the unsynchronized control. We also measured the apparent association complex of the binding to be 0.014 s -1 . We conclude that (1) SPR-based assays can monitor DNA-nuclear protein binding and that (2) for this particular cis-regulatory element, maximum DNA-nuclear protein binding occurs during G1 phase

Metadata Effectiveness in Internet Discovery: An Analysis of Digital Collection Metadata Elements and Internet Search Engine Keywords

Science.gov (United States)

Yang, Le

2016-01-01

This study analyzed digital item metadata and keywords from Internet search engines to learn what metadata elements actually facilitate discovery of digital collections through Internet keyword searching and how significantly each metadata element affects the discovery of items in a digital repository. The study found that keywords from Internet…

Genome-wide identification of regulatory elements and reconstruction of gene regulatory networks of the green alga Chlamydomonas reinhardtii under carbon deprivation.

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Flavia Vischi Winck

Full Text Available The unicellular green alga Chlamydomonas reinhardtii is a long-established model organism for studies on photosynthesis and carbon metabolism-related physiology. Under conditions of air-level carbon dioxide concentration [CO2], a carbon concentrating mechanism (CCM is induced to facilitate cellular carbon uptake. CCM increases the availability of carbon dioxide at the site of cellular carbon fixation. To improve our understanding of the transcriptional control of the CCM, we employed FAIRE-seq (formaldehyde-assisted Isolation of Regulatory Elements, followed by deep sequencing to determine nucleosome-depleted chromatin regions of algal cells subjected to carbon deprivation. Our FAIRE data recapitulated the positions of known regulatory elements in the promoter of the periplasmic carbonic anhydrase (Cah1 gene, which is upregulated during CCM induction, and revealed new candidate regulatory elements at a genome-wide scale. In addition, time series expression patterns of 130 transcription factor (TF and transcription regulator (TR genes were obtained for cells cultured under photoautotrophic condition and subjected to a shift from high to low [CO2]. Groups of co-expressed genes were identified and a putative directed gene-regulatory network underlying the CCM was reconstructed from the gene expression data using the recently developed IOTA (inner composition alignment method. Among the candidate regulatory genes, two members of the MYB-related TF family, Lcr1 (Low-CO 2 response regulator 1 and Lcr2 (Low-CO2 response regulator 2, may play an important role in down-regulating the expression of a particular set of TF and TR genes in response to low [CO2]. The results obtained provide new insights into the transcriptional control of the CCM and revealed more than 60 new candidate regulatory genes. Deep sequencing of nucleosome-depleted genomic regions indicated the presence of new, previously unknown regulatory elements in the C. reinhardtii genome

Co-suppression of sterol-regulatory element binding protein ...

African Journals Online (AJOL)

Administrator

2011-06-22

Jun 22, 2011 ... In Arabidopsis,. At5g35220 gene being sterol regulatory element-binding protein site 2, protease and metalloendopeptidase activity were required for chloroplast development and play a role in regulation of endodermal plastid size and number that are involved in ethylene-dependent gravitropism of light-.

Organization of cis-acting regulatory elements in osmotic- and cold-stress-responsive promoters.

Science.gov (United States)

Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo

2005-02-01

cis-Acting regulatory elements are important molecular switches involved in the transcriptional regulation of a dynamic network of gene activities controlling various biological processes, including abiotic stress responses, hormone responses and developmental processes. In particular, understanding regulatory gene networks in stress response cascades depends on successful functional analyses of cis-acting elements. The ever-improving accuracy of transcriptome expression profiling has led to the identification of various combinations of cis-acting elements in the promoter regions of stress-inducible genes involved in stress and hormone responses. Here we discuss major cis-acting elements, such as the ABA-responsive element (ABRE) and the dehydration-responsive element/C-repeat (DRE/CRT), that are a vital part of ABA-dependent and ABA-independent gene expression in osmotic and cold stress responses.

Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells.

Science.gov (United States)

Zhao, Ming-Tao; Shao, Ning-Yi; Hu, Shijun; Ma, Ning; Srinivasan, Rajini; Jahanbani, Fereshteh; Lee, Jaecheol; Zhang, Sophia L; Snyder, Michael P; Wu, Joseph C

2017-11-10

Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type-specific gene expression in the human heart. We aimed to decipher the cell type-specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression. We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31 + CD144 + ), cardiac progenitor cells (Sca-1 + ), fibroblasts (DDR2 + ), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type-specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression. Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering

Identification of functional elements and regulatory circuits by Drosophila modENCODE.

Science.gov (United States)

Roy, Sushmita; Ernst, Jason; Kharchenko, Peter V; Kheradpour, Pouya; Negre, Nicolas; Eaton, Matthew L; Landolin, Jane M; Bristow, Christopher A; Ma, Lijia; Lin, Michael F; Washietl, Stefan; Arshinoff, Bradley I; Ay, Ferhat; Meyer, Patrick E; Robine, Nicolas; Washington, Nicole L; Di Stefano, Luisa; Berezikov, Eugene; Brown, Christopher D; Candeias, Rogerio; Carlson, Joseph W; Carr, Adrian; Jungreis, Irwin; Marbach, Daniel; Sealfon, Rachel; Tolstorukov, Michael Y; Will, Sebastian; Alekseyenko, Artyom A; Artieri, Carlo; Booth, Benjamin W; Brooks, Angela N; Dai, Qi; Davis, Carrie A; Duff, Michael O; Feng, Xin; Gorchakov, Andrey A; Gu, Tingting; Henikoff, Jorja G; Kapranov, Philipp; Li, Renhua; MacAlpine, Heather K; Malone, John; Minoda, Aki; Nordman, Jared; Okamura, Katsutomo; Perry, Marc; Powell, Sara K; Riddle, Nicole C; Sakai, Akiko; Samsonova, Anastasia; Sandler, Jeremy E; Schwartz, Yuri B; Sher, Noa; Spokony, Rebecca; Sturgill, David; van Baren, Marijke; Wan, Kenneth H; Yang, Li; Yu, Charles; Feingold, Elise; Good, Peter; Guyer, Mark; Lowdon, Rebecca; Ahmad, Kami; Andrews, Justen; Berger, Bonnie; Brenner, Steven E; Brent, Michael R; Cherbas, Lucy; Elgin, Sarah C R; Gingeras, Thomas R; Grossman, Robert; Hoskins, Roger A; Kaufman, Thomas C; Kent, William; Kuroda, Mitzi I; Orr-Weaver, Terry; Perrimon, Norbert; Pirrotta, Vincenzo; Posakony, James W; Ren, Bing; Russell, Steven; Cherbas, Peter; Graveley, Brenton R; Lewis, Suzanna; Micklem, Gos; Oliver, Brian; Park, Peter J; Celniker, Susan E; Henikoff, Steven; Karpen, Gary H; Lai, Eric C; MacAlpine, David M; Stein, Lincoln D; White, Kevin P; Kellis, Manolis

2010-12-24

To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.

Antioxidant response elements: Discovery, classes, regulation and potential applications

Directory of Open Access Journals (Sweden)

Azhwar Raghunath

2018-07-01

Full Text Available Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs, which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress. Keywords: Antioxidant response elements, Antioxidant genes, ARE-reporter constructs, ARE SNPs, Keap1/Nrf2/ARE pathway, Oxidative stress

Multiple cis-regulatory elements are involved in the complex regulation of the sieve element-specific MtSEO-F1 promoter from Medicago truncatula.

Science.gov (United States)

Bucsenez, M; Rüping, B; Behrens, S; Twyman, R M; Noll, G A; Prüfer, D

2012-09-01

The sieve element occlusion (SEO) gene family includes several members that are expressed specifically in immature sieve elements (SEs) in the developing phloem of dicotyledonous plants. To determine how this restricted expression profile is achieved, we analysed the SE-specific Medicago truncatula SEO-F1 promoter (PMtSEO-F1) by constructing deletion, substitution and hybrid constructs and testing them in transgenic tobacco plants using green fluorescent protein as a reporter. This revealed four promoter regions, each containing cis-regulatory elements that activate transcription in SEs. One of these segments also contained sufficient information to suppress PMtSEO-F1 transcription in the phloem companion cells (CCs). Subsequent in silico analysis revealed several candidate cis-regulatory elements that PMtSEO-F1 shares with other SEO promoters. These putative sieve element boxes (PSE boxes) are promising candidates for cis-regulatory elements controlling the SE-specific expression of PMtSEO-F1. © 2012 German Botanical Society and The Royal Botanical Society of the Netherlands.

'Masurium' and the 'early transuranium elements' or how discovery of nuclear fission was not clearly seen

International Nuclear Information System (INIS)

Keller, C.

1988-01-01

Fifty years after the discovery of fission, the scientific community is aware that this type of nuclear reaction could have been discovered more than a decade earlier. Noddack, Tacke and Berg announced in 1925 the discovery of elements Z = 43 (masurium) and rhenium (Z = 75), the first one could be detected only in U-bearing minerals. A recent re-examination by P.H.M. von Assche of the published data clearly showed that the original claim for element Z = 43 of the authors in 1925 was correct and, therefore, they detected not only element Z = 43 but also the first fission product. Because this discovery of element Z = 43 could not be repeated by other authors as that time, the scientific credibility of Noddack-Tacke was very low in order to give credit to her proposal that the 'early' transuranium elements by Enrico Fermi might also be fragments of known (lighter) elements. Enrico Fermi in 1934 obtained these 'early' (and as we today know: wrong) transuranium isotopes by irradiation of uranium with neutrons. A 'wrong' periodic system in the thirties which placed Th, Pa and U as 6d-elements and not as 5f-actinides chemically helped to consider these fission products as transuranium elements Z = 93/94. In 1937/38 I. Curie and P. Savitch discovered an 'actinium-nuclide' with 3,5 h half-life which, however, had properties similar to lanthanium and not to actinium, as they stated. (orig.) [de

Two regulatory RNA elements affect TisB-dependent depolarization and persister formation.

Science.gov (United States)

Berghoff, Bork A; Hoekzema, Mirthe; Aulbach, Lena; Wagner, E Gerhart H

2017-03-01

Bacterial survival strategies involve phenotypic diversity which is generated by regulatory factors and noisy expression of effector proteins. The question of how bacteria exploit regulatory RNAs to make decisions between phenotypes is central to a general understanding of these universal regulators. We investigated the TisB/IstR-1 toxin-antitoxin system of Escherichia coli to appreciate the role of the RNA antitoxin IstR-1 in TisB-dependent depolarization of the inner membrane and persister formation. Persisters are phenotypic variants that have become transiently drug-tolerant by arresting growth. The RNA antitoxin IstR-1 sets a threshold for TisB-dependent depolarization under DNA-damaging conditions, resulting in two sub-populations: polarized and depolarized cells. Furthermore, our data indicate that an inhibitory 5' UTR structure in the tisB mRNA serves as a regulatory RNA element that delays TisB translation to avoid inappropriate depolarization when DNA damage is low. Investigation of the persister sub-population further revealed that both regulatory RNA elements affect persister levels as well as persistence time. This work provides an intriguing example of how bacteria exploit regulatory RNAs to control phenotypic heterogeneity. © 2016 John Wiley & Sons Ltd.

RegRNA: an integrated web server for identifying regulatory RNA motifs and elements

OpenAIRE

Huang, Hsi-Yuan; Chien, Chia-Hung; Jen, Kuan-Hua; Huang, Hsien-Da

2006-01-01

Numerous regulatory structural motifs have been identified as playing essential roles in transcriptional and post-transcriptional regulation of gene expression. RegRNA is an integrated web server for identifying the homologs of regulatory RNA motifs and elements against an input mRNA sequence. Both sequence homologs and structural homologs of regulatory RNA motifs can be recognized. The regulatory RNA motifs supported in RegRNA are categorized into several classes: (i) motifs in mRNA 5′-untra...

Antioxidant response elements: Discovery, classes, regulation and potential applications.

Science.gov (United States)

Raghunath, Azhwar; Sundarraj, Kiruthika; Nagarajan, Raju; Arfuso, Frank; Bian, Jinsong; Kumar, Alan P; Sethi, Gautam; Perumal, Ekambaram

2018-07-01

Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs), which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Cracking the regulatory code of biosynthetic gene clusters as a strategy for natural product discovery.

Science.gov (United States)

Rigali, Sébastien; Anderssen, Sinaeda; Naômé, Aymeric; van Wezel, Gilles P

2018-01-05

The World Health Organization (WHO) describes antibiotic resistance as "one of the biggest threats to global health, food security, and development today", as the number of multi- and pan-resistant bacteria is rising dangerously. Acquired resistance phenomena also impair antifungals, antivirals, anti-cancer drug therapy, while herbicide resistance in weeds threatens the crop industry. On the positive side, it is likely that the chemical space of natural products goes far beyond what has currently been discovered. This idea is fueled by genome sequencing of microorganisms which unveiled numerous so-called cryptic biosynthetic gene clusters (BGCs), many of which are transcriptionally silent under laboratory culture conditions, and by the fact that most bacteria cannot yet be cultivated in the laboratory. However, brute force antibiotic discovery does not yield the same results as it did in the past, and researchers have had to develop creative strategies in order to unravel the hidden potential of microorganisms such as Streptomyces and other antibiotic-producing microorganisms. Identifying the cis elements and their corresponding transcription factors(s) involved in the control of BGCs through bioinformatic approaches is a promising strategy. Theoretically, we are a few 'clicks' away from unveiling the culturing conditions or genetic changes needed to activate the production of cryptic metabolites or increase the production yield of known compounds to make them economically viable. In this opinion article, we describe and illustrate the idea beyond 'cracking' the regulatory code for natural product discovery, by presenting a series of proofs of concept, and discuss what still should be achieved to increase the rate of success of this strategy. Copyright © 2018 Elsevier Inc. All rights reserved.

The nomenclature of MHC class I gene regulatory regions - the case of two different downstream regulatory elements

Czech Academy of Sciences Publication Activity Database

Hatina, J.; Jansa, Petr; Forejt, Jiří

2001-01-01

Roč. 37, 12-13 (2001), s. 799-800 ISSN 0161-5890 Institutional research plan: CEZ:AV0Z5052915 Keywords : MHC I gene regulatory elements Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.973, year: 2001

Identification of sparsely distributed clusters of cis-regulatory elements in sets of co-expressed genes

OpenAIRE

Kreiman, Gabriel

2004-01-01

Sequence information and high‐throughput methods to measure gene expression levels open the door to explore transcriptional regulation using computational tools. Combinatorial regulation and sparseness of regulatory elements throughout the genome allow organisms to control the spatial and temporal patterns of gene expression. Here we study the organization of cis‐regulatory elements in sets of co‐regulated genes. We build an algorithm to search for combinations of transcription factor binding...

Regulatory elements of the floral homeotic gene AGAMOUS identified by phylogenetic footprinting and shadowing.

Energy Technology Data Exchange (ETDEWEB)

Hong, R. L., Hamaguchi, L., Busch, M. A., and Weigel, D.

2003-06-01

OAK-B135 In Arabidopsis thaliana, cis-regulatory sequences of the floral homeotic gene AGAMOUS (AG) are located in the second intron. This 3 kb intron contains binding sites for two direct activators of AG, LEAFY (LFY) and WUSCHEL (WUS), along with other putative regulatory elements. We have used phylogenetic footprinting and the related technique of phylogenetic shadowing to identify putative cis-regulatory elements in this intron. Among 29 Brassicaceae, several other motifs, but not the LFY and WUS binding sites previously identified, are largely invariant. Using reporter gene analyses, we tested six of these motifs and found that they are all functionally important for activity of AG regulatory sequences in A. thaliana. Although there is little obvious sequence similarity outside the Brassicaceae, the intron from cucumber AG has at least partial activity in A. thaliana. Our studies underscore the value of the comparative approach as a tool that complements gene-by-gene promoter dissection, but also highlight that sequence-based studies alone are insufficient for a complete identification of cis-regulatory sites.

10 CFR 13.21 - Discovery.

Science.gov (United States)

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Discovery. 13.21 Section 13.21 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) The following types of discovery are...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

A saturation screen for cis-acting regulatory DNA in the Hox genes of Ciona intestinalis

Energy Technology Data Exchange (ETDEWEB)

Keys, David N.; Lee, Byung-in; Di Gregorio, Anna; Harafuji, Naoe; Detter, Chris; Wang, Mei; Kahsai, Orsalem; Ahn, Sylvia; Arellano, Andre; Zhang, Quin; Trong, Stephan; Doyle, Sharon A.; Satoh, Noriyuki; Satou, Yutaka; Saiga, Hidetoshi; Christian, Allen; Rokhsar, Dan; Hawkins, Trevor L.; Levine, Mike; Richardson, Paul

2005-01-05

A screen for the systematic identification of cis-regulatory elements within large (>100 kb) genomic domains containing Hox genes was performed by using the basal chordate Ciona intestinalis. Randomly generated DNA fragments from bacterial artificial chromosomes containing two clusters of Hox genes were inserted into a vector upstream of a minimal promoter and lacZ reporter gene. A total of 222 resultant fusion genes were separately electroporated into fertilized eggs, and their regulatory activities were monitored in larvae. In sum, 21 separable cis-regulatory elements were found. These include eight Hox linked domains that drive expression in nested anterior-posterior domains of ectodermally derived tissues. In addition to vertebrate-like CNS regulation, the discovery of cis-regulatory domains that drive epidermal transcription suggests that C. intestinalis has arthropod-like Hox patterning in the epidermis.

The discovery of plutonium reorganized the periodic table and aided the discovery of new elements

International Nuclear Information System (INIS)

Clark, David L.

2009-01-01

they named neptunium after the planet Neptune. This rapidly set the stage for the discovery of the next succeeding element, plutonium (Seaborg, McMillan, Kennedy, and Wahl, 1940), named after the next planet away from the Sun, Pluto. The newly discovered elements were presumed to fit comfortably in the Periodic Table under rhenium and osmium, respectively. However, subsequent tracer chemical experiments showed that neptunium and plutonium were closer in their chemical properties to uranium than their presumed homologues, rhenium and osmium. Spectroscopic evidence also indicated that the new elements were not typical transition elements, but had f-electrons in their valence shell. Thus, several researchers, including McMillan and Wahl, and Zachariasen at Los Alamos, suggested that these elements might be part of a second inner-transition series in which the 5f-electron subshell was being filled. It was not clear, however, where the new series would begin. McMillian had proposed a 'uraninide series' that started with neptunium, but attempts to isolate elements with atomic numbers 95 and 96 based on assumed similarities to uranium were unsuccessful. Both Wahl and Zacharias en had proposed a thoride series that started with protactinium. In 1944, Seaborg proposed that the series started with thorium, and that all of the elements heavier than actinium constituted an 'actinide' series similar to the lanthanides. Because the 5f-shell began filling in the same relative position as the 4f-shell, the electronic configuration of elements in the two series would be similar. Guided by the hypothesis that elements 95 and 96 were homologues of europium and gadolinium, new experiments were designed and the elements were uniquely synthesized and separated from all others. The new elements were subsequently named americium and curium. Seaborg's 'Actinide Concept' thus played a major role in the discovery of the transplutonium elements. It provided the framework that supported synthesis

Both positive and negative regulatory elements mediate expression of a photoregulated CAB gene from Nicotiana plumbaginifolia.

Science.gov (United States)

Castresana, C; Garcia-Luque, I; Alonso, E; Malik, V S; Cashmore, A R

1988-01-01

We have analyzed promoter regulatory elements from a photoregulated CAB gene (Cab-E) isolated from Nicotiana plumbaginifolia. These studies have been performed by introducing chimeric gene constructs into tobacco cells via Agrobacterium tumefaciens-mediated transformation. Expression studies on the regenerated transgenic plants have allowed us to characterize three positive and one negative cis-acting elements that influence photoregulated expression of the Cab-E gene. Within the upstream sequences we have identified two positive regulatory elements (PRE1 and PRE2) which confer maximum levels of photoregulated expression. These sequences contain multiple repeated elements related to the sequence-ACCGGCCCACTT-. We have also identified within the upstream region a negative regulatory element (NRE) extremely rich in AT sequences, which reduces the level of gene expression in the light. We have defined a light regulatory element (LRE) within the promoter region extending from -396 to -186 bp which confers photoregulated expression when fused to a constitutive nopaline synthase ('nos') promoter. Within this region there is a 132-bp element, extending from -368 to -234 bp, which on deletion from the Cab-E promoter reduces gene expression from high levels to undetectable levels. Finally, we have demonstrated for a full length Cab-E promoter conferring high levels of photoregulated expression, that sequences proximal to the Cab-E TATA box are not replaceable by corresponding sequences from a 'nos' promoter. This contrasts with the apparent equivalence of these Cab-E and 'nos' TATA box-proximal sequences in truncated promoters conferring low levels of photoregulated expression. Images PMID:2901343

Application of alpha spectrometry to the discovery of new elements by heavy-ion-beam bombardment

International Nuclear Information System (INIS)

Nitschke, J.M.

1983-05-01

Starting with polonium in 1898, α-spectrometry has played a decisive role in the discovery of new, heavy elements. For even-even nuclei, α-spectra have proved simple to interpret and exhibit systematic trends that allow extrapolation to unknown isotopes. The early discovery of the natural α-decay series led to the very powerful method of genetically linking the decay of new elements to the well-established α-emission of daughter and granddaughter nuclei. This technique has been used for all recent discoveries of new elements including Z = 109. Up to mendelevium (Z = 101), thin samples suitable for α-spectrometry were prepared by chemical methods. With the advent of heavy-ion accelerators new sample preparation methods emerged. These were based on the large momentum transfer associated with heavy-ion reactions, which produced energetic target recoils that, when ejected from the target, could be thermalized in He gas. Subsequent electrical deposition or a He-jet technique yielded samples that were not only thin enough for α-spectroscopy, but also for α- and #betta#-recoil experiments. Many variations of these methods have been developed and are discussed. For the synthesis of element 106 an aerosol-based recoil transport technique was devised. In the most recent experiments, α-spectrometry has been coupled with the magnetic analysis of the recoils. The time from production to analysis of an isotope has thereby been reduced to 10 - 6 s; while it was 10 - 1 to 10 0 s for He-jets and 10 1 to 10 3 s for rapid chemical separations. Experiments are now in progress to synthesize super heavy elements (SHE) and to analyze them with these latest techniques. Again, α-spectrometry will play a major role since the expected signature for the decay of a SHE is a sequence of α-decays followed by spontaneous fission

Peak-valley-peak pattern of histone modifications delineates active regulatory elements and their directionality

DEFF Research Database (Denmark)

Pundhir, Sachin; Bagger, Frederik Otzen; Lauridsen, Felicia Kathrine Bratt

2016-01-01

Formation of nucleosome free region (NFR) accompanied by specific histone modifications at flanking nucleosomes is an important prerequisite for enhancer and promoter activity. Due to this process, active regulatory elements often exhibit a distinct shape of histone signal in the form of a peak......-valley-peak (PVP) pattern. However, different features of PVP patterns and their robustness in predicting active regulatory elements have never been systematically analyzed. Here, we present PARE, a novel computational method that systematically analyzes the H3K4me1 or H3K4me3 PVP patterns to predict NFRs. We show...... four ENCODE cell lines and four hematopoietic differentiation stages, we identified several enhancers whose regulatory activity is stage specific and correlates positively with the expression of proximal genes in a particular stage. In conclusion, our results demonstrate that PVP patterns delineate...

Helping Students Understand Gene Regulation with Online Tools: A Review of MEME and Melina II, Motif Discovery Tools for Active Learning in Biology

Directory of Open Access Journals (Sweden)

David Treves

2012-08-01

Full Text Available Review of: MEME and Melina II, which are two free and easy-to-use online motif discovery tools that can be employed to actively engage students in learning about gene regulatory elements.

A conserved RNA structural element within the hepatitis B virus post-transcriptional regulatory element enhance nuclear export of intronless transcripts and repress the splicing mechanism.

Science.gov (United States)

Visootsat, Akasit; Payungporn, Sunchai; T-Thienprasert, Nattanan P

2015-12-01

Hepatitis B virus (HBV) infection is a primary cause of hepatocellular carcinoma and liver cirrhosis worldwide. To develop novel antiviral drugs, a better understanding of HBV gene expression regulation is vital. One important aspect is to understand how HBV hijacks the cellular machinery to export unspliced RNA from the nucleus. The HBV post-transcriptional regulatory element (HBV PRE) has been proposed to be the HBV RNA nuclear export element. However, the function remains controversial, and the core element is unclear. This study, therefore, aimed to identify functional regulatory elements within the HBV PRE and investigate their functions. Using bioinformatics programs based on sequence conservation and conserved RNA secondary structures, three regulatory elements were predicted, namely PRE 1151-1410, PRE 1520-1620 and PRE 1650-1684. PRE 1151-1410 significantly increased intronless and unspliced luciferase activity in both HepG2 and COS-7 cells. Likewise, PRE 1151-1410 significantly elevated intronless and unspliced HBV surface transcripts in liver cancer cells. Moreover, motif analysis predicted that PRE 1151-1410 contains several regulatory motifs. This study reported the roles of PRE 1151-1410 in intronless transcript nuclear export and the splicing mechanism. Additionally, these results provide knowledge in the field of HBV RNA regulation. Moreover, PRE 1151-1410 may be used to enhance the expression of other mRNAs in intronless reporter plasmids.

10 CFR 2.1018 - Discovery.

Science.gov (United States)

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Discovery. 2.1018 Section 2.1018 Energy NUCLEAR REGULATORY... Geologic Repository § 2.1018 Discovery. (a)(1) Parties, potential parties, and interested governmental participants in the high-level waste licensing proceeding may obtain discovery by one or more of the following...

Anti-regulatory T cells

DEFF Research Database (Denmark)

Andersen, Mads Hald

2017-01-01

responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells—termed anti-regulatory T cells (anti-Tregs)—that target immune-suppressive cells. Thus, regulatory cells can now be defined as both cells that suppress immune...... reactions as well as effector cells that counteract the effects of suppressor cells and support immune reactions. Self-reactive anti-Tregs have been described that specifically recognize human leukocyte antigen-restricted epitopes derived from proteins that are normally expressed by regulatory immune cells......Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host...

PlantCARE, a plant cis-acting regulatory element database

OpenAIRE

Rombauts, Stephane; Déhais, Patrice; Van Montagu, Marc; Rouzé, Pierre

1999-01-01

PlantCARE is a database of plant cis- acting regulatory elements, enhancers and repressors. Besides the transcription motifs found on a sequence, it also offers a link to the EMBL entry that contains the full gene sequence as well as a description of the conditions in which a motif becomes functional. The information on these sites is given by matrices, consensus and individual site sequences on particular genes, depending on the available information. PlantCARE is a relational database avail...

Large-scale discovery of promoter motifs in Drosophila melanogaster.

Directory of Open Access Journals (Sweden)

Thomas A Down

2007-01-01

Full Text Available A key step in understanding gene regulation is to identify the repertoire of transcription factor binding motifs (TFBMs that form the building blocks of promoters and other regulatory elements. Identifying these experimentally is very laborious, and the number of TFBMs discovered remains relatively small, especially when compared with the hundreds of transcription factor genes predicted in metazoan genomes. We have used a recently developed statistical motif discovery approach, NestedMICA, to detect candidate TFBMs from a large set of Drosophila melanogaster promoter regions. Of the 120 motifs inferred in our initial analysis, 25 were statistically significant matches to previously reported motifs, while 87 appeared to be novel. Analysis of sequence conservation and motif positioning suggested that the great majority of these discovered motifs are predictive of functional elements in the genome. Many motifs showed associations with specific patterns of gene expression in the D. melanogaster embryo, and we were able to obtain confident annotation of expression patterns for 25 of our motifs, including eight of the novel motifs. The motifs are available through Tiffin, a new database of DNA sequence motifs. We have discovered many new motifs that are overrepresented in D. melanogaster promoter regions, and offer several independent lines of evidence that these are novel TFBMs. Our motif dictionary provides a solid foundation for further investigation of regulatory elements in Drosophila, and demonstrates techniques that should be applicable in other species. We suggest that further improvements in computational motif discovery should narrow the gap between the set of known motifs and the total number of transcription factors in metazoan genomes.

Cis-regulatory elements in the primate brain: from functional specialization to neurodegeneration

NARCIS (Netherlands)

Vermunt, Marit W.

2017-01-01

Over the last decade, the noncoding part of the genome has been shown to harbour thousands of cis-regulatory elements, such as enhancers, that activate well-defined gene expression programs. Here, we charted active enhancers in a multiplicity of human brain regions to understand the role of

Discovery of transcription factors and regulatory regions driving in vivo tumor development by ATAC-seq and FAIRE-seq open chromatin profiling.

Directory of Open Access Journals (Sweden)

Kristofer Davie

2015-02-01

Full Text Available Genomic enhancers regulate spatio-temporal gene expression by recruiting specific combinations of transcription factors (TFs. When TFs are bound to active regulatory regions, they displace canonical nucleosomes, making these regions biochemically detectable as nucleosome-depleted regions or accessible/open chromatin. Here we ask whether open chromatin profiling can be used to identify the entire repertoire of active promoters and enhancers underlying tissue-specific gene expression during normal development and oncogenesis in vivo. To this end, we first compare two different approaches to detect open chromatin in vivo using the Drosophila eye primordium as a model system: FAIRE-seq, based on physical separation of open versus closed chromatin; and ATAC-seq, based on preferential integration of a transposon into open chromatin. We find that both methods reproducibly capture the tissue-specific chromatin activity of regulatory regions, including promoters, enhancers, and insulators. Using both techniques, we screened for regulatory regions that become ectopically active during Ras-dependent oncogenesis, and identified 3778 regions that become (over-activated during tumor development. Next, we applied motif discovery to search for candidate transcription factors that could bind these regions and identified AP-1 and Stat92E as key regulators. We validated the importance of Stat92E in the development of the tumors by introducing a loss of function Stat92E mutant, which was sufficient to rescue the tumor phenotype. Additionally we tested if the predicted Stat92E responsive regulatory regions are genuine, using ectopic induction of JAK/STAT signaling in developing eye discs, and observed that similar chromatin changes indeed occurred. Finally, we determine that these are functionally significant regulatory changes, as nearby target genes are up- or down-regulated. In conclusion, we show that FAIRE-seq and ATAC-seq based open chromatin profiling

Identification of high-confidence RNA regulatory elements by combinatorial classification of RNA-protein binding sites.

Science.gov (United States)

Li, Yang Eric; Xiao, Mu; Shi, Binbin; Yang, Yu-Cheng T; Wang, Dong; Wang, Fei; Marcia, Marco; Lu, Zhi John

2017-09-08

Crosslinking immunoprecipitation sequencing (CLIP-seq) technologies have enabled researchers to characterize transcriptome-wide binding sites of RNA-binding protein (RBP) with high resolution. We apply a soft-clustering method, RBPgroup, to various CLIP-seq datasets to group together RBPs that specifically bind the same RNA sites. Such combinatorial clustering of RBPs helps interpret CLIP-seq data and suggests functional RNA regulatory elements. Furthermore, we validate two RBP-RBP interactions in cell lines. Our approach links proteins and RNA motifs known to possess similar biochemical and cellular properties and can, when used in conjunction with additional experimental data, identify high-confidence RBP groups and their associated RNA regulatory elements.

Prediction of regulatory elements

DEFF Research Database (Denmark)

Sandelin, Albin

2008-01-01

Finding the regulatory mechanisms responsible for gene expression remains one of the most important challenges for biomedical research. A major focus in cellular biology is to find functional transcription factor binding sites (TFBS) responsible for the regulation of a downstream gene. As wet......-lab methods are time consuming and expensive, it is not realistic to identify TFBS for all uncharacterized genes in the genome by purely experimental means. Computational methods aimed at predicting potential regulatory regions can increase the efficiency of wet-lab experiments significantly. Here, methods...

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

Directory of Open Access Journals (Sweden)

Khetani Radhika S

2006-05-01

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

Discovering regulatory motifs in the Plasmodium genome using comparative genomics

OpenAIRE

Wu, Jie; Sieglaff, Douglas H.; Gervin, Joshua; Xie, Xiaohui S.

2008-01-01

Motivation: Understanding gene regulation in Plasmodium, the causative agent of malaria, is an important step in deciphering its complex life cycle as well as leading to possible new targets for therapeutic applications. Very little is known about gene regulation in Plasmodium, and in particular, few regulatory elements have been identified. Such discovery has been significantly hampered by the high A-T content of some of the genomes of Plasmodium species, as well as the challenge in associat...

Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer.

Science.gov (United States)

Shafiee, Mohamad N; Mongan, Nigel; Seedhouse, Claire; Chapman, Caroline; Deen, Suha; Abu, Jafaru; Atiomo, William

2017-05-01

Women with polycystic ovary syndrome have a three-fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein-1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein-1 gene expression with serum lipid profiles. A cross-sectional study was performed at Nottingham University Hospital, UK. A total of 102 women (polycystic ovary syndrome, endometrial cancer and controls; 34 participants in each group) were recruited. Clinical and biochemical assessments were performed before endometrial biopsies were obtained from all participants. Taqman real-time polymerase chain reaction for endometrial sterol regulatory element binding protein-1 gene and its systemic protein expression were analyzed. The body mass indices of women with polycystic ovary syndrome (29.28 ± 2.91 kg/m 2 ) and controls (28.58 ± 2.62 kg/m 2 ) were not significantly different. Women with endometrial cancer had a higher mean body mass index (32.22 ± 5.70 kg/m 2 ). Sterol regulatory element binding protein-1 gene expression was significantly increased in polycystic ovary syndrome and endometrial cancer endometrium compared with controls (p ovary syndrome, but this was not statistically significant. Similarly, statistically insignificant positive correlations were found between endometrial sterol regulatory element binding protein-1 gene expression and body mass index in endometrial cancer (r = 0.643, p = 0.06) and waist-hip ratio (r = 0.096, p = 0.073). Sterol regulatory element binding protein-1 gene expression was significantly positively correlated with triglyceride in both polycystic ovary syndrome and endometrial cancer (p = 0.028 and p = 0.027, respectively). Quantitative serum sterol regulatory element

Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA

OpenAIRE

Dibrov, Sergey; McLean, Jaime; Hermann, Thomas

2011-01-01

An oligonucleotide representing a regulatory element of human thymidylate synthase mRNA has been crystallized as a dimer. The structure of the asymmetric dimer has been determined at 1.97 Å resolution.

Discovery of element 112

Energy Technology Data Exchange (ETDEWEB)

Hofmann, S. [GSI, Darmstadt (Germany)

1996-12-31

The new elements 110, 111, and 112 were synthesized and unambiguously identified in experiments at SHIP. Due to strong shell effects the dominant decay mode is not fission, but emission of alpha particles. Theoretical investigations predict that maximum shell effects should exist in nuclei near proton number 114 and neutron number 184. Measurements give hope that isotopes of element 114 close to the island of spherical Superheavy Elements could be produced by fusion reactions using {sup 118}Pb as target. systematic studies of the reaction cross-sections indicate that transfer of nucleons is the important process to initiate the fusion.

Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins.

Science.gov (United States)

Zerenturk, Eser J; Sharpe, Laura J; Brown, Andrew J

2012-10-01

3β-Hydroxysterol Δ24-reductase (DHCR24) catalyzes a final step in cholesterol synthesis, and has been ascribed diverse functions, such as being anti-apoptotic and anti-inflammatory. How this enzyme is regulated transcriptionally by sterols is currently unclear. Some studies have suggested that its expression is regulated by Sterol Regulatory Element Binding Proteins (SREBPs) while another suggests it is through the Liver X Receptor (LXR). However, these transcription factors have opposing effects on cellular sterol levels, so it is likely that one predominates. Here we establish that sterol regulation of DHCR24 occurs predominantly through SREBP-2, and identify the particular region of the DHCR24 promoter to which SREBP-2 binds. We demonstrate that sterol regulation is mediated by two sterol regulatory elements (SREs) in the promoter of the gene, assisted by two nearby NF-Y binding sites. Moreover, we present evidence that the dual SREs work cooperatively to regulate DHCR24 expression by comparison to two known SREBP target genes, the LDL receptor with one SRE, and farnesyl-diphosphate farnesyltransferase 1, with two SREs. Copyright © 2012 Elsevier B.V. All rights reserved.

Extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection.

Directory of Open Access Journals (Sweden)

Yoichiro Shibata

2012-06-01

Full Text Available Understanding the molecular basis for phenotypic differences between humans and other primates remains an outstanding challenge. Mutations in non-coding regulatory DNA that alter gene expression have been hypothesized as a key driver of these phenotypic differences. This has been supported by differential gene expression analyses in general, but not by the identification of specific regulatory elements responsible for changes in transcription and phenotype. To identify the genetic source of regulatory differences, we mapped DNaseI hypersensitive (DHS sites, which mark all types of active gene regulatory elements, genome-wide in the same cell type isolated from human, chimpanzee, and macaque. Most DHS sites were conserved among all three species, as expected based on their central role in regulating transcription. However, we found evidence that several hundred DHS sites were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific DHS site gains are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within these DHS sites are linked with species-specific changes in chromatin accessibility. Together, these indicate that the regulatory elements identified here are genetic contributors to transcriptional and phenotypic differences among primate species.

Tissue-Specific Enrichment of Lymphoma Risk Loci in Regulatory Elements.

Science.gov (United States)

Hayes, James E; Trynka, Gosia; Vijai, Joseph; Offit, Kenneth; Raychaudhuri, Soumya; Klein, Robert J

2015-01-01

Though numerous polymorphisms have been associated with risk of developing lymphoma, how these variants function to promote tumorigenesis is poorly understood. Here, we report that lymphoma risk SNPs, especially in the non-Hodgkin's lymphoma subtype chronic lymphocytic leukemia, are significantly enriched for co-localization with epigenetic marks of active gene regulation. These enrichments were seen in a lymphoid-specific manner for numerous ENCODE datasets, including DNase-hypersensitivity as well as multiple segmentation-defined enhancer regions. Furthermore, we identify putatively functional SNPs that are both in regulatory elements in lymphocytes and are associated with gene expression changes in blood. We developed an algorithm, UES, that uses a Monte Carlo simulation approach to calculate the enrichment of previously identified risk SNPs in various functional elements. This multiscale approach integrating multiple datasets helps disentangle the underlying biology of lymphoma, and more broadly, is generally applicable to GWAS results from other diseases as well.

Deciphering RNA regulatory elements in trypanosomatids: one piece at a time or genome-wide?

Science.gov (United States)

Gazestani, Vahid H; Lu, Zhiquan; Salavati, Reza

2014-05-01

Morphological and metabolic changes in the life cycle of Trypanosoma brucei are accomplished by precise regulation of hundreds of genes. In the absence of transcriptional control, RNA-binding proteins (RBPs) shape the structure of gene regulatory maps in this organism, but our knowledge about their target RNAs, binding sites, and mechanisms of action is far from complete. Although recent technological advances have revolutionized the RBP-based approaches, the main framework for the RNA regulatory element (RRE)-based approaches has not changed over the last two decades in T. brucei. In this Opinion, after highlighting the current challenges in RRE inference, we explain some genome-wide solutions that can significantly boost our current understanding about gene regulatory networks in T. brucei. Copyright © 2014 Elsevier Ltd. All rights reserved.

PROSPECT improves cis-acting regulatory element prediction by integrating expression profile data with consensus pattern searches

Science.gov (United States)

Fujibuchi, Wataru; Anderson, John S. J.; Landsman, David

2001-01-01

Consensus pattern and matrix-based searches designed to predict cis-acting transcriptional regulatory sequences have historically been subject to large numbers of false positives. We sought to decrease false positives by incorporating expression profile data into a consensus pattern-based search method. We have systematically analyzed the expression phenotypes of over 6000 yeast genes, across 121 expression profile experiments, and correlated them with the distribution of 14 known regulatory elements over sequences upstream of the genes. Our method is based on a metric we term probabilistic element assessment (PEA), which is a ranking of potential sites based on sequence similarity in the upstream regions of genes with similar expression phenotypes. For eight of the 14 known elements that we examined, our method had a much higher selectivity than a naïve consensus pattern search. Based on our analysis, we have developed a web-based tool called PROSPECT, which allows consensus pattern-based searching of gene clusters obtained from microarray data. PMID:11574681

Ancient Transposable Elements Transformed the Uterine Regulatory Landscape and Transcriptome during the Evolution of Mammalian Pregnancy

Directory of Open Access Journals (Sweden)

Vincent J. Lynch

2015-02-01

Full Text Available A major challenge in biology is determining how evolutionarily novel characters originate; however, mechanistic explanations for the origin of new characters are almost completely unknown. The evolution of pregnancy is an excellent system in which to study the origin of novelties because mammals preserve stages in the transition from egg laying to live birth. To determine the molecular bases of this transition, we characterized the pregnant/gravid uterine transcriptome from tetrapods to trace the evolutionary history of uterine gene expression. We show that thousands of genes evolved endometrial expression during the origins of mammalian pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. Furthermore, thousands of cis-regulatory elements that mediate decidualization and cell-type identity in decidualized stromal cells are derived from ancient mammalian transposable elements (TEs. Our results indicate that one of the defining mammalian novelties evolved from DNA sequences derived from ancient mammalian TEs co-opted into hormone-responsive regulatory elements distributed throughout the genome.

Nsite, NsiteH and NsiteM Computer Tools for Studying Tran-scription Regulatory Elements

KAUST Repository

Shahmuradov, Ilham

2015-07-02

Summary: Gene transcription is mostly conducted through interactions of various transcription factors and their binding sites on DNA (regulatory elements, REs). Today, we are still far from understanding the real regulatory content of promoter regions. Computer methods for identification of REs remain a widely used tool for studying and understanding transcriptional regulation mechanisms. The Nsite, NsiteH and NsiteM programs perform searches for statistically significant (non-random) motifs of known human, animal and plant one-box and composite REs in a single genomic sequence, in a pair of aligned homologous sequences and in a set of functionally related sequences, respectively.

Effects of sterol regulatory element-binding protein (SREBP in chickens

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Alipour Fahimeh

2012-02-01

Full Text Available Abstract Sterol regulatory element binding protein- 1 and -2 (SREBP-1 and -2 are key transcription factors involved in the biosynthesis of cholesterol and fatty acids. The SREBP have mostly been studied in rodents in which lipogenesis is regulated in both liver and adipose tissue. There is, though, a paucity of information on birds, in which lipogenesis occurs essentially in the liver as in humans. Since a prelude to the investigation of the role of SREBP in lipid metabolism regulation in chicken, we review Size and Tissue expression Pattern of SREBP and role of this protein in chickens.

Defective distal regulatory element at the 5' upstream of rat prolactin gene of steroid-nonresponsive GH-subclone.

Science.gov (United States)

Kumar, V; Wong, D T; Pasion, S G; Biswas, D K

1987-12-08

The prolactin-nonproducing (PRL-) GH cell strains (rat pituitary tumor cells in culture). GH12C1 and F1BGH12C1, do not respond to steroid hormones estradiol or hydrocortisone (HC). However, the stimulatory effect of estradiol and the inhibitory effect of hydrocortisone on prolactin synthesis can be demonstrated in the prolactin-producing GH cell strain, GH4C1. In this investigation we have examined the 5' end flanking region of rat prolactin (rat PRL) gene of steroid-responsive, GH4C1 cells to identify the positive and negative regulatory elements and to verify the status of these elements in steroid-nonresponsive F1BGH12C1 cells. Results presented in this report demonstrate that the basel level expression of the co-transferred Neo gene (neomycin phosphoribosyl transferase) is modulated by the distal upstream regulatory elements of rat PRL gene in response to steroid hormones. The expression of adjacent Neo gene is inhibited by dexamethasone and is stimulated by estradiol in transfectants carrying distal regulatory elements (SRE) of steroid-responsive cells. These responses are not observed in transfectants with the rat PRL upstream sequences derived from steroid-nonresponsive cells. The basal level expression of the host cell alpha-2 tubulin gene is not affected by dexamethasone. We report here the identification of the distal steroid regulatory element (SRE) located between 3.8 and 7.8 kb upstream of the transcription initiation site of rat PRL gene. Both the positive and the negative effects of steroid hormones can be identified within this upstream sequence. This distal SRE appears to be nonfunctional in steroid-nonresponsive cells. Though the proximal SRE is functional, the defect in the distal SRE makes the GH substrain nonresponsive to steroid hormones. These results suggest that both the proximal and the distal SREs are essential for the mediation of action of steroid hormones in GH cells.

In silico modeling of epigenetic-induced changes in photoreceptor cis-regulatory elements.

Science.gov (United States)

Hossain, Reafa A; Dunham, Nicholas R; Enke, Raymond A; Berndsen, Christopher E

2018-01-01

DNA methylation is a well-characterized epigenetic repressor of mRNA transcription in many plant and vertebrate systems. However, the mechanism of this repression is not fully understood. The process of transcription is controlled by proteins that regulate recruitment and activity of RNA polymerase by binding to specific cis-regulatory sequences. Cone-rod homeobox (CRX) is a well-characterized mammalian transcription factor that controls photoreceptor cell-specific gene expression. Although much is known about the functions and DNA binding specificity of CRX, little is known about how DNA methylation modulates CRX binding affinity to genomic cis-regulatory elements. We used bisulfite pyrosequencing of human ocular tissues to measure DNA methylation levels of the regulatory regions of RHO , PDE6B, PAX6 , and LINE1 retrotransposon repeats. To describe the molecular mechanism of repression, we used molecular modeling to illustrate the effect of DNA methylation on human RHO regulatory sequences. In this study, we demonstrate an inverse correlation between DNA methylation in regulatory regions adjacent to the human RHO and PDE6B genes and their subsequent transcription in human ocular tissues. Docking of CRX to the DNA models shows that CRX interacts with the grooves of these sequences, suggesting changes in groove structure could regulate binding. Molecular dynamics simulations of the RHO promoter and enhancer regions show changes in the flexibility and groove width upon epigenetic modification. Models also demonstrate changes in the local dynamics of CRX binding sites within RHO regulatory sequences which may account for the repression of CRX-dependent transcription. Collectively, these data demonstrate epigenetic regulation of CRX binding sites in human retinal tissue and provide insight into the mechanism of this mode of epigenetic regulation to be tested in future experiments.

FK506 biosynthesis is regulated by two positive regulatory elements in Streptomyces tsukubaensis

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Goranovič Dušan

2012-10-01

Full Text Available Abstract Background FK506 (Tacrolimus is an important immunosuppressant, produced by industrial biosynthetic processes using various Streptomyces species. Considering the complex structure of FK506, it is reasonable to expect complex regulatory networks controlling its biosynthesis. Regulatory elements, present in gene clusters can have a profound influence on the final yield of target product and can play an important role in development of industrial bioprocesses. Results Three putative regulatory elements, namely fkbR, belonging to the LysR-type family, fkbN, a large ATP-binding regulator of the LuxR family (LAL-type and allN, a homologue of AsnC family regulatory proteins, were identified in the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488, a progenitor of industrial strains used for production of FK506. Inactivation of fkbN caused a complete disruption of FK506 biosynthesis, while inactivation of fkbR resulted in about 80% reduction of FK506 yield. No functional role in the regulation of the FK506 gene cluster has been observed for the allN gene. Using RT-PCR and a reporter system based on a chalcone synthase rppA, we demonstrated, that in the wild type as well as in fkbN- and fkbR-inactivated strains, fkbR is transcribed in all stages of cultivation, even before the onset of FK506 production, whereas fkbN expression is initiated approximately with the initiation of FK506 production. Surprisingly, inactivation of fkbN (or fkbR does not abolish the transcription of the genes in the FK506 gene cluster in general, but may reduce expression of some of the tested biosynthetic genes. Finally, introduction of a second copy of the fkbR or fkbN genes under the control of the strong ermE* promoter into the wild type strain resulted in 30% and 55% of yield improvement, respectively. Conclusions Our results clearly demonstrate the positive regulatory role of fkbR and fkbN genes in FK506 biosynthesis in S. tsukubaensis NRRL 18488. We

77 FR 23770 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Science.gov (United States)

2012-04-20

...: The financial markets as a whole should benefit from [limit order display] because the price discovery... revised tier sizes and corresponding liquidity minimum amounts are in the best interest of the market for...-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of Amendment No. 1...

Characterization of a putative cis-regulatory element that controls transcriptional activity of the pig uroplakin II gene promoter

International Nuclear Information System (INIS)

Kwon, Deug-Nam; Park, Mi-Ryung; Park, Jong-Yi; Cho, Ssang-Goo; Park, Chankyu; Oh, Jae-Wook; Song, Hyuk; Kim, Jae-Hwan; Kim, Jin-Hoi

2011-01-01

Highlights: → The sequences of -604 to -84 bp of the pUPII promoter contained the region of a putative negative cis-regulatory element. → The core promoter was located in the 5F-1. → Transcription factor HNF4 can directly bind in the pUPII core promoter region, which plays a critical role in controlling promoter activity. → These features of the pUPII promoter are fundamental to development of a target-specific vector. -- Abstract: Uroplakin II (UPII) is a one of the integral membrane proteins synthesized as a major differentiation product of mammalian urothelium. UPII gene expression is bladder specific and differentiation dependent, but little is known about its transcription response elements and molecular mechanism. To identify the cis-regulatory elements in the pig UPII (pUPII) gene promoter region, we constructed pUPII 5' upstream region deletion mutants and demonstrated that each of the deletion mutants participates in controlling the expression of the pUPII gene in human bladder carcinoma RT4 cells. We also identified a new core promoter region and putative negative cis-regulatory element within a minimal promoter region. In addition, we showed that hepatocyte nuclear factor 4 (HNF4) can directly bind in the pUPII core promoter (5F-1) region, which plays a critical role in controlling promoter activity. Transient cotransfection experiments showed that HNF4 positively regulates pUPII gene promoter activity. Thus, the binding element and its binding protein, HNF4 transcription factor, may be involved in the mechanism that specifically regulates pUPII gene transcription.

Systematic discovery of regulatory motifs in Fusarium graminearum by comparing four Fusarium genomes

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Kistler Corby

2010-03-01

Full Text Available Abstract Background Fusarium graminearum (Fg, a major fungal pathogen of cultivated cereals, is responsible for billions of dollars in agriculture losses. There is a growing interest in understanding the transcriptional regulation of this organism, especially the regulation of genes underlying its pathogenicity. The generation of whole genome sequence assemblies for Fg and three closely related Fusarium species provides a unique opportunity for such a study. Results Applying comparative genomics approaches, we developed a computational pipeline to systematically discover evolutionarily conserved regulatory motifs in the promoter, downstream and the intronic regions of Fg genes, based on the multiple alignments of sequenced Fusarium genomes. Using this method, we discovered 73 candidate regulatory motifs in the promoter regions. Nearly 30% of these motifs are highly enriched in promoter regions of Fg genes that are associated with a specific functional category. Through comparison to Saccharomyces cerevisiae (Sc and Schizosaccharomyces pombe (Sp, we observed conservation of transcription factors (TFs, their binding sites and the target genes regulated by these TFs related to pathways known to respond to stress conditions or phosphate metabolism. In addition, this study revealed 69 and 39 conserved motifs in the downstream regions and the intronic regions, respectively, of Fg genes. The top intronic motif is the splice donor site. For the downstream regions, we noticed an intriguing absence of the mammalian and Sc poly-adenylation signals among the list of conserved motifs. Conclusion This study provides the first comprehensive list of candidate regulatory motifs in Fg, and underscores the power of comparative genomics in revealing functional elements among related genomes. The conservation of regulatory pathways among the Fusarium genomes and the two yeast species reveals their functional significance, and provides new insights in their

Human polyomavirus JCV late leader peptide region contains important regulatory elements

International Nuclear Information System (INIS)

Akan, Ilhan; Sariyer, Ilker Kudret; Biffi, Renato; Palermo, Victoria; Woolridge, Stefanie; White, Martyn K.; Amini, Shohreh; Khalili, Kamel; Safak, Mahmut

2006-01-01

Transcription is a complex process that relies on the cooperative interaction between sequence-specific factors and the basal transcription machinery. The strength of a promoter depends on upstream or downstream cis-acting DNA elements, which bind transcription factors. In this study, we investigated whether DNA elements located downstream of the JCV late promoter, encompassing the late leader peptide region, which encodes agnoprotein, play regulatory roles in the JCV lytic cycle. For this purpose, the entire coding region of the leader peptide was deleted and the functional consequences of this deletion were analyzed. We found that viral gene expression and replication were drastically reduced. Gene expression also decreased from a leader peptide point mutant but to a lesser extent. This suggested that the leader peptide region of JCV might contain critical cis-acting DNA elements to which transcription factors bind and regulate viral gene expression and replication. We analyzed the entire coding region of the late leader peptide by a footprinting assay and identified three major regions (region I, II and III) that were protected by nuclear proteins. Further investigation of the first two protected regions by band shift assays revealed a new band that appeared in new infection cycles, suggesting that viral infection induces new factors that interact with the late leader peptide region of JCV. Analysis of the effect of the leader peptide region on the promoter activity of JCV by transfection assays demonstrated that this region has a positive and negative effect on the large T antigen (LT-Ag)-mediated activation of the viral early and late promoters, respectively. Furthermore, a partial deletion analysis of the leader peptide region encompassing the protected regions I and II demonstrated a significant down-regulation of viral gene expression and replication. More importantly, these results were similar to that obtained from a complete deletion of the late leader

5' Region of the human interleukin 4 gene: structure and potential regulatory elements

Energy Technology Data Exchange (ETDEWEB)

Eder, A; Krafft-Czepa, H; Krammer, P H

1988-01-25

The lymphokine Interleukin 4 (IL-4) is secreted by antigen or mitogen activated T lymphocytes. IL-4 stimulates activation and differentiation of B lymphocytes and growth of T lymphocytes and mast cells. The authors isolated the human IL-4 gene from a lambda EMBL3 genomic library. As a probe they used a synthetic oligonucleotide spanning position 40 to 79 of the published IL-4 cDNA sequence. The 5' promoter region contains several sequence elements which may have a cis-acting regulatory function for IL-4 gene expression. These elements include a TATA-box, three CCAAT-elements (two are on the non-coding strand) and an octamer motif. A comparison of the 5' flanking region of the human murine IL-4 gene (4) shows that the region between position -306 and +44 is highly conserved (83% homology).

PlantCARE, a database of plant cis-acting regulatory elements and a portal to tools for in silico analysis of promoter sequences

OpenAIRE

Lescot, Magali; Déhais, Patrice; Thijs, Gert; Marchal, Kathleen; Moreau, Yves; Van de Peer, Yves; Rouzé, Pierre; Rombauts, Stephane

2002-01-01

PlantCARE is a database of plant cis-acting regulatory elements, enhancers and repressors. Regulatory elements are represented by positional matrices, consensus sequences and individual sites on particular promoter sequences. Links to the EMBL, TRANSFAC and MEDLINE databases are provided when available. Data about the transcription sites are extracted mainly from the literature, supplemented with an increasing number of in silico predicted data. Apart from a general description for specific t...

Elements in the transcriptional regulatory region flanking herpes simplex virus type 1 oriS stimulate origin function.

Science.gov (United States)

Wong, S W; Schaffer, P A

1991-05-01

Like other DNA-containing viruses, the three origins of herpes simplex virus type 1 (HSV-1) DNA replication are flanked by sequences containing transcriptional regulatory elements. In a transient plasmid replication assay, deletion of sequences comprising the transcriptional regulatory elements of ICP4 and ICP22/47, which flank oriS, resulted in a greater than 80-fold decrease in origin function compared with a plasmid, pOS-822, which retains these sequences. In an effort to identify specific cis-acting elements responsible for this effect, we conducted systematic deletion analysis of the flanking region with plasmid pOS-822 and tested the resulting mutant plasmids for origin function. Stimulation by cis-acting elements was shown to be both distance and orientation dependent, as changes in either parameter resulted in a decrease in oriS function. Additional evidence for the stimulatory effect of flanking sequences on origin function was demonstrated by replacement of these sequences with the cytomegalovirus immediate-early promoter, resulting in nearly wild-type levels of oriS function. In competition experiments, cotransfection of cells with the test plasmid, pOS-822, and increasing molar concentrations of a competitor plasmid which contained the ICP4 and ICP22/47 transcriptional regulatory regions but lacked core origin sequences resulted in a significant reduction in the replication efficiency of pOS-822, demonstrating that factors which bind specifically to the oriS-flanking sequences are likely involved as auxiliary proteins in oriS function. Together, these studies demonstrate that trans-acting factors and the sites to which they bind play a critical role in the efficiency of HSV-1 DNA replication from oriS in transient-replication assays.

Synthesis of (±)-amathaspiramide F and discovery of an unusual stereocontrolling element for the [2,3]-Stevens rearrangement.

Science.gov (United States)

Soheili, Arash; Tambar, Uttam K

2013-10-04

A formal total synthesis of (±)-amathaspiramide F through a tandem palladium-catalyzed allylic amination/[2,3]-Stevens rearrangement is reported. The unexpected diastereoselectivity of the [2,3]-Stevens rearrangement was controlled by the substitution patterns of an aromatic ring. This discovery represents a new stereocontrolling element for [2,3]-sigmatropic rearrangements in complex molecular settings.

Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.

Science.gov (United States)

Coetzee, Simon G; Shen, Howard C; Hazelett, Dennis J; Lawrenson, Kate; Kuchenbaecker, Karoline; Tyrer, Jonathan; Rhie, Suhn K; Levanon, Keren; Karst, Alison; Drapkin, Ronny; Ramus, Susan J; Couch, Fergus J; Offit, Kenneth; Chenevix-Trench, Georgia; Monteiro, Alvaro N A; Antoniou, Antonis; Freedman, Matthew; Coetzee, Gerhard A; Pharoah, Paul D P; Noushmehr, Houtan; Gayther, Simon A

2015-07-01

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Diverse activities of viral cis-acting RNA regulatory elements revealed using multicolor, long-term, single-cell imaging.

Science.gov (United States)

Pocock, Ginger M; Zimdars, Laraine L; Yuan, Ming; Eliceiri, Kevin W; Ahlquist, Paul; Sherer, Nathan M

2017-02-01

Cis-acting RNA structural elements govern crucial aspects of viral gene expression. How these structures and other posttranscriptional signals affect RNA trafficking and translation in the context of single cells is poorly understood. Herein we describe a multicolor, long-term (>24 h) imaging strategy for measuring integrated aspects of viral RNA regulatory control in individual cells. We apply this strategy to demonstrate differential mRNA trafficking behaviors governed by RNA elements derived from three retroviruses (HIV-1, murine leukemia virus, and Mason-Pfizer monkey virus), two hepadnaviruses (hepatitis B virus and woodchuck hepatitis virus), and an intron-retaining transcript encoded by the cellular NXF1 gene. Striking behaviors include "burst" RNA nuclear export dynamics regulated by HIV-1's Rev response element and the viral Rev protein; transient aggregations of RNAs into discrete foci at or near the nuclear membrane triggered by multiple elements; and a novel, pulsiform RNA export activity regulated by the hepadnaviral posttranscriptional regulatory element. We incorporate single-cell tracking and a data-mining algorithm into our approach to obtain RNA element-specific, high-resolution gene expression signatures. Together these imaging assays constitute a tractable, systems-based platform for studying otherwise difficult to access spatiotemporal features of viral and cellular gene regulation. © 2017 Pocock et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Moving through the Stressed Genome: Emerging Regulatory Roles for Transposons in Plant Stress Response.

Science.gov (United States)

Negi, Pooja; Rai, Archana N; Suprasanna, Penna

2016-01-01

The recognition of a positive correlation between organism genome size with its transposable element (TE) content, represents a key discovery of the field of genome biology. Considerable evidence accumulated since then suggests the involvement of TEs in genome structure, evolution and function. The global genome reorganization brought about by transposon activity might play an adaptive/regulatory role in the host response to environmental challenges, reminiscent of McClintock's original 'Controlling Element' hypothesis. This regulatory aspect of TEs is also garnering support in light of the recent evidences, which project TEs as "distributed genomic control modules." According to this view, TEs are capable of actively reprogramming host genes circuits and ultimately fine-tuning the host response to specific environmental stimuli. Moreover, the stress-induced changes in epigenetic status of TE activity may allow TEs to propagate their stress responsive elements to host genes; the resulting genome fluidity can permit phenotypic plasticity and adaptation to stress. Given their predominating presence in the plant genomes, nested organization in the genic regions and potential regulatory role in stress response, TEs hold unexplored potential for crop improvement programs. This review intends to present the current information about the roles played by TEs in plant genome organization, evolution, and function and highlight the regulatory mechanisms in plant stress responses. We will also briefly discuss the connection between TE activity, host epigenetic response and phenotypic plasticity as a critical link for traversing the translational bridge from a purely basic study of TEs, to the applied field of stress adaptation and crop improvement.

Identification of functional elements and regulatory circuits by Drosophila modENCODE

Energy Technology Data Exchange (ETDEWEB)

Roy, Sushmita; Ernst, Jason; Kharchenko, Peter V.; Kheradpour, Pouya; Negre, Nicolas; Eaton, Matthew L.; Landolin, Jane M.; Bristow, Christopher A.; Ma, Lijia; Lin, Michael F.; Washietl, Stefan; Arshinoff, Bradley I.; Ay, Ferhat; Meyer, Patrick E.; Robine, Nicolas; Washington, Nicole L.; Stefano, Luisa Di; Berezikov, Eugene; Brown, Christopher D.; Candeias, Rogerio; Carlson, Joseph W.; Carr, Adrian; Jungreis, Irwin; Marbach, Daniel; Sealfon, Rachel; Tolstorukov, Michael Y.; Will, Sebastian; Alekseyenko, Artyom A.; Artieri, Carlo; Booth, Benjamin W.; Brooks, Angela N.; Dai, Qi; Davis, Carrie A.; Duff, Michael O.; Feng, Xin; Gorchakov, Andrey A.; Gu, Tingting; Henikoff, Jorja G.; Kapranov, Philipp; Li, Renhua; MacAlpine, Heather K.; Malone, John; Minoda, Aki; Nordman, Jared; Okamura, Katsutomo; Perry, Marc; Powell, Sara K.; Riddle, Nicole C.; Sakai, Akiko; Samsonova, Anastasia; Sandler, Jeremy E.; Schwartz, Yuri B.; Sher, Noa; Spokony, Rebecca; Sturgill, David; van Baren, Marijke; Wan, Kenneth H.; Yang, Li; Yu, Charles; Feingold, Elise; Good, Peter; Guyer, Mark; Lowdon, Rebecca; Ahmad, Kami; Andrews, Justen; Berger, Bonnie; Brenner, Steven E.; Brent, Michael R.; Cherbas, Lucy; Elgin, Sarah C. R.; Gingeras, Thomas R.; Grossman, Robert; Hoskins, Roger A.; Kaufman, Thomas C.; Kent, William; Kuroda, Mitzi I.; Orr-Weaver, Terry; Perrimon, Norbert; Pirrotta, Vincenzo; Posakony, James W.; Ren, Bing; Russell, Steven; Cherbas, Peter; Graveley, Brenton R.; Lewis, Suzanna; Micklem, Gos; Oliver, Brian; Park, Peter J.; Celniker, Susan E.; Henikoff, Steven; Karpen, Gary H.; Lai, Eric C.; MacAlpine, David M.; Stein, Lincoln D.; White, Kevin P.; Kellis, Manolis

2010-12-22

To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation. Several years after the complete genetic sequencing of many species, it is still unclear how to translate genomic information into a functional map of cellular and developmental programs. The Encyclopedia of DNA Elements (ENCODE) (1) and model organism ENCODE (modENCODE) (2) projects use diverse genomic assays to comprehensively annotate the Homo sapiens (human), Drosophila melanogaster (fruit fly), and Caenorhabditis elegans (worm) genomes, through systematic generation and computational integration of functional genomic data sets. Previous genomic studies in flies have made seminal contributions to our understanding of basic biological mechanisms and genome functions, facilitated by genetic, experimental, computational, and manual annotation of the euchromatic and heterochromatic genome (3), small genome size, short life cycle, and a deep knowledge of development, gene function, and chromosome biology. The functions

POWRS: position-sensitive motif discovery.

Directory of Open Access Journals (Sweden)

Ian W Davis

Full Text Available Transcription factors and the short, often degenerate DNA sequences they recognize are central regulators of gene expression, but their regulatory code is challenging to dissect experimentally. Thus, computational approaches have long been used to identify putative regulatory elements from the patterns in promoter sequences. Here we present a new algorithm "POWRS" (POsition-sensitive WoRd Set for identifying regulatory sequence motifs, specifically developed to address two common shortcomings of existing algorithms. First, POWRS uses the position-specific enrichment of regulatory elements near transcription start sites to significantly increase sensitivity, while providing new information about the preferred localization of those elements. Second, POWRS forgoes position weight matrices for a discrete motif representation that appears more resistant to over-generalization. We apply this algorithm to discover sequences related to constitutive, high-level gene expression in the model plant Arabidopsis thaliana, and then experimentally validate the importance of those elements by systematically mutating two endogenous promoters and measuring the effect on gene expression levels. This provides a foundation for future efforts to rationally engineer gene expression in plants, a problem of great importance in developing biotech crop varieties.BSD-licensed Python code at http://grassrootsbio.com/papers/powrs/.

A compact, in vivo screen of all 6-mers reveals drivers of tissue-specific expression and guides synthetic regulatory element design.

Science.gov (United States)

Smith, Robin P; Riesenfeld, Samantha J; Holloway, Alisha K; Li, Qiang; Murphy, Karl K; Feliciano, Natalie M; Orecchia, Lorenzo; Oksenberg, Nir; Pollard, Katherine S; Ahituv, Nadav

2013-07-18

Large-scale annotation efforts have improved our ability to coarsely predict regulatory elements throughout vertebrate genomes. However, it is unclear how complex spatiotemporal patterns of gene expression driven by these elements emerge from the activity of short, transcription factor binding sequences. We describe a comprehensive promoter extension assay in which the regulatory potential of all 6 base-pair (bp) sequences was tested in the context of a minimal promoter. To enable this large-scale screen, we developed algorithms that use a reverse-complement aware decomposition of the de Bruijn graph to design a library of DNA oligomers incorporating every 6-bp sequence exactly once. Our library multiplexes all 4,096 unique 6-mers into 184 double-stranded 15-bp oligomers, which is sufficiently compact for in vivo testing. We injected each multiplexed construct into zebrafish embryos and scored GFP expression in 15 tissues at two developmental time points. Twenty-seven constructs produced consistent expression patterns, with the majority doing so in only one tissue. Functional sequences are enriched near biologically relevant genes, match motifs for developmental transcription factors, and are required for enhancer activity. By concatenating tissue-specific functional sequences, we generated completely synthetic enhancers for the notochord, epidermis, spinal cord, forebrain and otic lateral line, and show that short regulatory sequences do not always function modularly. This work introduces a unique in vivo catalog of short, functional regulatory sequences and demonstrates several important principles of regulatory element organization. Furthermore, we provide resources for designing compact, reverse-complement aware k-mer libraries.

Regulatory elements involved in tax-mediated transactivation of the HTLV-I LTR.

Science.gov (United States)

Seeler, J S; Muchardt, C; Podar, M; Gaynor, R B

1993-10-01

HTLV-I is the etiologic agent of adult T-cell leukemia. In this study, we investigated the regulatory elements and cellular transcription factors which function in modulating HTLV-I gene expression in response to the viral transactivator protein, tax. Transfection experiments into Jurkat cells of a variety of site-directed mutants in the HTLV-1 LTR indicated that each of the three motifs A, B, and C within the 21-bp repeats, the binding sites for the Ets family of proteins, and the TATA box all influenced the degree of tax-mediated activation. Tax is also able to activate gene expression of other viral and cellular promoters. Tax activation of the IL-2 receptor and the HIV-1 LTR is mediated through NF-kappa B motifs. Interestingly, sequences in the 21-bp repeat B and C motifs contain significant homology with NF-kappa B regulatory elements. We demonstrated that an NF-kappa B binding protein, PRDII-BF1, but not the rel protein, bound to the B and C motifs in the 21-bp repeat. PRDII-BF1 was also able to stimulate activation of HTLV-I gene expression by tax. The role of the Ets proteins on modulating tax activation was also studied. Ets 1 but not Ets 2 was capable of increasing the degree of tax activation of the HTLV-I LTR. These results suggest that tax activates gene expression by either direct or indirect interaction with several cellular transcription factors that bind to the HTLV-I LTR.

BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements.

Science.gov (United States)

Bhagwat, Anand S; Roe, Jae-Seok; Mok, Beverly Y L; Hohmann, Anja F; Shi, Junwei; Vakoc, Christopher R

2016-04-19

The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. A shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Spatially conserved regulatory elements identified within human and mouse Cd247 gene using high-throughput sequencing data from the ENCODE project

DEFF Research Database (Denmark)

Pundhir, Sachin; Hannibal, Tine Dahlbæk; Bang-Berthelsen, Claus Heiner

2014-01-01

. In this study, we have utilized the wealth of high-throughput sequencing data produced during the Encyclopedia of DNA Elements (ENCODE) project to identify spatially conserved regulatory elements within the Cd247 gene from human and mouse. We show the presence of two transcription factor binding sites...

Promzea: a pipeline for discovery of co-regulatory motifs in maize and other plant species and its application to the anthocyanin and phlobaphene biosynthetic pathways and the Maize Development Atlas.

Science.gov (United States)

Liseron-Monfils, Christophe; Lewis, Tim; Ashlock, Daniel; McNicholas, Paul D; Fauteux, François; Strömvik, Martina; Raizada, Manish N

2013-03-15

The discovery of genetic networks and cis-acting DNA motifs underlying their regulation is a major objective of transcriptome studies. The recent release of the maize genome (Zea mays L.) has facilitated in silico searches for regulatory motifs. Several algorithms exist to predict cis-acting elements, but none have been adapted for maize. A benchmark data set was used to evaluate the accuracy of three motif discovery programs: BioProspector, Weeder and MEME. Analysis showed that each motif discovery tool had limited accuracy and appeared to retrieve a distinct set of motifs. Therefore, using the benchmark, statistical filters were optimized to reduce the false discovery ratio, and then remaining motifs from all programs were combined to improve motif prediction. These principles were integrated into a user-friendly pipeline for motif discovery in maize called Promzea, available at http://www.promzea.org and on the Discovery Environment of the iPlant Collaborative website. Promzea was subsequently expanded to include rice and Arabidopsis. Within Promzea, a user enters cDNA sequences or gene IDs; corresponding upstream sequences are retrieved from the maize genome. Predicted motifs are filtered, combined and ranked. Promzea searches the chosen plant genome for genes containing each candidate motif, providing the user with the gene list and corresponding gene annotations. Promzea was validated in silico using a benchmark data set: the Promzea pipeline showed a 22% increase in nucleotide sensitivity compared to the best standalone program tool, Weeder, with equivalent nucleotide specificity. Promzea was also validated by its ability to retrieve the experimentally defined binding sites of transcription factors that regulate the maize anthocyanin and phlobaphene biosynthetic pathways. Promzea predicted additional promoter motifs, and genome-wide motif searches by Promzea identified 127 non-anthocyanin/phlobaphene genes that each contained all five predicted promoter

Retinal Expression of the Drosophila eyes absent Gene Is Controlled by Several Cooperatively Acting Cis-regulatory Elements

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Neuman, Sarah D.; Bashirullah, Arash; Kumar, Justin P.

2016-01-01

The eyes absent (eya) gene of the fruit fly, Drosophila melanogaster, is a member of an evolutionarily conserved gene regulatory network that controls eye formation in all seeing animals. The loss of eya leads to the complete elimination of the compound eye while forced expression of eya in non-retinal tissues is sufficient to induce ectopic eye formation. Within the developing retina eya is expressed in a dynamic pattern and is involved in tissue specification/determination, cell proliferation, apoptosis, and cell fate choice. In this report we explore the mechanisms by which eya expression is spatially and temporally governed in the developing eye. We demonstrate that multiple cis-regulatory elements function cooperatively to control eya transcription and that spacing between a pair of enhancer elements is important for maintaining correct gene expression. Lastly, we show that the loss of eya expression in sine oculis (so) mutants is the result of massive cell death and a progressive homeotic transformation of retinal progenitor cells into head epidermis. PMID:27930646

Characterization of noncoding regulatory DNA in the human genome.

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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.

The emergence of diagnostic imaging technologies in breast cancer: discovery, regulatory approval, reimbursement, and adoption in clinical guidelines.

Science.gov (United States)

Gold, Laura S; Klein, Gregory; Carr, Lauren; Kessler, Larry; Sullivan, Sean D

2012-01-25

In this article, we trace the chronology of developments in breast imaging technologies that are used for diagnosis and staging of breast cancer, including mammography, ultrasonography, magnetic resonance imaging, computed tomography, and positron emission tomography. We explore factors that affected clinical acceptance and utilization of these technologies from discovery to clinical use, including milestones in peer-reviewed publication, US Food and Drug Administration approval, reimbursement by payers, and adoption into clinical guidelines. The factors driving utilization of new imaging technologies are mainly driven by regulatory approval and reimbursement by payers rather than evidence that they provide benefits to patients. Comparative effectiveness research can serve as a useful tool to investigate whether these imaging modalities provide information that improves patient outcomes in real-world settings.

Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci.

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Canver, Matthew C; Lessard, Samuel; Pinello, Luca; Wu, Yuxuan; Ilboudo, Yann; Stern, Emily N; Needleman, Austen J; Galactéros, Frédéric; Brugnara, Carlo; Kutlar, Abdullah; McKenzie, Colin; Reid, Marvin; Chen, Diane D; Das, Partha Pratim; A Cole, Mitchel; Zeng, Jing; Kurita, Ryo; Nakamura, Yukio; Yuan, Guo-Cheng; Lettre, Guillaume; Bauer, Daniel E; Orkin, Stuart H

2017-04-01

Cas9-mediated, high-throughput, saturating in situ mutagenesis permits fine-mapping of function across genomic segments. Disease- and trait-associated variants identified in genome-wide association studies largely cluster at regulatory loci. Here we demonstrate the use of multiple designer nucleases and variant-aware library design to interrogate trait-associated regulatory DNA at high resolution. We developed a computational tool for the creation of saturating-mutagenesis libraries with single or multiple nucleases with incorporation of variants. We applied this methodology to the HBS1L-MYB intergenic region, which is associated with red-blood-cell traits, including fetal hemoglobin levels. This approach identified putative regulatory elements that control MYB expression. Analysis of genomic copy number highlighted potential false-positive regions, thus emphasizing the importance of off-target analysis in the design of saturating-mutagenesis experiments. Together, these data establish a widely applicable high-throughput and high-resolution methodology to identify minimal functional sequences within large disease- and trait-associated regions.

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

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Huang Hsien-Da

2008-11-01

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

Transcriptional regulatory elements in the noncoding region of human papillomavirus type 6

International Nuclear Information System (INIS)

Wu, Tzyy-Choou.

1989-01-01

The structure and function of the transcriptional regulatory region of human papillomavirus type 6 (HPV-6) has been investigated. To investigate tissue specific gene expression, a sensitive method to detect and localize HPV-6 viral DNA, mRNA and protein in plastic-embedded tissue sections of genital and respiratory tract papillomata by using in situ hybridization and immunoperoxidase assays has been developed. This method, using ultrathin sections and strand-specific 3 H labeled riboprobes, offers the advantages of superior morphological preservation and detection of viral genomes at low copy number with good resolution, and the modified immunocytochemistry provides better sensitivity. The results suggest that genital tract epithelium is more permissive for HPV-6 replication than respiratory tract epithelium. To study the tissue tropism of HPV-6 at the level of regulation of viral gene expression, the polymerase chain reaction was used to isolate the noncoding region (NCR) of HPV-6 in independent isolates. Nucleotide sequence analysis of molecularly cloned DNA identified base substitutions, deletions/insertions and tandem duplications. Transcriptional regulatory elements in the NCR were assayed in recombinant plasmids containing the bacterial gene for chloramphenicol acetyl transferase

Orientation-dependent interaction between Drosophila insulators is a property of this class of regulatory elements.

Science.gov (United States)

Kyrchanova, Olga; Chetverina, Darya; Maksimenko, Oksana; Kullyev, Andrey; Georgiev, Pavel

2008-12-01

Insulators are defined as a class of regulatory elements that delimit independent transcriptional domains within eukaryotic genomes. According to previous data, an interaction (pairing) between some Drosophila insulators can support distant activation of a promoter by an enhancer. Here, we have demonstrated that pairs of well-studied insulators such as scs-scs, scs'-scs', 1A2-1A2 and Wari-Wari support distant activation of the white promoter by the yeast GAL4 activator in an orientation-dependent manner. The same is true for the efficiency of the enhancer that stimulates white expression in the eyes. In all insulator pairs tested, stimulation of the white gene was stronger when insulators were inserted between the eye enhancer or GAL4 and the white promoter in opposite orientations relative to each other. As shown previously, Zw5, Su(Hw) and dCTCF proteins are required for the functioning of different insulators that do not interact with each other. Here, strong functional interactions have been revealed between DNA fragments containing binding sites for either Zw5 or Su(Hw) or dCTCF protein but not between heterologous binding sites [Zw5-Su(Hw), dCTCF-Su(Hw), or dCTCF-Zw5]. These results suggest that insulator proteins can support selective interactions between distant regulatory elements.

The synthetic elements

Energy Technology Data Exchange (ETDEWEB)

Hoffman, D.C.

1990-05-01

Prior to 1940, the heaviest element known was uranium, discovered in 1789. Since that time the elements 93 through 109 have been synthesized and identified and the elements 43, 61, 85, and 87 which were missing form the periodic tables of the 1930's have been discovered. The techniques and problems involved in these discoveries and the placement of the transuranium elements in the periodic table will be discussed. The production and positive identification of elements heavier than Md (Z=101), which have very short half-lives and can only be produced an atom-at-a-time, are very difficult and there have been controversies concerning their discovery. Some of the new methods which have been developed and used in these studies will be described. The prospects for production of still heavier elements will be considered.

The synthetic elements

International Nuclear Information System (INIS)

Hoffman, D.C.

1990-05-01

Prior to 1940, the heaviest element known was uranium, discovered in 1789. Since that time the elements 93 through 109 have been synthesized and identified and the elements 43, 61, 85, and 87 which were missing form the periodic tables of the 1930's have been discovered. The techniques and problems involved in these discoveries and the placement of the transuranium elements in the periodic table will be discussed. The production and positive identification of elements heavier than Md (Z=101), which have very short half-lives and can only be produced an atom-at-a-time, are very difficult and there have been controversies concerning their discovery. Some of the new methods which have been developed and used in these studies will be described. The prospects for production of still heavier elements will be considered

Cis-regulatory element based targeted gene finding: genome-wide identification of abscisic acid- and abiotic stress-responsive genes in Arabidopsis thaliana.

Science.gov (United States)

Zhang, Weixiong; Ruan, Jianhua; Ho, Tuan-Hua David; You, Youngsook; Yu, Taotao; Quatrano, Ralph S

2005-07-15

A fundamental problem of computational genomics is identifying the genes that respond to certain endogenous cues and environmental stimuli. This problem can be referred to as targeted gene finding. Since gene regulation is mainly determined by the binding of transcription factors and cis-regulatory DNA sequences, most existing gene annotation methods, which exploit the conservation of open reading frames, are not effective in finding target genes. A viable approach to targeted gene finding is to exploit the cis-regulatory elements that are known to be responsible for the transcription of target genes. Given such cis-elements, putative target genes whose promoters contain the elements can be identified. As a case study, we apply the above approach to predict the genes in model plant Arabidopsis thaliana which are inducible by a phytohormone, abscisic acid (ABA), and abiotic stress, such as drought, cold and salinity. We first construct and analyze two ABA specific cis-elements, ABA-responsive element (ABRE) and its coupling element (CE), in A.thaliana, based on their conservation in rice and other cereal plants. We then use the ABRE-CE module to identify putative ABA-responsive genes in A.thaliana. Based on RT-PCR verification and the results from literature, this method has an accuracy rate of 67.5% for the top 40 predictions. The cis-element based targeted gene finding approach is expected to be widely applicable since a large number of cis-elements in many species are available.

Single nucleotide polymorphism in transcriptional regulatory regions and expression of environmentally responsive genes

International Nuclear Information System (INIS)

Wang, Xuting; Tomso, Daniel J.; Liu Xuemei; Bell, Douglas A.

2005-01-01

Single nucleotide polymorphisms (SNPs) in the human genome are DNA sequence variations that can alter an individual's response to environmental exposure. SNPs in gene coding regions can lead to changes in the biological properties of the encoded protein. In contrast, SNPs in non-coding gene regulatory regions may affect gene expression levels in an allele-specific manner, and these functional polymorphisms represent an important but relatively unexplored class of genetic variation. The main challenge in analyzing these SNPs is a lack of robust computational and experimental methods. Here, we first outline mechanisms by which genetic variation can impact gene regulation, and review recent findings in this area; then, we describe a methodology for bioinformatic discovery and functional analysis of regulatory SNPs in cis-regulatory regions using the assembled human genome sequence and databases on sequence polymorphism and gene expression. Our method integrates SNP and gene databases and uses a set of computer programs that allow us to: (1) select SNPs, from among the >9 million human SNPs in the NCBI dbSNP database, that are similar to cis-regulatory element (RE) consensus sequences; (2) map the selected dbSNP entries to the human genome assembly in order to identify polymorphic REs near gene start sites; (3) prioritize the candidate polymorphic RE containing genes by searching the existing genotype and gene expression data sets. The applicability of this system has been demonstrated through studies on p53 responsive elements and is being extended to additional pathways and environmentally responsive genes

Knowledge-based analysis of microarrays for the discovery of transcriptional regulation relationships.

Science.gov (United States)

Seok, Junhee; Kaushal, Amit; Davis, Ronald W; Xiao, Wenzhong

2010-01-18

The large amount of high-throughput genomic data has facilitated the discovery of the regulatory relationships between transcription factors and their target genes. While early methods for discovery of transcriptional regulation relationships from microarray data often focused on the high-throughput experimental data alone, more recent approaches have explored the integration of external knowledge bases of gene interactions. In this work, we develop an algorithm that provides improved performance in the prediction of transcriptional regulatory relationships by supplementing the analysis of microarray data with a new method of integrating information from an existing knowledge base. Using a well-known dataset of yeast microarrays and the Yeast Proteome Database, a comprehensive collection of known information of yeast genes, we show that knowledge-based predictions demonstrate better sensitivity and specificity in inferring new transcriptional interactions than predictions from microarray data alone. We also show that comprehensive, direct and high-quality knowledge bases provide better prediction performance. Comparison of our results with ChIP-chip data and growth fitness data suggests that our predicted genome-wide regulatory pairs in yeast are reasonable candidates for follow-up biological verification. High quality, comprehensive, and direct knowledge bases, when combined with appropriate bioinformatic algorithms, can significantly improve the discovery of gene regulatory relationships from high throughput gene expression data.

Discovery of cis-elements between sorghum and rice using co-expression and evolutionary conservation

Directory of Open Access Journals (Sweden)

Haberer Georg

2009-06-01

Full Text Available Abstract Background The spatiotemporal regulation of gene expression largely depends on the presence and absence of cis-regulatory sites in the promoter. In the economically highly important grass family, our knowledge of transcription factor binding sites and transcriptional networks is still very limited. With the completion of the sorghum genome and the available rice genome sequence, comparative promoter analyses now allow genome-scale detection of conserved cis-elements. Results In this study, we identified thousands of phylogenetic footprints conserved between orthologous rice and sorghum upstream regions that are supported by co-expression information derived from three different rice expression data sets. In a complementary approach, cis-motifs were discovered by their highly conserved co-occurrence in syntenic promoter pairs. Sequence conservation and matches to known plant motifs support our findings. Expression similarities of gene pairs positively correlate with the number of motifs that are shared by gene pairs and corroborate the importance of similar promoter architectures for concerted regulation. This strongly suggests that these motifs function in the regulation of transcript levels in rice and, presumably also in sorghum. Conclusion Our work provides the first large-scale collection of cis-elements for rice and sorghum and can serve as a paradigm for cis-element analysis through comparative genomics in grasses in general.

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

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Arindam Deb

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

A New Algorithm for Identifying Cis-Regulatory Modules Based on Hidden Markov Model

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Haitao Guo

2017-01-01

Full Text Available The discovery of cis-regulatory modules (CRMs is the key to understanding mechanisms of transcription regulation. Since CRMs have specific regulatory structures that are the basis for the regulation of gene expression, how to model the regulatory structure of CRMs has a considerable impact on the performance of CRM identification. The paper proposes a CRM discovery algorithm called ComSPS. ComSPS builds a regulatory structure model of CRMs based on HMM by exploring the rules of CRM transcriptional grammar that governs the internal motif site arrangement of CRMs. We test ComSPS on three benchmark datasets and compare it with five existing methods. Experimental results show that ComSPS performs better than them.

A New Algorithm for Identifying Cis-Regulatory Modules Based on Hidden Markov Model

Science.gov (United States)

2017-01-01

The discovery of cis-regulatory modules (CRMs) is the key to understanding mechanisms of transcription regulation. Since CRMs have specific regulatory structures that are the basis for the regulation of gene expression, how to model the regulatory structure of CRMs has a considerable impact on the performance of CRM identification. The paper proposes a CRM discovery algorithm called ComSPS. ComSPS builds a regulatory structure model of CRMs based on HMM by exploring the rules of CRM transcriptional grammar that governs the internal motif site arrangement of CRMs. We test ComSPS on three benchmark datasets and compare it with five existing methods. Experimental results show that ComSPS performs better than them. PMID:28497059

Changes in Cis-regulatory Elements during Morphological Evolution

Directory of Open Access Journals (Sweden)

Yu-Lee Paul

2012-10-01

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

Historical aspects of the discovery of plutonium

International Nuclear Information System (INIS)

Clark, David L.

2016-01-01

The historical events that led up to the discovery of plutonium and subsequently, how that discovery helped shape the modern period table of the elements, and ushered in a new era of nuclear science and technology are discussed. When the first of the transuranium elements, neptunium was discovered, it was realized that the radioactive βdecay of "2"3"9Np should lead to the formation of element 94. The scale of the experiments at that time, however, precluded its identification. Plutonium was first produced late in 1940 by Seaborg, McMillan, Kennedy, and Wahl1,2 by bombarding uranium with deuterons to produce the isotope "2"3"8Pu

The solar element

DEFF Research Database (Denmark)

Kragh, Helge

2009-01-01

of the nineteenth century. In the modest form of a yellow spectral line known as D3, 'helium' was sometimes supposed to exist in the Sun's atmosphere, an idea which is traditionally ascribed to J. Norman Lockyer. Did Lockyer discover helium as a solar element? How was the suggestion received by chemists, physicists...... and astronomers in the period until the spring of 1895, when William Ramsay serendipitously found the gas in uranium minerals? The hypothetical element helium was fairly well known, yet Ramsay's discovery owed little or nothing to Lockyer's solar element. Indeed, for a brief while it was thought that the two...... elements might be different. The complex story of how helium became established as both a solar and terrestrial element involves precise observations as well as airy speculations. It is a story that is unique among the discovery histories of the chemical elements....

β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies.

Science.gov (United States)

Rivella, Stefano

2015-04-01

β-thalassemias are monogenic disorders characterized by defective synthesis of the β-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the β-globin gene or its regulatory elements have been associated with β-thalassemias. Due to the complexity of the regulation of the β-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of β-globin and abnormal erythropoiesis, as well as current and novel therapies. Copyright© Ferrata Storti Foundation.

[Analysis of cis-regulatory element distribution in gene promoters of Gossypium raimondii and Arabidopsis thaliana].

Science.gov (United States)

Sun, Gao-Fei; He, Shou-Pu; Du, Xiong-Ming

2013-10-01

Cotton genomic studies have boomed since the release of Gossypium raimondii draft genome. In this study, cis-regulatory element (CRE) in 1 kb length sequence upstream 5' UTR of annotated genes were selected and scanned in the Arabidopsis thaliana (At) and Gossypium raimondii (Gr) genomes, based on the database of PLACE (Plant cis-acting Regulatory DNA Elements). According to the definition of this study, 44 (12.3%) and 57 (15.5%) CREs presented "peak-like" distribution in the 1 kb selected sequences of both genomes, respectively. Thirty-four of them were peak-like distributed in both genomes, which could be further categorized into 4 types based on their core sequences. The coincidence of TATABOX peak position and their actual position ((-) -30 bp) indicated that the position of a common CRE was conservative in different genes, which suggested that the peak position of these CREs was their possible actual position of transcription factors. The position of a common CRE was also different between the two genomes due to stronger length variation of 5' UTR in Gr than At. Furthermore, most of the peak-like CREs were located in the region of -110 bp-0 bp, which suggested that concentrated distribution might be conductive to the interaction of transcription factors, and then regulate the gene expression in downstream.

Functional dissection of the promoter of the pollen-specific gene NTP303 reveals a novel pollen-specific, and conserved cis-regulatory element.

Science.gov (United States)

Weterings, K; Schrauwen, J; Wullems, G; Twell, D

1995-07-01

Regulatory elements within the promoter of the pollen-specific NTP303 gene from tobacco were analysed by transient and stable expression analyses. Analysis of precisely targeted mutations showed that the NTP303 promoter is not regulated by any of the previously described pollen-specific cis-regulatory elements. However, two adjacent regions from -103 to -86 bp and from -86 to -59 bp were shown to contain sequences which positively regulated the NTP303 promoter. Both of these regions were capable of driving pollen-specific expression from a heterologous promoter, independent of orientation and in an additive manner. The boundaries of the minimal, functional NTP303 promoter were determined to lie within the region -86 to -51 bp. The sequence AAATGA localized from -94 to -89 bp was identified as a novel cis-acting element, of which the TGA triplet was shown to comprise an active part. This element was shown to be completely conserved in the similarly regulated promoter of the Bp 10 gene from Brassica napus encoding a homologue of the NTP303 gene.

RNA regulatory networks in animals and plants: a long noncoding RNA perspective.

Science.gov (United States)

Bai, Youhuang; Dai, Xiaozhuan; Harrison, Andrew P; Chen, Ming

2015-03-01

A recent highlight of genomics research has been the discovery of many families of transcripts which have function but do not code for proteins. An important group is long noncoding RNAs (lncRNAs), which are typically longer than 200 nt, and whose members originate from thousands of loci across genomes. We review progress in understanding the biogenesis and regulatory mechanisms of lncRNAs. We describe diverse computational and high throughput technologies for identifying and studying lncRNAs. We discuss the current knowledge of functional elements embedded in lncRNAs as well as insights into the lncRNA-based regulatory network in animals. We also describe genome-wide studies of large amount of lncRNAs in plants, as well as knowledge of selected plant lncRNAs with a focus on biotic/abiotic stress-responsive lncRNAs. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Discovery and development of new antibacterial drugs: learning from experience?

Science.gov (United States)

Jackson, Nicole; Czaplewski, Lloyd; Piddock, Laura J V

2018-06-01

Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.

Technical summaries of Scotian Shelf - significant and commercial discoveries

International Nuclear Information System (INIS)

Dickey, J.E.; Bigelow, S.F.; Edens, J.A.; Brown, D.E.; Smith, B.; Makrides, C.; Mader, R.

1997-03-01

An independent assessment of the recoverable hydrocarbon resource currently held under' Significant and Commercial Discovery' status offshore Nova Scotia was presented. A generalized description of the regulatory issues regarding the discovered resources within the Scotian Basin was included. Twenty discoveries have been declared significant and two have been declared commercial, pursuant to the Canada-Nova Scotia Offshore Petroleum Resources Accord Implementation Acts. Salient facts about each discovery were documented. The information included the wells drilled within the structure, significant flow tests, geological and geophysical attributes, structural cross-section and areal extent, petrophysical parameters, hydrocarbons in place and anticipated hydrocarbon recoverable resource. tabs., figs

Moving through the stressed genome: Emerging regulatory roles for transposons in plant stress tolerance

Directory of Open Access Journals (Sweden)

Negi Pooja

2016-10-01

Full Text Available The recognition of a positive correlation between organism genome size with its transposable element (TE content, represents a key discovery of the field of genome biology. Considerable evidence accumulated since then suggests the involvement of TEs in genome structure, evolution and function. The global genome reorganization brought about by transposon activity might play an adaptive/regulatory role in the host response to environmental challenges, reminiscent of McClintock’s original ’Controlling Element’ hypothesis. This regulatory aspect of TEs is also garnering support in light of the recent evidences which project TEs as distributed genomic control modules. According to this view, TEs are capable of actively reprogramming host genes circuits and ultimately fine-tuning the host response to specific environmental stimuli. Moreover, the stress-induced changes in epigenetic status of TE activity may allow TEs to propagate their stress responsive elements to host genes; the resulting genome fluidity can permit phenotypic plasticity and adaptation to stress. Given their predominating presence in the plant genomes, nested organization in the genic regions and potential regulatory role in stress response, TEs hold unexplored potential for crop improvement programs. This review intends to present the current information about the roles played by TEs in plant genome organization, evolution and function, and highlight the regulatory mechanisms in plant stress responses. We will also briefly discuss the connection between TE activity, host epigenetic response and phenotypic plasticity as a critical link for traversing the translational bridge from a purely basic study of TEs, to the applied field of stress adaptation and crop improvement.

Moving through the Stressed Genome: Emerging Regulatory Roles for Transposons in Plant Stress Response

Science.gov (United States)

Negi, Pooja; Rai, Archana N.; Suprasanna, Penna

2016-01-01

The recognition of a positive correlation between organism genome size with its transposable element (TE) content, represents a key discovery of the field of genome biology. Considerable evidence accumulated since then suggests the involvement of TEs in genome structure, evolution and function. The global genome reorganization brought about by transposon activity might play an adaptive/regulatory role in the host response to environmental challenges, reminiscent of McClintock's original ‘Controlling Element’ hypothesis. This regulatory aspect of TEs is also garnering support in light of the recent evidences, which project TEs as “distributed genomic control modules.” According to this view, TEs are capable of actively reprogramming host genes circuits and ultimately fine-tuning the host response to specific environmental stimuli. Moreover, the stress-induced changes in epigenetic status of TE activity may allow TEs to propagate their stress responsive elements to host genes; the resulting genome fluidity can permit phenotypic plasticity and adaptation to stress. Given their predominating presence in the plant genomes, nested organization in the genic regions and potential regulatory role in stress response, TEs hold unexplored potential for crop improvement programs. This review intends to present the current information about the roles played by TEs in plant genome organization, evolution, and function and highlight the regulatory mechanisms in plant stress responses. We will also briefly discuss the connection between TE activity, host epigenetic response and phenotypic plasticity as a critical link for traversing the translational bridge from a purely basic study of TEs, to the applied field of stress adaptation and crop improvement. PMID:27777577

Quantifying the Ease of Scientific Discovery.

Science.gov (United States)

Arbesman, Samuel

2011-02-01

It has long been known that scientific output proceeds on an exponential increase, or more properly, a logistic growth curve. The interplay between effort and discovery is clear, and the nature of the functional form has been thought to be due to many changes in the scientific process over time. Here I show a quantitative method for examining the ease of scientific progress, another necessary component in understanding scientific discovery. Using examples from three different scientific disciplines - mammalian species, chemical elements, and minor planets - I find the ease of discovery to conform to an exponential decay. In addition, I show how the pace of scientific discovery can be best understood as the outcome of both scientific output and ease of discovery. A quantitative study of the ease of scientific discovery in the aggregate, such as done here, has the potential to provide a great deal of insight into both the nature of future discoveries and the technical processes behind discoveries in science.

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

Directory of Open Access Journals (Sweden)

Junhua Li

2014-01-01

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

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

Science.gov (United States)

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

2015-08-15

Higher plant species diverged extensively with regard to the moment (flowering time) and position (inflorescence architecture) at which flowers are formed. This seems largely caused by variation in the expression patterns of conserved genes that specify floral meristem identity (FMI), rather than changes in the encoded proteins. Here, we report a functional comparison of the promoters of homologous FMI genes from Arabidopsis, petunia, tomato and Antirrhinum. Analysis of promoter-reporter constructs in petunia and Arabidopsis, as well as complementation experiments, showed that the divergent expression of leafy (LFY) and the petunia homolog aberrant leaf and flower (ALF) results from alterations in the upstream regulatory network rather than cis-regulatory changes. The divergent expression of unusual floral organs (UFO) from Arabidopsis, and the petunia homolog double top (DOT), however, is caused by the loss or gain of cis-regulatory promoter elements, which respond to trans-acting factors that are expressed in similar patterns in both species. Introduction of pUFO:UFO causes no obvious defects in Arabidopsis, but in petunia it causes the precocious and ectopic formation of flowers. This provides an example of how a change in a cis-regulatory region can account for a change in the plant body plan. © 2015. Published by The Company of Biologists Ltd.

Identification of putative cis-regulatory elements in Cryptosporidium parvum by de novo pattern finding

Directory of Open Access Journals (Sweden)

Kissinger Jessica C

2007-01-01

Full Text Available Abstract Background Cryptosporidium parvum is a unicellular eukaryote in the phylum Apicomplexa. It is an obligate intracellular parasite that causes diarrhea and is a significant AIDS-related pathogen. Cryptosporidium parvum is not amenable to long-term laboratory cultivation or classical molecular genetic analysis. The parasite exhibits a complex life cycle, a broad host range, and fundamental mechanisms of gene regulation remain unknown. We have used data from the recently sequenced genome of this organism to uncover clues about gene regulation in C. parvum. We have applied two pattern finding algorithms MEME and AlignACE to identify conserved, over-represented motifs in the 5' upstream regions of genes in C. parvum. To support our findings, we have established comparative real-time -PCR expression profiles for the groups of genes examined computationally. Results We find that groups of genes that share a function or belong to a common pathway share upstream motifs. Different motifs are conserved upstream of different groups of genes. Comparative real-time PCR studies show co-expression of genes within each group (in sub-sets during the life cycle of the parasite, suggesting co-regulation of these genes may be driven by the use of conserved upstream motifs. Conclusion This is one of the first attempts to characterize cis-regulatory elements in the absence of any previously characterized elements and with very limited expression data (seven genes only. Using de novo pattern finding algorithms, we have identified specific DNA motifs that are conserved upstream of genes belonging to the same metabolic pathway or gene family. We have demonstrated the co-expression of these genes (often in subsets using comparative real-time-PCR experiments thus establishing evidence for these conserved motifs as putative cis-regulatory elements. Given the lack of prior information concerning expression patterns and organization of promoters in C. parvum we

Regulatory inspection practices on fuel elements and core lay-out at NPPs

International Nuclear Information System (INIS)

Van Binnebeek, J.J.; Liuhto, Pekka; Badel, D.; Klonk, H.; Seidel, F.; Fichtinger, G.; Manzella, P.; Koizumi, Hiroyoshi; Delgado, Jose Luis; Gutierrez Ruiz, Luis Miguel; Bouvrie, E. des; Gil, J.; Forsberg, Staffan; Wand, H.; Warren, Tom; Gallo, R.

1998-01-01

The basic description of the reactor core of a nuclear power plant (NPP) is an important part of the Safety Analysis Report in all countries. Due to increased interest by regulatory authorities in the Member countries, in 1996 WGIP proposed looking at inspection aspects on fuel elements and core lay-out at nuclear power plants. The CNRA subsequently approved proceeding with this report. The report deals primarily with inspection practices and inspection requirements during nuclear power plant (NPP) operation with special emphasis on refuelling procedures. All license related topics, such as fuel and core design (mechanical, neutronic, thermal-hydraulic), as well as inspection philosophy and practices on fuel fabrication are included as appropriate serving as background information and may not be completely described. WGIP members describe their country's inspection programme according to the structure of a questionnaire (appendix 1). The individual contributions are contained in the appendix 2 and are compiled within the main chapters (1 through 3). Report Structure: 1. Licensing and Quality Assurance (QA) requirements for nuclear fuel; 2. Regulatory inspection programme during NPP operation and refuelling outages; 3. Procedures for inspection practices and inspection programme. Appendix: Questionnaire and Country specific contributions. Contributions are presented by Belgium, Finland, France, Germany, Hungary, Italy, Japan, Mexico, The Netherlands, Spain, Sweden, Switzerland, United Kingdom, USA

Positive- and negative-acting regulatory elements contribute to the tissue-specific expression of INNER NO OUTER, a YABBY-type transcription factor gene in Arabidopsis

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Simon Marissa K

2012-11-01

Full Text Available Abstract Background The INNER NO OUTER (INO gene, which encodes a YABBY-type transcription factor, specifies and promotes the growth of the outer integument of the ovule in Arabidopsis. INO expression is limited to the abaxial cell layer of the developing outer integument of the ovule and is regulated by multiple regions of the INO promoter, including POS9, a positive element that when present in quadruplicate can produce low-level expression in the normal INO pattern. Results Significant redundancy in activity between different regions of the INO promoter is demonstrated. For specific regulatory elements, multimerization or the addition of the cauliflower mosaic virus 35S general enhancer was able to activate expression of reporter gene constructs that were otherwise incapable of expression on their own. A new promoter element, POS6, is defined and is shown to include sufficient positive regulatory information to reproduce the endogenous pattern of expression in ovules, but other promoter regions are necessary to fully suppress expression outside of ovules. The full-length INO promoter, but not any of the INO promoter deletions tested, is able to act as an enhancer-blocking insulator to prevent the ectopic activation of expression by the 35S enhancer. Sequence conservation between the promoter regions of Arabidopsis thaliana, Brassica oleracea and Brassica rapa aligns closely with the functional definition of the POS6 and POS9 regions, and with a defined INO minimal promoter. The B. oleracea INO promoter is sufficient to promote a similar pattern and level of reporter gene expression in Arabidopsis to that observed for the Arabidopsis promoter. Conclusions At least two independent regions of the INO promoter contain sufficient regulatory information to direct the specific pattern but not the level of INO gene expression. These regulatory regions act in a partially redundant manner to promote the expression in a specific pattern in the ovule and

MicroRNAs as regulatory elements in psoriasis

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Liu Yuan

2016-01-01

Full Text Available Psoriasis is a chronic, autoimmune, and complex genetic disorder that affects 23% of the European population. The symptoms of Psoriatic skin are inflammation, raised and scaly lesions. microRNA, which is short, nonprotein-coding, regulatory RNAs, plays critical roles in psoriasis. microRNA participates in nearly all biological processes, such as cell differentiation, development and metabolism. Recent researches reveal that multitudinous novel microRNAs have been identified in skin. Some of these substantial novel microRNAs play as a class of posttranscriptional gene regulator in skin disease, such as psoriasis. In order to insight into microRNAs biological functions and verify microRNAs biomarker, we review diverse references about characterization, profiling and subtype of microRNAs. Here we will share our opinions about how and which microRNAs are as regulatory in psoriasis.

Polonium: 110th anniversary of its discovery

International Nuclear Information System (INIS)

Mould, R. F.

2008-01-01

It is appropriate that the 110 Th anniversary of the discovery of polonium by Marie and Pierre Curie is commemorated in a Polish journal since this element was named for Poland and was also the element discovered by the Curies before they discovered radium. Polonium's discovery and characteristics are described. Polonium has never been used in medicine, and was largely forgotten apart from a few minor industrial uses, and as a trigger for a nuclear weapon, until the murder in November 2006 in London using 210 Polonium, of the ex-KGB officer Alexander Litvinenko. Polonium had previously been linked, without any definite proof, with the deaths of a few scientists who had worked with the element, including Irene and Frederick Joliet-Curie. This review ends with possible evidence for such links. (authors)

Model-driven discovery of underground metabolic functions in Escherichia coli

DEFF Research Database (Denmark)

Guzmán, Gabriela I.; Utrilla, José; Nurk, Sergey

2015-01-01

-scale models, which have been widely used for predicting growth phenotypes in various environments or following a genetic perturbation; however, these predictions occasionally fail. Failed predictions of gene essentiality offer an opportunity for targeting biological discovery, suggesting the presence......E, and gltA and prpC. This study demonstrates how a targeted model-driven approach to discovery can systematically fill knowledge gaps, characterize underground metabolism, and elucidate regulatory mechanisms of adaptation in response to gene KO perturbations....

Safety culture as a matter of regulatory control and regulatory effectiveness

International Nuclear Information System (INIS)

Camargo, C.T.M.; Furieri, E.B.; Arrieta, L.A.I.; Almeida, C.U.C.

2002-01-01

More than 15 years have passed since the term 'safety culture' was introduced by the International Nuclear Safety Advisory Group (INSAG), and although the concept now is widely accepted, practical applications and characteristics have been disseminated mainly for nuclear power plant operating organizations. There is still a lack of international guidance on the use of safety culture as a regulatory matter and on the application of the concept within regulatory organizations. This work explores the meaning of safety culture in two different fields: as an element of safety management systems it shall be a matter of regulatory control; as a complementary tool for quality management it should be used to enhance regulatory effectiveness. Brazilian recent experience on regulating nuclear power reactors provide some examples on how the concept of safety culture may influence regulatory strategies and regulatory management. (author)

Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element.

Science.gov (United States)

Lim, Chun Shen; Brown, Chris M

2016-09-01

Many viruses contain RNA elements that modulate splicing and/or promote nuclear export of their RNAs. The RNAs of the major human pathogen, hepatitis B virus (HBV) contain a large (~600 bases) composite cis-acting 'post-transcriptional regulatory element' (PRE). This element promotes expression from these naturally intronless transcripts. Indeed, the related woodchuck hepadnavirus PRE (WPRE) is used to enhance expression in gene therapy and other expression vectors. These PRE are likely to act through a combination of mechanisms, including promotion of RNA nuclear export. Functional components of both the HBV PRE and WPRE are 2 conserved RNA cis-acting stem-loop (SL) structures, SLα and SLβ. They are within the coding regions of polymerase (P) gene, and both P and X genes, respectively. Based on previous studies using mutagenesis and/or nuclear magnetic resonance (NMR), here we propose 2 covariance models for SLα and SLβ. The model for the 30-nucleotide SLα contains a G-bulge and a CNGG(U) apical loop of which the first and the fourth loop residues form a CG pair and the fifth loop residue is bulged out, as observed in the NMR structure. The model for the 23-nucleotide SLβ contains a 7-base-pair stem and a 9-nucleotide loop. Comparison of the models with other RNA structural elements, as well as similarity searches of human transcriptome and viral genomes demonstrate that SLα and SLβ are specific to HBV transcripts. However, they are well conserved among the hepadnaviruses of non-human primates, the woodchuck and ground squirrel.

Electronic Data Discovery: Integrating Due Process into Cyber Forensic Practice

Directory of Open Access Journals (Sweden)

John W. Bagby

2006-03-01

Full Text Available Most organizations and government agencies regularly become engaged in litigation with suppliers, customers, clients, employees, competitors, shareholders, prosecutors or regulatory agencies that nearly assures the need to organize, retain, find and produce business records and correspondence, e-mails, accounting records or other data relevant to disputed issues. This article discusses some high visibility cases that constrain how metadata and content is routinely made available to opposing parties in civil litigation, to prosecutors in criminal prosecutions and to agency staff in regulatory enforcement litigation. Public policy, as implemented in the rules of evidence and pretrial discovery, restrict electronic data discovery (EDD as it becomes a predominant and potentially costly pre-trial activity pivotal to modern litigation. This article discusses these constraints while identifying opportunities for the interdisciplinary activities among litigators, forensic experts and information technology professionals.

FARE-CAFE: a database of functional and regulatory elements of cancer-associated fusion events.

Science.gov (United States)

Korla, Praveen Kumar; Cheng, Jack; Huang, Chien-Hung; Tsai, Jeffrey J P; Liu, Yu-Hsuan; Kurubanjerdjit, Nilubon; Hsieh, Wen-Tsong; Chen, Huey-Yi; Ng, Ka-Lok

2015-01-01

Chromosomal translocation (CT) is of enormous clinical interest because this disorder is associated with various major solid tumors and leukemia. A tumor-specific fusion gene event may occur when a translocation joins two separate genes. Currently, various CT databases provide information about fusion genes and their genomic elements. However, no database of the roles of fusion genes, in terms of essential functional and regulatory elements in oncogenesis, is available. FARE-CAFE is a unique combination of CTs, fusion proteins, protein domains, domain-domain interactions, protein-protein interactions, transcription factors and microRNAs, with subsequent experimental information, which cannot be found in any other CT database. Genomic DNA information including, for example, manually collected exact locations of the first and second break points, sequences and karyotypes of fusion genes are included. FARE-CAFE will substantially facilitate the cancer biologist's mission of elucidating the pathogenesis of various types of cancer. This database will ultimately help to develop 'novel' therapeutic approaches. Database URL: http://ppi.bioinfo.asia.edu.tw/FARE-CAFE. © The Author(s) 2015. Published by Oxford University Press.

Roundup litigation discovery documents: implications for public health and journal ethics.

Science.gov (United States)

Krimsky, Sheldon; Gillam, Carey

2018-06-08

This paper reviews the court-released discovery documents obtained from litigation against Monsanto over its herbicide Roundup and through Freedom of Information Act requests (requests to regulatory agencies and public universities in the United States). We sought evidence of corporate malfeasance and undisclosed conflicts of interest with respect to issues of scientific integrity. The findings include evidence of ghostwriting, interference in journal publication, and undue influence of a federal regulatory agency.

Logical knowledge representation of regulatory relations in biomedical pathways

DEFF Research Database (Denmark)

Zambach, Sine; Hansen, Jens Ulrik

2010-01-01

Knowledge on regulatory relations, in for example regulatory pathways in biology, is used widely in experiment design by biomedical researchers and in systems biology. The knowledge has typically either been represented through simple graphs or through very expressive differential equation...... simulations of smaller parts of a pathway. In this work we suggest a knowledge representation of the most basic relations in regulatory processes regulates, positively regulates and negatively regulates in logics based on a semantic analysis. We discuss the usage of these relations in biology and in articial...... intelligence for hypothesis development in drug discovery....

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

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James J. Lewis

2016-09-01

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

Assessment of regulatory effectiveness. Peer discussions on regulatory practices

International Nuclear Information System (INIS)

1999-09-01

This report arises from the seventh series of peer discussions on regulatory practices entitled 'Assessment of Regulatory Effectiveness'. The term 'regulatory effectiveness' covers the quality of the work and level of performance of a regulatory body. In this sense, regulatory effectiveness applies to regulatory body activities aimed at preventing safety degradation and ensuring that an acceptable level of safety is being maintained by the regulated operating organizations. In addition, regulatory effectiveness encompasses the promotion of safety improvements, the timely and cost effective performance of regulatory functions in a manner which ensures the confidence of the operating organizations, the general public and the government, and striving for continuous improvements to performance. Senior regulators from 22 Member States participated in two peer group discussions during March and May 1999. The discussions were focused on the elements of an effective regulatory body, possible indicators of regulatory effectiveness and its assessment. This report presents the outcome of these meetings and recommendations of good practices identified by senior regulators, which do not necessarily reflect those of the governments of the nominating Member States, the organizations they belong to, or the International Atomic Energy Agency. In order to protect people and the environment from hazards associated with nuclear facilities, the main objective of a nuclear regulatory body is to ensure that a high level of safety in the nuclear activities under its jurisdiction is achieved, maintained and within the control of operating organizations. Even if it is possible to directly judge objective safety levels at nuclear facilities, such safety levels would not provide an exclusive indicator of regulatory effectiveness. The way the regulatory body ensures the safety of workers and the public and the way it discharges its responsibilities also determine its effectiveness. Hence the

HBVRegDB: Annotation, comparison, detection and visualization of regulatory elements in hepatitis B virus sequences

Directory of Open Access Journals (Sweden)

Firth Andrew E

2007-12-01

Full Text Available Abstract Background The many Hepadnaviridae sequences available have widely varied functional annotation. The genomes are very compact (~3.2 kb but contain multiple layers of functional regulatory elements in addition to coding regions. Key regions are subject to purifying selection, as mutations in these regions will produce non-functional viruses. Results These genomic sequences have been organized into a structured database to facilitate research at the molecular level. HBVRegDB is a comparative genomic analysis tool with an integrated underlying sequence database. The database contains genomic sequence data from representative viruses. In addition to INSDC and RefSeq annotation, HBVRegDB also contains expert and systematically calculated annotations (e.g. promoters and comparative genome analysis results (e.g. blastn, tblastx. It also contains analyses based on curated HBV alignments. Information about conserved regions – including primary conservation (e.g. CDS-Plotcon and RNA secondary structure predictions (e.g. Alidot – is integrated into the database. A large amount of data is graphically presented using the GBrowse (Generic Genome Browser adapted for analysis of viral genomes. Flexible query access is provided based on any annotated genomic feature. Novel regulatory motifs can be found by analysing the annotated sequences. Conclusion HBVRegDB serves as a knowledge database and as a comparative genomic analysis tool for molecular biologists investigating HBV. It is publicly available and complementary to other viral and HBV focused datasets and tools http://hbvregdb.otago.ac.nz. The availability of multiple and highly annotated sequences of viral genomes in one database combined with comparative analysis tools facilitates detection of novel genomic elements.

Sterol regulatory element binding protein 2 overexpression is associated with reduced adipogenesis and ectopic fat accumulation in transgenic spontaneously hypertensive rats

Czech Academy of Sciences Publication Activity Database

Landa, Vladimír; Zídek, Václav; Mlejnek, Petr; Šimáková, Miroslava; Šilhavý, Jan; Trnovská, J.; Kazdová, L.; Pravenec, Michal

2014-01-01

Roč. 63, č. 5 (2014), s. 587-590 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LH12061 Institutional support: RVO:67985823 Keywords : sterol regulatory element binding protein 2 * transgenic * spontaneously hypertensive rat * lipid metabolism Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.293, year: 2014

Comparative analysis of regulatory elements between Escherichia coli and Klebsiella pneumoniae by genome-wide transcription start site profiling.

Directory of Open Access Journals (Sweden)

Donghyuk Kim

Full Text Available Genome-wide transcription start site (TSS profiles of the enterobacteria Escherichia coli and Klebsiella pneumoniae were experimentally determined through modified 5' RACE followed by deep sequencing of intact primary mRNA. This identified 3,746 and 3,143 TSSs for E. coli and K. pneumoniae, respectively. Experimentally determined TSSs were then used to define promoter regions and 5' UTRs upstream of coding genes. Comparative analysis of these regulatory elements revealed the use of multiple TSSs, identical sequence motifs of promoter and Shine-Dalgarno sequence, reflecting conserved gene expression apparatuses between the two species. In both species, over 70% of primary transcripts were expressed from operons having orthologous genes during exponential growth. However, expressed orthologous genes in E. coli and K. pneumoniae showed a strikingly different organization of upstream regulatory regions with only 20% identical promoters with TSSs in both species. Over 40% of promoters had TSSs identified in only one species, despite conserved promoter sequences existing in the other species. 662 conserved promoters having TSSs in both species resulted in the same number of comparable 5' UTR pairs, and that regulatory element was found to be the most variant region in sequence among promoter, 5' UTR, and ORF. In K. pneumoniae, 48 sRNAs were predicted and 36 of them were expressed during exponential growth. Among them, 34 orthologous sRNAs between two species were analyzed in depth, and the analysis showed that many sRNAs of K. pneumoniae, including pleiotropic sRNAs such as rprA, arcZ, and sgrS, may work in the same way as in E. coli. These results reveal a new dimension of comparative genomics such that a comparison of two genomes needs to be comprehensive over all levels of genome organization.

Assessment of Metabolome Annotation Quality: A Method for Evaluating the False Discovery Rate of Elemental Composition Searches

Science.gov (United States)

Matsuda, Fumio; Shinbo, Yoko; Oikawa, Akira; Hirai, Masami Yokota; Fiehn, Oliver; Kanaya, Shigehiko; Saito, Kazuki

2009-01-01

Background In metabolomics researches using mass spectrometry (MS), systematic searching of high-resolution mass data against compound databases is often the first step of metabolite annotation to determine elemental compositions possessing similar theoretical mass numbers. However, incorrect hits derived from errors in mass analyses will be included in the results of elemental composition searches. To assess the quality of peak annotation information, a novel methodology for false discovery rates (FDR) evaluation is presented in this study. Based on the FDR analyses, several aspects of an elemental composition search, including setting a threshold, estimating FDR, and the types of elemental composition databases most reliable for searching are discussed. Methodology/Principal Findings The FDR can be determined from one measured value (i.e., the hit rate for search queries) and four parameters determined by Monte Carlo simulation. The results indicate that relatively high FDR values (30–50%) were obtained when searching time-of-flight (TOF)/MS data using the KNApSAcK and KEGG databases. In addition, searches against large all-in-one databases (e.g., PubChem) always produced unacceptable results (FDR >70%). The estimated FDRs suggest that the quality of search results can be improved not only by performing more accurate mass analysis but also by modifying the properties of the compound database. A theoretical analysis indicates that FDR could be improved by using compound database with smaller but higher completeness entries. Conclusions/Significance High accuracy mass analysis, such as Fourier transform (FT)-MS, is needed for reliable annotation (FDR metabolome data. PMID:19847304

A 3.0-kb deletion including an erythroid cell-specific regulatory element in intron 1 of the ABO blood group gene in an individual with the Bm phenotype.

Science.gov (United States)

Sano, R; Kuboya, E; Nakajima, T; Takahashi, Y; Takahashi, K; Kubo, R; Kominato, Y; Takeshita, H; Yamao, H; Kishida, T; Isa, K; Ogasawara, K; Uchikawa, M

2015-04-01

We developed a sequence-specific primer PCR (SSP-PCR) for detection of a 5.8-kb deletion (B(m) 5.8) involving an erythroid cell-specific regulatory element in intron 1 of the ABO blood group gene. Using this SSP-PCR, we performed genetic analysis of 382 individuals with Bm or ABm. The 5.8-kb deletion was found in 380 individuals, and disruption of the GATA motif in the regulatory element was found in one individual. Furthermore, a novel 3.0-kb deletion involving the element (B(m) 3.0) was demonstrated in the remaining individual. Comparisons of single-nucleotide polymorphisms and microsatellites in intron 1 between B(m) 5.8 and B(m) 3.0 suggested that these deletions occurred independently. © 2014 International Society of Blood Transfusion.

Safety culture in regulatory expert organization : analysis result of survey for KINS employees

International Nuclear Information System (INIS)

Choi, G. S.; Choi, Y. S.

2003-01-01

Much has been discussed on safety culture of operating organizations, however, little has been done on that of regulatory organization. Current issues and activities related to nuclear safety culture at IAEA, OECD/NEA, etc. were investigated and relevant literatures were reviewed. Elements essential for safety culture of regulatory organization were proposed and survey questionnaire for employees of regulatory expert organization, KINS, was developed based on the elements proposed. The survey result was presented and its implications were discussed. Based on the result, elements of safety culture in regulatory organization were proposed. The result of this survey can be used in developing safety culture model of regulatory organization, measurement method and also promotion of safety culture in regulatory organization

Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Calcium Binding Properties and Allosteric Regulation of Downstream Regulatory Element Antagonist Modulator (DREAM).

Science.gov (United States)

Zhang, Jun; Li, Jing; Craig, Theodore A; Kumar, Rajiv; Gross, Michael L

2017-07-18

Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca 2+ -binding protein that also binds to a specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca 2+ but detaches from DRE under Ca 2+ stimulation, allowing gene expression. The Ca 2+ binding properties of DREAM and the consequences of the binding on protein structure are key to understanding the function of DREAM. Here we describe the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis to investigate the Ca 2+ binding properties and the subsequent conformational changes of full-length DREAM. We demonstrate that all EF-hands undergo large conformation changes upon calcium binding even though the EF-1 hand is not capable of binding to Ca 2+ . Moreover, EF-2 is a lower-affinity site compared to EF-3 and -4 hands. Comparison of HDX profiles between wild-type DREAM and two EF-1 mutated constructs illustrates that the conformational changes in the EF-1 hand are induced by long-range structural interactions. HDX analyses also reveal a conformational change in an N-terminal leucine-charged residue-rich domain (LCD) remote from Ca 2+ -binding EF-hands. This LCD domain is responsible for the direct interaction between DREAM and cAMP response element-binding protein (CREB) and regulates the recruitment of the co-activator, CREB-binding protein. These long-range interactions strongly suggest how conformational changes transmit the Ca 2+ signal to CREB-mediated gene transcription.

Discovery stories in the science classroom

Science.gov (United States)

Arya, Diana Jaleh

School science has been criticized for its lack of emphasis on the tentative, dynamic nature of science as a process of learning more about our world. This criticism is the guiding force for this present body of work, which focuses on the question: what are the educational benefits for middle school students of reading texts that highlight the process of science in the form of a discovery narrative? This dissertation traces my journey through a review of theoretical perspectives of narrative, an analysis of first-hand accounts of scientific discovery, the complex process of developing age-appropriate, cohesive and engaging science texts for middle school students, and a comparison study (N=209) that seeks to determine the unique benefits of the scientific discovery narrative for the interest in and retained understanding of conceptual information presented in middle school science texts. A total of 209 middle school participants in nine different classrooms from two different schools participated in the experimental study. Each subject read two science texts that differed in topic (the qualities of and uses for radioactive elements and the use of telescopic technology to see planets in space) and genre (the discovery narrative and the "conceptually known exposition" comparison text). The differences between the SDN and CKE versions for each topic were equivalent in all possible ways (initial introduction, overall conceptual accuracy, elements of human interest, coherence and readability level), save for the unique components of the discovery narrative (i.e., love for their work, acknowledgement of the known, identification of the unknown and the explorative or experimental process to discovery). Participants generally chose the discovery narrative version as the more interesting of the two texts. Additional findings from the experimental study suggest that science texts in the form of SDNs elicit greater long-term retention of key conceptual information, especially

A procedure to improve the information flow in the assessment of discoveries of oil and gas resources in the Brazilian context

Energy Technology Data Exchange (ETDEWEB)

Rosa, Henrique; Suslick, Saul B.; Sousa, Sergio H.G. de [Universidade Estadual de Campinas, SP (Brazil). Inst. of Geosciences; Castro, Jonas Q. [ANP - Brazilian National Petroleum Agency, Rio de Janeiro, RJ (Brazil)

2004-07-01

This paper is focused on the elaboration of a standardization model for the existing flow of information between the Petroleum National Agency (ANP) and the concessionaire companies in the event of the discovery of any potentially commercial hydrocarbon resources inside their concession areas. The method proposed by Rosa (2003) included the analysis of a small sample of Oil and Gas Discovery Assessment Plans (PADs), elaborated by companies that operate in exploratory blocks in Brazil, under the regulatory context introduced by the Petroleum Law (Law 9478, August, 6th, 1997). The analysis of these documents made it possible to identify and target the problems originated from the lack of standardization. The results obtained facilitated the development of a model that helps the creation process of Oil and Gas Discovery Assessment Plans. It turns out that the standardization procedures suggested provide considerable advantages while speeding up several technical and regulatory steps. A software called 'ePADs' was developed to consolidate the automation of the several steps in the model for the standardization of the Oil and Gas Discovery Assessment Plans. A preliminary version has been tested with several different types of discoveries indicating a good performance by complying with all regulatory aspects and operational requirements. (author)

Detection of Weakly Conserved Ancestral Mammalian RegulatorySequences by Primate Comparisons

Energy Technology Data Exchange (ETDEWEB)

Wang, Qian-fei; Prabhakar, Shyam; Chanan, Sumita; Cheng,Jan-Fang; Rubin, Edward M.; Boffelli, Dario

2006-06-01

Genomic comparisons between human and distant, non-primatemammals are commonly used to identify cis-regulatory elements based onconstrained sequence evolution. However, these methods fail to detectcryptic functional elements, which are too weakly conserved among mammalsto distinguish from nonfunctional DNA. To address this problem, weexplored the potential of deep intra-primate sequence comparisons. Wesequenced the orthologs of 558 kb of human genomic sequence, coveringmultiple loci involved in cholesterol homeostasis, in 6 nonhumanprimates. Our analysis identified 6 noncoding DNA elements displayingsignificant conservation among primates, but undetectable in more distantcomparisons. In vitro and in vivo tests revealed that at least three ofthese 6 elements have regulatory function. Notably, the mouse orthologsof these three functional human sequences had regulatory activity despitetheir lack of significant sequence conservation, indicating that they arecryptic ancestral cis-regulatory elements. These regulatory elementscould still be detected in a smaller set of three primate speciesincluding human, rhesus and marmoset. Since the human and rhesus genomesequences are already available, and the marmoset genome is activelybeing sequenced, the primate-specific conservation analysis describedhere can be applied in the near future on a whole-genome scale, tocomplement the annotation provided by more distant speciescomparisons.

Management of the Regulatory Authority Information

International Nuclear Information System (INIS)

Suman, H.

2003-01-01

Safe Management of the Regulatory Authority Information is one of the essential elements to ensure the effectiveness of the regulatory program as a whole. This paper briefly describes the information management basis in RNRO, which is in charge of the regulatory authority tasks in Syria. SINA-2, a computational tool prepared in RNRO for managing the information related to the inventory of radiation sources and users, is also introduced

Transuranium elements: Past, present, and future

International Nuclear Information System (INIS)

Seaborg, G.T.

1995-01-01

In this illustrative Account the authors shall concentrate on four of these elements, chosen for their current interest or pivotal role. The story of plutonium is one of the most dramatic in the history of science, and today, plutonium is at the focus of an extraordinary dilemma. Mendelevium (element 101) has played a pivotal role in blazing the trail for the discovery of the heaviest elements on the basis of open-quotes one atom at a timeclose quotes production. Seaborgium (element 106) was recently named in my honor by the discoverers and may be the last element, at least for some time, for which it will be possible to determine many chemical properties. And element 110 represents recent evidence, after a lapse of 10 years, for the discovery of a chemical element. Recent (1994) recommendations of the IUPAC Commission on the Nomenclature of Inorganic Chemistry for the renaming of elements 104-108 have met with widespread rejection. The author is using the names proposed by the acknowledged discoverers (elements 106-109) or, in the case of the disputed elements 104 and 105, the most logical names. 21 refs., 5 figs

The Transuranium Elements - Present Status: Nobel Lecture

Science.gov (United States)

Seaborg, G. T.

1951-12-12

The discovery of the transuranium elements and the work done on them up to the present time are reviewed. The properties of these elements, their relationship to other elements, their place in the periodic table, and the possibility of production and identification of other transuranium elements are discussed briefly.

Regulatory regime and its influence in the nuclear safety

International Nuclear Information System (INIS)

Laaksonen, J.

1999-01-01

Main elements of nuclear regulatory regime in general is presented. These elements are: national rules and safety regulations, system of nuclear facility licensing, activities of regulatory body. Regulatory body is needed to specify the national safety regulations, review and assess the safety documentation presented to support license application, make inspections to verify fulfilment of safety regulations and license conditions, monitor the quality of work processes of user organization, and to assess whether these processes provide a high safety level, promote high safety culture, promote maintenance and development of national infrastructure relevant to nuclear safety, etc

History, Discovery, and Classification of lncRNAs.

Science.gov (United States)

Jarroux, Julien; Morillon, Antonin; Pinskaya, Marina

2017-01-01

The RNA World Hypothesis suggests that prebiotic life revolved around RNA instead of DNA and proteins. Although modern cells have changed significantly in 4 billion years, RNA has maintained its central role in cell biology. Since the discovery of DNA at the end of the nineteenth century, RNA has been extensively studied. Many discoveries such as housekeeping RNAs (rRNA, tRNA, etc.) supported the messenger RNA model that is the pillar of the central dogma of molecular biology, which was first devised in the late 1950s. Thirty years later, the first regulatory non-coding RNAs (ncRNAs) were initially identified in bacteria and then in most eukaryotic organisms. A few long ncRNAs (lncRNAs) such as H19 and Xist were characterized in the pre-genomic era but remained exceptions until the early 2000s. Indeed, when the sequence of the human genome was published in 2001, studies showed that only about 1.2% encodes proteins, the rest being deemed "non-coding." It was later shown that the genome is pervasively transcribed into many ncRNAs, but their functionality remained controversial. Since then, regulatory lncRNAs have been characterized in many species and were shown to be involved in processes such as development and pathologies, revealing a new layer of regulation in eukaryotic cells. This newly found focus on lncRNAs, together with the advent of high-throughput sequencing, was accompanied by the rapid discovery of many novel transcripts which were further characterized and classified according to specific transcript traits.In this review, we will discuss the many discoveries that led to the study of lncRNAs, from Friedrich Miescher's "nuclein" in 1869 to the elucidation of the human genome and transcriptome in the early 2000s. We will then focus on the biological relevance during lncRNA evolution and describe their basic features as genes and transcripts. Finally, we will present a non-exhaustive catalogue of lncRNA classes, thus illustrating the vast complexity of

Reexamining the P-Element Invasion of Drosophila melanogaster Through the Lens of piRNA Silencing

Science.gov (United States)

Kelleher, Erin S.

2016-01-01

Transposable elements (TEs) are both important drivers of genome evolution and genetic parasites with potentially dramatic consequences for host fitness. The recent explosion of research on regulatory RNAs reveals that small RNA-mediated silencing is a conserved genetic mechanism through which hosts repress TE activity. The invasion of the Drosophila melanogaster genome by P elements, which happened on a historical timescale, represents an incomparable opportunity to understand how small RNA-mediated silencing of TEs evolves. Repression of P-element transposition emerged almost concurrently with its invasion. Recent studies suggest that this repression is implemented in part, and perhaps predominantly, by the Piwi-interacting RNA (piRNA) pathway, a small RNA-mediated silencing pathway that regulates TE activity in many metazoan germlines. In this review, I consider the P-element invasion from both a molecular and evolutionary genetic perspective, reconciling classic studies of P-element regulation with the new mechanistic framework provided by the piRNA pathway. I further explore the utility of the P-element invasion as an exemplar of the evolution of piRNA-mediated silencing. In light of the highly-conserved role for piRNAs in regulating TEs, discoveries from this system have taxonomically broad implications for the evolution of repression. PMID:27516614

Structural and functional analysis of mouse Msx1 gene promoter: sequence conservation with human MSX1 promoter points at potential regulatory elements.

Science.gov (United States)

Gonzalez, S M; Ferland, L H; Robert, B; Abdelhay, E

1998-06-01

Vertebrate Msx genes are related to one of the most divergent homeobox genes of Drosophila, the muscle segment homeobox (msh) gene, and are expressed in a well-defined pattern at sites of tissue interactions. This pattern of expression is conserved in vertebrates as diverse as quail, zebrafish, and mouse in a range of sites including neural crest, appendages, and craniofacial structures. In the present work, we performed structural and functional analyses in order to identify potential cis-acting elements that may be regulating Msx1 gene expression. To this end, a 4.9-kb segment of the 5'-flanking region was sequenced and analyzed for transcription-factor binding sites. Four regions showing a high concentration of these sites were identified. Transfection assays with fragments of regulatory sequences driving the expression of the bacterial lacZ reporter gene showed that a region of 4 kb upstream of the transcription start site contains positive and negative elements responsible for controlling gene expression. Interestingly, a fragment of 130 bp seems to contain the minimal elements necessary for gene expression, as its removal completely abolishes gene expression in cultured cells. These results are reinforced by comparison of this region with the human Msx1 gene promoter, which shows extensive conservation, including many consensus binding sites, suggesting a regulatory role for them.

Basic elements of a regulatory programme for radiation safety

International Nuclear Information System (INIS)

Bilbao, A.A.

2000-01-01

In this lecture the objectives of IAEA TECDOC 1067: Organization and implementation of a national regulatory infrastructure governing protection against ionizing radiation and the safety of sources (1999) is presented

Recent research on the heavy transuranium elements

International Nuclear Information System (INIS)

Seaborg, G.T.

1988-09-01

This review is devoted to recent research (performed in the 1980s) on the heavy members of the group, defined as the transcurium elements (with a few references to related work on lighter elements). It covers the discovery of the three heaviest elements, the discovery of new isotopes, investigation of interesting decay properties of some previously known isotopes, investigations of some heavy ion reaction mechanisms in this region, and recent investigations of nuclear and chemical properties. It is not exhaustive in its coverage, is necessarily succinct, and inevitably places emphasis on those aspects with which the author is most familiar. 92 refs., 3 figs

Secure neighborhood discovery: A fundamental element for mobile ad hoc networking

DEFF Research Database (Denmark)

Papadimitratos, P.; Poturalski, M.; Schaller, P.

2008-01-01

Pervasive computing systems will likely be deployed in the near future, with the proliferation of wireless devices and the emergence of ad hoc networking as key enablers. Coping with mobility and the volatility of wireless communications in such systems is critical. Neighborhood discovery (ND......) - the discovery of devices directly reachable for communication or in physical proximity - becomes a fundamental requirement and building block for various applications. However, the very nature of wireless mobile networks makes it easy to abuse ND and thereby compromise the overlying protocols and applications....... Thus, providing methods to mitigate this vulnerability and secure ND is crucial. In this article we focus on this problem and provide definitions of neighborhood types and ND protocol properties, as well as a broad classification of attacks. Our ND literature survey reveals that securing ND is indeed...

Proceedings of transuranium elements

International Nuclear Information System (INIS)

Anon.

1992-01-01

The identification of the first synthetic elements was established by chemical evidence. Conclusive proof of the synthesis of the first artificial element, technetium, was published in 1937 by Perrier and Segre. An essential aspect of their achievement was the prediction of the chemical properties of element 43, which had been missing from the periodic table and which was expected to have properties similar to those of manganese and rhenium. The discovery of other artificial elements, astatine and francium, was facilitated in 1939-1940 by the prediction of their chemical properties. A little more than 50 years ago, in the spring of 1940, Edwin McMillan and Philip Abelson synthesized element 93, neptunium, and confirmed its uniqueness by chemical means. On August 30, 1940, Glenn Seaborg, Arthur Wahl, and the late Joseph Kennedy began their neutron irradiations of uranium nitrate hexahydrate. A few months later they synthesized element 94, later named plutonium, by observing the alpha particles emitted from uranium oxide targets that had been bombarded with deuterons. Shortly thereafter they proved that is was the second transuranium element by establishing its unique oxidation-reduction behavior. The symposium honored the scientists and engineers whose vision and dedication led to the discovery of the transuranium elements and to the understanding of the influence of 5f electrons on their electronic structure and bonding. This volume represents a record of papers presented at the symposium

iFORM: Incorporating Find Occurrence of Regulatory Motifs.

Science.gov (United States)

Ren, Chao; Chen, Hebing; Yang, Bite; Liu, Feng; Ouyang, Zhangyi; Bo, Xiaochen; Shu, Wenjie

2016-01-01

Accurately identifying the binding sites of transcription factors (TFs) is crucial to understanding the mechanisms of transcriptional regulation and human disease. We present incorporating Find Occurrence of Regulatory Motifs (iFORM), an easy-to-use and efficient tool for scanning DNA sequences with TF motifs described as position weight matrices (PWMs). Both performance assessment with a receiver operating characteristic (ROC) curve and a correlation-based approach demonstrated that iFORM achieves higher accuracy and sensitivity by integrating five classical motif discovery programs using Fisher's combined probability test. We have used iFORM to provide accurate results on a variety of data in the ENCODE Project and the NIH Roadmap Epigenomics Project, and the tool has demonstrated its utility in further elucidating individual roles of functional elements. Both the source and binary codes for iFORM can be freely accessed at https://github.com/wenjiegroup/iFORM. The identified TF binding sites across human cell and tissue types using iFORM have been deposited in the Gene Expression Omnibus under the accession ID GSE53962.

Hubble 15 years of discovery

CERN Document Server

Lindberg Christensen, Lars; Kornmesser, M

2006-01-01

Hubble: 15 Years of Discovery was a key element of the European Space Agency's 15th anniversary celebration activities for the 1990 launch of the NASA/ESA Hubble Space Telescope. As an observatory in space, Hubble is one of the most successful scientific projects of all time, both in terms of scientific output and its immediate public appeal.

Regulatory control of fuel design and manufacturing

International Nuclear Information System (INIS)

1994-01-01

The regulatory control of the design and manufacturing of the nuclear fuel and of the control rods aims to ensure conformance to set requirements during normal operating conditions, anticipated operational transients and postulated accident conditions. The regulatory control of design, manufacturing, receiving inspections and the start of operation of the nuclear fuel are specified in the guide. The regulatory control procedure also applies to the control rods and the shield elements

Environmental regulatory reform in Poland: lessons for industrializing economies

Energy Technology Data Exchange (ETDEWEB)

Brown, H.S.; Angel, D. [Clark University, Worcester, MA (USA). George Perkins Marsh Institute

2000-09-01

This paper examines the environmental regulatory reform in Poland during the 1990s and uses the findings to consider the extent to which elements of successful regulatory systems are transferable across national boundaries. Drawing on five case studies of privatized firms, a mailed questionnaire, and policy and institutional analysis, it investigates how Poland developed an effective system for managing industrial pollution while also achieving considerable socioeconomic progress. The fundamental legitimacy of the regulators and regulatory process, the availability of information about firms and regulatory intents, and the capacity for case-specific decision-making are among the key explanatory factors. The study also shows how in Poland a good 'fit' between regulatory institutions and policies on one hand and their social context on the other hand has evolved, and how it contributes to the effectiveness of the regulatory system. Industrializing economies can indeed simultaneously pursue environmental protection and socioeconomic welfare, but elements of a proven regulatory system cannot be automatically adopted among countries and cultures. Learning from each other's experience must be sensitive to the cultural and institutional context of each regulatory system. 42 refs., 3 figs., 1 tab.

Elements beyond uranium

International Nuclear Information System (INIS)

Seaborg, G.T.; Loveland, W.D.

1990-01-01

This book is the 12th volume in a series on transuranium elements. Varied techniques for production of these elements, the methods used in the identification, and the exquisitely refined microchemical techniques required to deal wth samples sometimes involving only a few atoms are described in detail. The chapter on synthesis of the new elements is liberally laced with reminiscences of the proud progenitors as well as the criteria for the discovery of a new chemical element. The authors lament that the superheavy elements (elements in the region of atomic number 114) still elude detection even though their creation should be possible, and some, at least, should survive long enough to be detected. One chapter in the book is devoted to practical applictions of uranium, and the transuranic elements

Regulatory guidance document

International Nuclear Information System (INIS)

1994-05-01

The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM's evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7

Microevolution of cis-regulatory elements: an example from the pair-rule segmentation gene fushi tarazu in the Drosophila melanogaster subgroup.

Directory of Open Access Journals (Sweden)

Mohammed Bakkali

Full Text Available The importance of non-coding DNAs that control transcription is ever noticeable, but the characterization and analysis of the evolution of such DNAs presents challenges not found in the analysis of coding sequences. In this study of the cis-regulatory elements of the pair rule segmentation gene fushi tarazu (ftz I report the DNA sequences of ftz's zebra element (promoter and a region containing the proximal enhancer from a total of 45 fly lines belonging to several populations of the species Drosophila melanogaster, D. simulans, D. sechellia, D. mauritiana, D. yakuba, D. teissieri, D. orena and D. erecta. Both elements evolve at slower rate than ftz synonymous sites, thus reflecting their functional importance. The promoter evolves more slowly than the average for ftz's coding sequence while, on average, the enhancer evolves more rapidly, suggesting more functional constraint and effective purifying selection on the former. Comparative analysis of the number and nature of base substitutions failed to detect significant evidence for positive/adaptive selection in transcription-factor-binding sites. These seem to evolve at similar rates to regions not known to bind transcription factors. Although this result reflects the evolutionary flexibility of the transcription factor binding sites, it also suggests a complex and still not completely understood nature of even the characterized cis-regulatory sequences. The latter seem to contain more functional parts than those currently identified, some of which probably transcription factor binding. This study illustrates ways in which functional assignments of sequences within cis-acting sequences can be used in the search for adaptive evolution, but also highlights difficulties in how such functional assignment and analysis can be carried out.

CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome.

Science.gov (United States)

Zhang, Zijun; Xing, Yi

2017-09-19

Crosslinking or RNA immunoprecipitation followed by sequencing (CLIP-seq or RIP-seq) allows transcriptome-wide discovery of RNA regulatory sites. As CLIP-seq/RIP-seq reads are short, existing computational tools focus on uniquely mapped reads, while reads mapped to multiple loci are discarded. We present CLAM (CLIP-seq Analysis of Multi-mapped reads). CLAM uses an expectation-maximization algorithm to assign multi-mapped reads and calls peaks combining uniquely and multi-mapped reads. To demonstrate the utility of CLAM, we applied it to a wide range of public CLIP-seq/RIP-seq datasets involving numerous splicing factors, microRNAs and m6A RNA methylation. CLAM recovered a large number of novel RNA regulatory sites inaccessible by uniquely mapped reads. The functional significance of these sites was demonstrated by consensus motif patterns and association with alternative splicing (splicing factors), transcript abundance (AGO2) and mRNA half-life (m6A). CLAM provides a useful tool to discover novel protein-RNA interactions and RNA modification sites from CLIP-seq and RIP-seq data, and reveals the significant contribution of repetitive elements to the RNA regulatory landscape of the human transcriptome. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

HISTORY OF THE ORIGIN OF THE CHEMICAL ELEMENTS AND THEIR DISCOVERIES.

Energy Technology Data Exchange (ETDEWEB)

HOLDEN,N.E.

2001-06-29

What do we mean by a chemical element? A chemical element is matter, all of whose atoms are alike in having the same positive charge on the nucleus and the same number of extra-nuclear electrons. As we shall see in the following elemental review, the origin of the chemical elements show a wide diversity with some of these elements having an origin in antiquity, other elements having been discovered within the past few hundred years and still others have been synthesized within the past fifty years via nuclear reactions on heavy elements since these other elements are unstable and radioactive and do not exist in nature.

Improved accuracy of supervised CRM discovery with interpolated Markov models and cross-species comparison.

Science.gov (United States)

Kazemian, Majid; Zhu, Qiyun; Halfon, Marc S; Sinha, Saurabh

2011-12-01

Despite recent advances in experimental approaches for identifying transcriptional cis-regulatory modules (CRMs, 'enhancers'), direct empirical discovery of CRMs for all genes in all cell types and environmental conditions is likely to remain an elusive goal. Effective methods for computational CRM discovery are thus a critically needed complement to empirical approaches. However, existing computational methods that search for clusters of putative binding sites are ineffective if the relevant TFs and/or their binding specificities are unknown. Here, we provide a significantly improved method for 'motif-blind' CRM discovery that does not depend on knowledge or accurate prediction of TF-binding motifs and is effective when limited knowledge of functional CRMs is available to 'supervise' the search. We propose a new statistical method, based on 'Interpolated Markov Models', for motif-blind, genome-wide CRM discovery. It captures the statistical profile of variable length words in known CRMs of a regulatory network and finds candidate CRMs that match this profile. The method also uses orthologs of the known CRMs from closely related genomes. We perform in silico evaluation of predicted CRMs by assessing whether their neighboring genes are enriched for the expected expression patterns. This assessment uses a novel statistical test that extends the widely used Hypergeometric test of gene set enrichment to account for variability in intergenic lengths. We find that the new CRM prediction method is superior to existing methods. Finally, we experimentally validate 12 new CRM predictions by examining their regulatory activity in vivo in Drosophila; 10 of the tested CRMs were found to be functional, while 6 of the top 7 predictions showed the expected activity patterns. We make our program available as downloadable source code, and as a plugin for a genome browser installed on our servers. © The Author(s) 2011. Published by Oxford University Press.

Croatian energy regulatory council - independent Croatian regulatory body

International Nuclear Information System (INIS)

Klepo, M.

2002-01-01

By means of approving five energy laws, the Republic of Croatia established an appropriate legislative framework for energy sector regulation. A series of sub-law acts is presently being elaborated as well as some additional documents in order to bring about transparent and non-discriminatory provisions for the establishment of electric energy, gas, oil/oil derivatives and thermal energy markets, i.e. for the introduction and management of market activities and public services. A considerable share of these activities relates to the definition of transparent regulatory mechanisms that would guarantee the implementation of regulation rules based on the law, and be carried out by the independent regulatory body - Croatian Energy Regulatory Council. The Council's rights and obligations include firm executive functions, which present obligations to every energy entity. A dissatisfied party may set in motion a settlement of dispute, if it maintains that the decisions are not based on the law or reveal a flaw in the procedure. Therefore, it is the Council's priority to always make careful and law-abiding decisions. This paper gives insight into the regulatory framework elements based on the laws including the Council's organisational structure and non-profit entities that will prepare act proposals for the Council and perform other professional activities. (author)

H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element.

OpenAIRE

Hamada, K; Gleason, S L; Levi, B Z; Hirschfeld, S; Appella, E; Ozato, K

1989-01-01

Transcription of major histocompatibility complex (MHC) class I genes is regulated by the conserved MHC class I regulatory element (CRE). The CRE has two factor-binding sites, region I and region II, both of which elicit enhancer function. By screening a mouse lambda gt 11 library with the CRE as a probe, we isolated a cDNA clone that encodes a protein capable of binding to region II of the CRE. This protein, H-2RIIBP (H-2 region II binding protein), bound to the native region II sequence, bu...

Nuclear regulatory decision making

International Nuclear Information System (INIS)

Wieland, Patricia; Almeida, Ivan Pedro Salati de

2011-01-01

The scientific considerations upon which the nuclear regulations are based provide objective criteria for decisions on nuclear safety matters. However, the decisions that a regulatory agency takes go far beyond granting or not an operating license based on assessment of compliance. It may involve decisions about hiring experts or research, appeals, responses to other government agencies, international agreements, etc.. In all cases, top management of the regulatory agency should hear and decide the best balance between the benefits of regulatory action and undue risks and other associated impacts that may arise, including issues of credibility and reputation. The establishment of a decision framework based on well established principles and criteria ensures performance stability and consistency, preventing individual subjectivity. This article analyzes the challenges to the decision-making by regulatory agencies to ensure coherence and consistency in decisions, even in situations where there is uncertainty, lack of reliable information and even divergence of opinions among experts. The article explores the basic elements for a framework for regulatory decision-making. (author)

Nuclear regulatory decision making

International Nuclear Information System (INIS)

2005-01-01

The fundamental objective of all nuclear safety regulatory bodies is to ensure that nuclear utilities operate their plants at all times in an acceptably safe manner. In meeting this objective, the regulatory body should strive to ensure that its regulatory decisions are technically sound, consistent from case to case, and timely. In addition, the regulator must be aware that its decisions and the circumstances surrounding those decisions can affect how its stakeholders, such as government policy makers, the industry it regulates, and the public, view it as an effective and credible regulator. In order to maintain the confidence of those stakeholders, the regulator should make sure that its decisions are transparent, have a clear basis in law and regulations, and are seen by impartial observers to be fair to all parties. Based on the work of a Nuclear Energy Agency (NEA) expert group, this report discusses some of the basic principles and criteria that a regulatory body should consider in making decisions and describes the elements of an integrated framework for regulatory decision making. (author)

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

Energy Technology Data Exchange (ETDEWEB)

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

2005-06-13

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

In silico analysis, mapping of regulatory elements and corresponding dna-protein interaction in polyphenol oxidase gene promoter from different rice varieties

International Nuclear Information System (INIS)

Mahmood, T.; Rehman, M.; Aziz, E.

2015-01-01

Polyphenol oxidase (PPO) is an important enzyme that has positive impact regarding plant resistance against different biotic and abiotic stresses. In the present study PPO promoter from six different rice varieties was amplified and then analyzed for cis- and trans-acting elements. The study revealed a total of 79 different cis-acting regulatory elements including 11 elements restricted to only one or other variety. Among six varieties Pakhal-Basmati had highest number (5) of these elements, whereas C-622 and Rachna-Basmati have no such sequences. Rachna-Basmati, IR-36-Basmati and Kashmir- Basmati had 1, 2 and 3 unique elements, respectively. Different elementsrelated to pathogen, salt and water stresses were found, which may be helpful in controlling PPO activity according to changing environment. Moreover, HADDOCK was used to understand molecular mechanism of PPO regulation and it was found that DNA-protein interactions are stabilized by many potential hydrogen bonds. Adenine and arginine were the most reactive residues in DNA and proteins respectively.Structural comparison of different protein-DNA complexes show that even a highly conserved transcriptional factor can adopt different conformations when they contact a different DNA binding sequence, however their stable interactions depend on the number of hydrogen bonds formed and distance. (author)

Transplutonium elements - a literature survey

International Nuclear Information System (INIS)

Sivaramakrishnan, C.K.; Jadhav, A.V.

1974-01-01

The report surveys reported work on the discovery of transplutonium elements and their production through various methods like bombardment of heavy elements with charged ions, successive neutron captures on heavy elements in reactors and multiple neutron captures by heavy elements during nuclear explosions. Estimated yields of transplutonium elements in special targets irradiated in reactors, and also as byproducts from spent power reactor fuels are quoted. Various chemical procedures adopted for recovery of these elements from irradiated target and also from power reactor fuel reprocessing streams are described. A brief survey of shielded facilities available at various centres for transplutonium programmes is also included. Major uses of some of these heavy elements are described. (author)

Regulatory Hybridization in the Transnational Sphere

DEFF Research Database (Denmark)

Kjær, Poul Fritz; Jurcys, Paulius; Yrakami, Ren

Hybridization has become a defining feature of regulatory frameworks. The combined forces of globalization and privatization together with increased reliance on self-regulation have resulted in the emergence of a multitude of regulatory arrangements which combine elements from several legal orders....... This book offers a conceptual framework as well as numerous empirical explorations capable of increasing our understanding of regulatory hybridization. A number of central dichotomies are deconstructed: national vs. transnational law; international vs. transnational law; convergence vs. divergence; … read...... moresoft law vs. hard law; territorial vs. non-territorial, ‘top-down’ vs. ‘bottom-up’ globalization and national vs. global just as the implications of regulatory hybridization for the question of choice of court and conflict of laws are analyzed....

Identification and characterization of a silencer regulatory element in the 3'-flanking region of the murine CD46 gene.

Science.gov (United States)

Nomura, M; Tsujimura, A; Begum, N A; Matsumoto, M; Wabiko, H; Toyoshima, K; Seya, T

2000-01-01

The murine membrane cofactor protein (CD46) gene is expressed exclusively in testis, in contrast to human CD46, which is expressed ubiquitously. To elucidate the mechanism of differential CD46 gene expression among species, we cloned entire murine CD46 genomic DNA and possible regulatory regions were placed in the flanking region of the luciferase reporter gene. The reporter gene assay revealed a silencing activity not in the promoter, but in the 3'-flanking region of the gene and the silencer-like element was identified within a 0.2-kb region between 0.6 and 0.8 kb downstream of the stop codon. This silencer-like element was highly similar to that of the pig MHC class-I gene. The introduction of a mutation into this putative silencer element of murine CD46 resulted in an abrogation of the silencing effect. Electrophoretic mobility-shift assay indicated the presence of the binding molecule(s) for this silencer sequence in murine cell lines and tissues. A size difference of the protein-silencer-element complex was observed depending upon the solubilizers used for preparation of the nuclear extracts. A mutated silencer sequence failed to interact with the binding molecules. The level of the binding factor was lower in the testicular germ cells compared with other organs. Thus the silencer element and its binding factor may play a role in transcriptional regulation of murine CD46 gene expression. These results imply that the effects of the CD46 silencer element encompass the innate immune and reproductive systems, and in mice may determine the testicular germ-cell-dominant expression of CD46. PMID:11023821

Mission Risk Reduction Regulatory Change Management

Science.gov (United States)

Scroggins, Sharon

2007-01-01

NASA Headquarters Environmental Management Division supports NASA's mission to pioneer the future in space exploration, scientific discovery, and aeronautics research by integrating environmental considerations into programs and projects early-on, thereby proactively reducing NASA's exposure to institutional, programmatic and operational risk. As part of this effort, NASA established the Principal Center for Regulatory Risk Analysis and Communication (RRAC PC) as a resource for detecting, analyzing, and communicating environmental regulatory risks to the NASA stakeholder community. The RRAC PC focuses on detecting emerging environmental regulations and other operational change drivers that may pose risks to NASA programs and facilities, and effectively communicating the potential risks. For example, regulatory change may restrict how and where certain activities or operations may be conducted. Regulatory change can also directly affect the ability to use certain materials by mandating a production phase-out or restricting usage applications of certain materials. Regulatory change can result in significant adverse impacts to NASA programs and facilities due to NASA's stringent performance requirements for materials and components related to human-rated space vehicles. Even if a regulation does not directly affect NASA operations, U.S. and international regulations can pose program risks indirectly through requirements levied on manufacturers and vendors of components and materials. For example, manufacturers can change their formulations to comply with new regulatory requirements. Such changes can require time-consuming and costly requalification certification for use in human spaceflight programs. The RRAC PC has implemented a system for proactively managing regulatory change to minimize potential adverse impacts to NASA programs and facilities. This presentation highlights the process utilized by the RRACPC to communicate regulatory change and the associated

Concept relation discovery and innovation enabling technology (CORDIET)

NARCIS (Netherlands)

Poelmans, J.; Elzinga, P.; Neznanov, A.; Viaene, S.; Kuznetsov, S.O.; Ignatov, D.; Dedene, G.

2011-01-01

Concept Relation Discovery and Innovation Enabling Technology (CORDIET), is a toolbox for gaining new knowledge from unstructured text data. At the core of CORDIET is the C-K theory which captures the essential elements of innovation. The tool uses Formal Concept Analysis (FCA), Emergent Self

Repetitive Elements in Mycoplasma hyopneumoniae Transcriptional Regulation.

Directory of Open Access Journals (Sweden)

Amanda Malvessi Cattani

Full Text Available Transcriptional regulation, a multiple-step process, is still poorly understood in the important pig pathogen Mycoplasma hyopneumoniae. Basic motifs like promoters and terminators have already been described, but no other cis-regulatory elements have been found. DNA repeat sequences have been shown to be an interesting potential source of cis-regulatory elements. In this work, a genome-wide search for tandem and palindromic repetitive elements was performed in the intergenic regions of all coding sequences from M. hyopneumoniae strain 7448. Computational analysis demonstrated the presence of 144 tandem repeats and 1,171 palindromic elements. The DNA repeat sequences were distributed within the 5' upstream regions of 86% of transcriptional units of M. hyopneumoniae strain 7448. Comparative analysis between distinct repetitive sequences found in related mycoplasma genomes demonstrated different percentages of conservation among pathogenic and nonpathogenic strains. qPCR assays revealed differential expression among genes showing variable numbers of repetitive elements. In addition, repeats found in 206 genes already described to be differentially regulated under different culture conditions of M. hyopneumoniae strain 232 showed almost 80% conservation in relation to M. hyopneumoniae strain 7448 repeats. Altogether, these findings suggest a potential regulatory role of tandem and palindromic DNA repeats in the M. hyopneumoniae transcriptional profile.

Repetitive Elements in Mycoplasma hyopneumoniae Transcriptional Regulation.

Science.gov (United States)

Cattani, Amanda Malvessi; Siqueira, Franciele Maboni; Guedes, Rafael Lucas Muniz; Schrank, Irene Silveira

2016-01-01

Transcriptional regulation, a multiple-step process, is still poorly understood in the important pig pathogen Mycoplasma hyopneumoniae. Basic motifs like promoters and terminators have already been described, but no other cis-regulatory elements have been found. DNA repeat sequences have been shown to be an interesting potential source of cis-regulatory elements. In this work, a genome-wide search for tandem and palindromic repetitive elements was performed in the intergenic regions of all coding sequences from M. hyopneumoniae strain 7448. Computational analysis demonstrated the presence of 144 tandem repeats and 1,171 palindromic elements. The DNA repeat sequences were distributed within the 5' upstream regions of 86% of transcriptional units of M. hyopneumoniae strain 7448. Comparative analysis between distinct repetitive sequences found in related mycoplasma genomes demonstrated different percentages of conservation among pathogenic and nonpathogenic strains. qPCR assays revealed differential expression among genes showing variable numbers of repetitive elements. In addition, repeats found in 206 genes already described to be differentially regulated under different culture conditions of M. hyopneumoniae strain 232 showed almost 80% conservation in relation to M. hyopneumoniae strain 7448 repeats. Altogether, these findings suggest a potential regulatory role of tandem and palindromic DNA repeats in the M. hyopneumoniae transcriptional profile.

The beneficial effect of donor-specific transfusions: a review of existing explanations and a new hypothesis based on a relatively unapplied theory of T cell immunoregulation. A regulatory hypothesis in progress...

Science.gov (United States)

Wendel, T D

2000-06-01

The mechanism by which donor specific transfusions protect a graft from the recipient's immune system is unknown. It is likely that this beneficial mechanism is a subset or distinct exhibition of the general rules governing the regulation of the immune system. This phenomenon provides a strong framework for investigation of immune regulation, considering its potential consanguinity to immune regulation, that it is a paradox representing a manifestation of regulatory rules, and that it provides a wealth of clinical experience and experimentation from which to make inferences. Vital in any exploration of immune regulation, is the promise held in reducing the immune system to its chief elemental regulatory mechanisms and interactions. Strangely, the majority of this consequential work may have already been accomplished by Gershon, Green and colleagues with their elegant demarcation of T cell regulation into suppressor and contrasuppressor pathways. The practical and theoretical implications of this discovery seem to be, for the most part, ignored by mainstream immunology. It is doubtful, based on the quality and quantity of their work, or confirming work by other laboratories that they were inaccurate in their findings. It remains a horrible waste that their discoveries are not in immunology's pantheon of hallowed discoveries and are little used. With all this kept in mind, a comprehensive hypothesis of regulation was put together based mainly on Gershon's portrait of the suppressor and contrasuppressor pathways' contributions to immune regulation and experimentation surrounding the unsolved paradox of donor specific transfusions.

In situ detection of a heat-shock regulatory element binding protein using a soluble short synthetic enhancer sequence

Energy Technology Data Exchange (ETDEWEB)

Harel-Bellan, A; Brini, A T; Farrar, W L [National Cancer Institute, Frederick, MD (USA); Ferris, D K [Program Resources, Inc., Frederick, MD (USA); Robin, P [Institut Gustave Roussy, Villejuif (France)

1989-06-12

In various studies, enhancer binding proteins have been successfully absorbed out by competing sequences inserted into plasmids, resulting in the inhibition of the plasmid expression. Theoretically, such a result could be achieved using synthetic enhancer sequences not inserted into plasmids. In this study, a double stranded DNA sequence corresponding to the human heat shock regulatory element was chemically synthesized. By in vitro retardation assays, the synthetic sequence was shown to bind specifically a protein in extracts from the human T cell line Jurkat. When the synthetic enhancer was electroporated into Jurkat cells, not only the enhancer was shown to remain undegraded into the cells for up to 2 days, but also its was shown to bind intracellularly a protein. The binding was specific and was modulated upon heat shock. Furthermore, the binding protein was shown to be of the expected molecular weight by UV crosslinking. However, when the synthetic enhancer element was co-electroporated with an HSP 70-CAT reporter construct, the expression of the reporter plasmid was consistently enhanced in the presence of the exogenous synthetic enhancer.

A Metadata Schema for Geospatial Resource Discovery Use Cases

Directory of Open Access Journals (Sweden)

Darren Hardy

2014-07-01

Full Text Available We introduce a metadata schema that focuses on GIS discovery use cases for patrons in a research library setting. Text search, faceted refinement, and spatial search and relevancy are among GeoBlacklight's primary use cases for federated geospatial holdings. The schema supports a variety of GIS data types and enables contextual, collection-oriented discovery applications as well as traditional portal applications. One key limitation of GIS resource discovery is the general lack of normative metadata practices, which has led to a proliferation of metadata schemas and duplicate records. The ISO 19115/19139 and FGDC standards specify metadata formats, but are intricate, lengthy, and not focused on discovery. Moreover, they require sophisticated authoring environments and cataloging expertise. Geographic metadata standards target preservation and quality measure use cases, but they do not provide for simple inter-institutional sharing of metadata for discovery use cases. To this end, our schema reuses elements from Dublin Core and GeoRSS to leverage their normative semantics, community best practices, open-source software implementations, and extensive examples already deployed in discovery contexts such as web search and mapping. Finally, we discuss a Solr implementation of the schema using a "geo" extension to MODS.

Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4.

Science.gov (United States)

Bondurand, Nadége; Fouquet, Virginie; Baral, Viviane; Lecerf, Laure; Loundon, Natalie; Goossens, Michel; Duriez, Benedicte; Labrune, Philippe; Pingault, Veronique

2012-09-01

Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.

Regulatory issues associated with the Multi-Purpose (MPC) system

International Nuclear Information System (INIS)

Roberts, J.P.; Desell, L.J.; Birch, M.L.; Morgan, R.G.

1994-01-01

The US Department of Energy Office of Civilian Radioactive Waste Management is developing a Multi-Purpose Canister system to promote compatibility between the waste program elements of storage, transportation, and disposal. The development of a Multi-Purpose Canister system requires meeting various regulatory requirements. These regulatory requirements are set forth in environmental and Nuclear Regulatory Commission (NRC) regulations. This paper discusses the more significant regulatory issues that must be addressed in the development of a Multi-Purpose Canister system by the Department of Energy

The 3' untranslated region of human Cyclin-Dependent Kinase 5 Regulatory subunit 1 contains regulatory elements affecting transcript stability

Directory of Open Access Journals (Sweden)

Ratti Antonia

2007-12-01

Full Text Available Abstract Background CDK5R1 plays a central role in neuronal migration and differentiation during central nervous system development. CDK5R1 has been implicated in neurodegenerative disorders and proposed as a candidate gene for mental retardation. The remarkable size of CDK5R1 3'-untranslated region (3'-UTR suggests a role in post-transcriptional regulation of CDK5R1 expression. Results The bioinformatic study shows a high conservation degree in mammals and predicts several AU-Rich Elements (AREs. The insertion of CDK5R1 3'-UTR into luciferase 3'-UTR causes a decreased luciferase activity in four transfected cell lines. We identified 3'-UTR subregions which tend to reduce the reporter gene expression, sometimes in a cell line-dependent manner. In most cases the quantitative analysis of luciferase mRNA suggests that CDK5R1 3'-UTR affects mRNA stability. A region, leading to a very strong mRNA destabilization, showed a significantly low half-life, indicating an accelerated mRNA degradation. The 3' end of the transcript, containing a class I ARE, specifically displays a stabilizing effect in neuroblastoma cell lines. We also observed the interaction of the stabilizing neuronal RNA-binding proteins ELAV with the CDK5R1 transcript in SH-SY5Y cells and identified three 3'-UTR sub-regions showing affinity for ELAV proteins. Conclusion Our findings evince the presence of both destabilizing and stabilizing regulatory elements in CDK5R1 3'-UTR and support the hypothesis that CDK5R1 gene expression is post-transcriptionally controlled in neurons by ELAV-mediated mechanisms. This is the first evidence of the involvement of 3'-UTR in the modulation of CDK5R1 expression. The fine tuning of CDK5R1 expression by 3'-UTR may have a role in central nervous system development and functioning, with potential implications in neurodegenerative and cognitive disorders.

New elements

International Nuclear Information System (INIS)

Flerov, G.

1976-01-01

The history is briefly described of the investigation of superheavy elements at the Joint Institute for Nuclear Research at Dubna. The significance of the investigation is assessed from the point of view of the nuclear structure study and major problems encountered in experimental efforts are indicated. Current experimental methods aiming at the discovery or the production of superheavy nuclei with Z approximately 114 are listed. (I.W.)

Resumption of pulsing the NSCR following the discovery of damaged fuel

International Nuclear Information System (INIS)

Feltz, D.E.; Rogers, R.D.

1984-01-01

Pulsing operations of the Nuclear Science Center Reactor (NSCR) at Texas A and M University were terminated in 1976 following the discovery of three damaged fuel elements during a routine inspection. A commitment was then made to the U.S. Nuclear Regulatory Commission to terminate pulsing of the NSCR until a thorough study of the damaged fuel had been completed. A report describing that study and discussing the possible mechanism of damage was issued in 1981. Based on a recommendation in the report to establish a limiting temperature to protect against damage, the USNRC issued a letter authorizing the reinitiation of pulsing the NSCR but limiting pulsing parameters 'to those in the current technical specifications or to a maximum calculated fuel temperature of 830 deg. C. It is felt based on the data obtained and fuel inspection results that the requirements of Phase I and Phase III of the Pulse Test Program for Core VIII have been met. Phase II of the test program will not be implemented unless there is a requirement for higher pulse energy and flux. The reproducibility of pulse data was very satisfactory

Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease*

Science.gov (United States)

Dewhurst, Henry; Sundararaman, Niveda

2016-01-01

Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable

Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease.

Science.gov (United States)

Torres, Matthew P; Dewhurst, Henry; Sundararaman, Niveda

2016-11-01

Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable

Feather development genes and associated regulatory innovation predate the origin of Dinosauria.

Science.gov (United States)

Lowe, Craig B; Clarke, Julia A; Baker, Allan J; Haussler, David; Edwards, Scott V

2015-01-01

The evolution of avian feathers has recently been illuminated by fossils and the identification of genes involved in feather patterning and morphogenesis. However, molecular studies have focused mainly on protein-coding genes. Using comparative genomics and more than 600,000 conserved regulatory elements, we show that patterns of genome evolution in the vicinity of feather genes are consistent with a major role for regulatory innovation in the evolution of feathers. Rates of innovation at feather regulatory elements exhibit an extended period of innovation with peaks in the ancestors of amniotes and archosaurs. We estimate that 86% of such regulatory elements and 100% of the nonkeratin feather gene set were present prior to the origin of Dinosauria. On the branch leading to modern birds, we detect a strong signal of regulatory innovation near insulin-like growth factor binding protein (IGFBP) 2 and IGFBP5, which have roles in body size reduction, and may represent a genomic signature for the miniaturization of dinosaurian body size preceding the origin of flight. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

A novel processing system of sterol regulatory element-binding protein-1c regulated by polyunsaturated fatty acid.

Science.gov (United States)

Nakakuki, Masanori; Kawano, Hiroyuki; Notsu, Tatsuto; Imada, Kazunori; Mizuguchi, Kiyoshi; Shimano, Hitoshi

2014-05-01

The proteolytic cascade is the key step in transactivation of sterol regulatory element-binding proteins (SREBPs), a transcriptional factor of lipid synthesis. Proteolysis of SREBP-2 is strictly regulated by sterols, but that of SREBP-1c was not strongly sterol-regulated, but inhibited by polyunsaturated fatty acids (PUFAs). In this study, the proteolytic processing of SREBP-1 and -2 was examined by transfection studies of cDNA-encoding mutants in which all the known cleavage sites were disrupted. In cultured cells, sterol-regulated SREBP-2 processing was completely eliminated by mutation of cleavage sites. In contrast, the corresponding SREBP-1c mutants as well as wild type exhibited large amounts of cleaved products in the nuclear extracts from culture cells and murine liver in vivo. The nuclear form of the mutant SREBP-1c was induced by delipidated condition and suppressed by eicosapentaenoic acid, an n-3 PUFA, but not by sterols. This novel processing mechanism was affected by neither SREBP cleavage-activating protein (SCAP) nor insulin-induced gene (Insig)-1, unlike SREBP-2, but abolished by a serine protease inhibitor. Through analysis of deletion mutant, a site-2 protease recognition sequence (DRSR) was identified to be involved in this novel processing. These findings suggest that SREBP-1c cleavage could be subjected to a novel PUFA-regulated cleavage system in addition to the sterol-regulatory SCAP/Insig system.

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

Directory of Open Access Journals (Sweden)

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

XcisClique: analysis of regulatory bicliques

Directory of Open Access Journals (Sweden)

Grene Ruth

2006-04-01

Full Text Available Abstract Background Modeling of cis-elements or regulatory motifs in promoter (upstream regions of genes is a challenging computational problem. In this work, set of regulatory motifs simultaneously present in the promoters of a set of genes is modeled as a biclique in a suitably defined bipartite graph. A biologically meaningful co-occurrence of multiple cis-elements in a gene promoter is assessed by the combined analysis of genomic and gene expression data. Greater statistical significance is associated with a set of genes that shares a common set of regulatory motifs, while simultaneously exhibiting highly correlated gene expression under given experimental conditions. Methods XcisClique, the system developed in this work, is a comprehensive infrastructure that associates annotated genome and gene expression data, models known cis-elements as regular expressions, identifies maximal bicliques in a bipartite gene-motif graph; and ranks bicliques based on their computed statistical significance. Significance is a function of the probability of occurrence of those motifs in a biclique (a hypergeometric distribution, and on the new sum of absolute values statistic (SAV that uses Spearman correlations of gene expression vectors. SAV is a statistic well-suited for this purpose as described in the discussion. Results XcisClique identifies new motif and gene combinations that might indicate as yet unidentified involvement of sets of genes in biological functions and processes. It currently supports Arabidopsis thaliana and can be adapted to other organisms, assuming the existence of annotated genomic sequences, suitable gene expression data, and identified regulatory motifs. A subset of Xcis Clique functionalities, including the motif visualization component MotifSee, source code, and supplementary material are available at https://bioinformatics.cs.vt.edu/xcisclique/.

Regulatory Immunotherapy in Bone Marrow Transplantation

Directory of Open Access Journals (Sweden)

Vanessa Morales-Tirado

2011-01-01

Full Text Available Every year individuals receive hematopoietic stem cell transplantation (HSCT to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT and regulatory T cells (Treg, and their current and potential roles in tolerance induction after allogeneic HSCT.

Safeguards inventory and process monitoring regulatory comparison

Energy Technology Data Exchange (ETDEWEB)

Cavaluzzi, Jack M. [Texas A & M Univ., College Station, TX (United States); Gibbs, Philip W. [Brookhaven National Lab. (BNL), Upton, NY (United States)

2013-06-27

Detecting the theft or diversion of the relatively small amount of fissile material needed to make a nuclear weapon given the normal operating capacity of many of today’s running nuclear production facilities is a difficult task. As throughput increases, the ability of the Material Control and Accountability (MC&A) Program to detect the material loss decreases because the statistical measurement uncertainty also increases. The challenge faced is the ability of current accounting, measurement, and material control programs to detect small yet significant losses under some regulatory approaches can decrease to the point where it is extremely low if not practically non-existent at normal operating capacities. Adding concern to this topic is that there are variations among regulatory bodies as far as what is considered a Significant Quantity (SQ). Some research suggests that thresholds should be lower than those found in any current regulation which if adopted would make meeting detection goals even more difficult. This paper reviews and compares the current regulatory requirements for the MA elements related to physical inventory, uncertainty of the Inventory Difference (ID), and Process Monitoring (PM) in the United States Department of Energy (DOE) and Nuclear Regulatory Commission (NRC), Rosatom of the Russian Federation and the Chinese Atomic Energy Agency (CAEA) of China. The comparison looks at how the regulatory requirements for the implementation of various MA elements perform across a range of operating capacities in example facilities.

Challenges in orphan drug development and regulatory policy in China.

Science.gov (United States)

Cheng, Alice; Xie, Zhi

2017-01-18

While regulatory policy is well defined for orphan drug development in the United States and Europe, rare disease policy in China is still evolving. Many Chinese patients currently pay out of pocket for international treatments that are not yet approved in China. The lack of a clear definition and therefore regulatory approval process for rare diseases has, until now, de-incentivized pharmaceutical companies to pursue rare disease drug development in China. In turn, many grassroots movements have begun to support rare disease patients and facilitate drug discovery through research. Recently, the Chinese FDA set new regulatory guidelines for drugs being developed in China, including an expedited review process for life-saving treatments. In this review, we discuss the effects of these new policy changes on and suggest potential solutions to innovate orphan drug development in China.

Transposable-element associated small RNAs in Bombyx mori genome.

Directory of Open Access Journals (Sweden)

Yimei Cai

Full Text Available Small RNAs are a group of regulatory RNA molecules that control gene expression at transcriptional or post-transcriptional levels among eukaryotes. The silkworm, Bombyx mori L., genome harbors abundant repetitive sequences derived from families of retrotransposons and transposons, which together constitute almost half of the genome space and provide ample resource for biogenesis of the three major small RNA families. We systematically discovered transposable-element (TE-associated small RNAs in B. mori genome based on a deep RNA-sequencing strategy and the effort yielded 182, 788 and 4,990 TE-associated small RNAs in the miRNA, siRNA and piRNA species, respectively. Our analysis suggested that the three small RNA species preferentially associate with different TEs to create sequence and functional diversity, and we also show evidence that a Bombyx non-LTR retrotransposon, bm1645, alone contributes to the generation of TE-associated small RNAs in a very significant way. The fact that bm1645-associated small RNAs partially overlap with each other implies a possibility that this element may be modulated by different mechanisms to generate different products with diverse functions. Taken together, these discoveries expand the small RNA pool in B. mori genome and lead to new knowledge on the diversity and functional significance of TE-associated small RNAs.

Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2

DEFF Research Database (Denmark)

Dathe, Katarina; Kjaer, Klaus W; Brehm, Anja

2009-01-01

Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5......). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval...... within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb....

Identification of putative regulatory motifs in the upstream regions of co-expressed functional groups of genes in Plasmodium falciparum

Directory of Open Access Journals (Sweden)

Joshi NV

2009-01-01

Full Text Available Abstract Background Regulation of gene expression in Plasmodium falciparum (Pf remains poorly understood. While over half the genes are estimated to be regulated at the transcriptional level, few regulatory motifs and transcription regulators have been found. Results The study seeks to identify putative regulatory motifs in the upstream regions of 13 functional groups of genes expressed in the intraerythrocytic developmental cycle of Pf. Three motif-discovery programs were used for the purpose, and motifs were searched for only on the gene coding strand. Four motifs – the 'G-rich', the 'C-rich', the 'TGTG' and the 'CACA' motifs – were identified, and zero to all four of these occur in the 13 sets of upstream regions. The 'CACA motif' was absent in functional groups expressed during the ring to early trophozoite transition. For functional groups expressed in each transition, the motifs tended to be similar. Upstream motifs in some functional groups showed 'positional conservation' by occurring at similar positions relative to the translational start site (TLS; this increases their significance as regulatory motifs. In the ribonucleotide synthesis, mitochondrial, proteasome and organellar translation machinery genes, G-rich, C-rich, CACA and TGTG motifs, respectively, occur with striking positional conservation. In the organellar translation machinery group, G-rich motifs occur close to the TLS. The same motifs were sometimes identified for multiple functional groups; differences in location and abundance of the motifs appear to ensure different modes of action. Conclusion The identification of positionally conserved over-represented upstream motifs throws light on putative regulatory elements for transcription in Pf.

Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs.

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Christopher D Brown

Full Text Available Genetic variants in cis-regulatory elements or trans-acting regulators frequently influence the quantity and spatiotemporal distribution of gene transcription. Recent interest in expression quantitative trait locus (eQTL mapping has paralleled the adoption of genome-wide association studies (GWAS for the analysis of complex traits and disease in humans. Under the hypothesis that many GWAS associations tag non-coding SNPs with small effects, and that these SNPs exert phenotypic control by modifying gene expression, it has become common to interpret GWAS associations using eQTL data. To fully exploit the mechanistic interpretability of eQTL-GWAS comparisons, an improved understanding of the genetic architecture and causal mechanisms of cell type specificity of eQTLs is required. We address this need by performing an eQTL analysis in three parts: first we identified eQTLs from eleven studies on seven cell types; then we integrated eQTL data with cis-regulatory element (CRE data from the ENCODE project; finally we built a set of classifiers to predict the cell type specificity of eQTLs. The cell type specificity of eQTLs is associated with eQTL SNP overlap with hundreds of cell type specific CRE classes, including enhancer, promoter, and repressive chromatin marks, regions of open chromatin, and many classes of DNA binding proteins. These associations provide insight into the molecular mechanisms generating the cell type specificity of eQTLs and the mode of regulation of corresponding eQTLs. Using a random forest classifier with cell specific CRE-SNP overlap as features, we demonstrate the feasibility of predicting the cell type specificity of eQTLs. We then demonstrate that CREs from a trait-associated cell type can be used to annotate GWAS associations in the absence of eQTL data for that cell type. We anticipate that such integrative, predictive modeling of cell specificity will improve our ability to understand the mechanistic basis of human

Splicing Regulatory Elements and mRNA-abundance of dlg1 and capt, Genetically Interacting with dFMRP in Drosophila Brain

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Maria Petrova

2014-09-01

Full Text Available To further understand the molecular and cellular mechanisms underlying the disease, we used the Drososphila FraX model and investigated a not well studied role of Drosophila Fragile X Mental Retardation Protein (dFMRP in alternative splicing of neuronal mRNAs to which it binds via a G-quartet sequence. By means of qRT-PCR we established the relative abundance of some isoforms of the gene dlg1, resulting from alternative exon skipping nearby a G-quartet and an exonic ESE-sequence, both acting as exonic splicing enhancers. We also investigated the relative mRNA-abundance of all capt-isoforms and the pre-mRNAs of both genes. We proposed a possible involvement of dFMRP in alternative splicing of genes, interacting with dfmr1. In the absence of dFMRP in larval and pupal brains, we found a change in the mRNA-level of one of the studied isoforms of dlg1 and of its pre-mRNA.We also established previously reported splicing regulatory elements and predicted computationally novel hexamere sequences in the exonic/intronic ends of both genes with p upative regulatory roles in alternative splicing.

Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies

Science.gov (United States)

2014-01-01

Expression quantitative trait loci (eQTL) mapping is a tool that can systematically identify genetic variation affecting gene expression. eQTL mapping studies have shown that certain genomic locations, referred to as regulatory hotspots, may affect the expression levels of many genes. Recently, studies have shown that various confounding factors may induce spurious regulatory hotspots. Here, we introduce a novel statistical method that effectively eliminates spurious hotspots while retaining genuine hotspots. Applied to simulated and real datasets, we validate that our method achieves greater sensitivity while retaining low false discovery rates compared to previous methods. PMID:24708878

The Cellular and Molecular Mechanisms of Immuno-suppression by Human Type 1 Regulatory T cells

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Silvia eGregori

2012-02-01

Full Text Available The immuno-regulatory mechanisms of IL-10-producing type 1 regulatory T (Tr1 cells have been widely studied over the years. However, several recent discoveries have shed new light on the cellular and molecular mechanisms that human Tr1 cells use to control immune responses and induce tolerance. In this review we outline the well-known and newly discovered regulatory properties of human Tr1 cells and provide an in-depth comparison of the known suppressor mechanisms of Tr1 cells with FOXP3+ Treg. We also highlight the role that Tr1 cells play in promoting and maintaining tolerance in autoimmunity, allergy, and transplantation.

Advances in chemical investigations of the heaviest elements

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Türler Andreas

2016-01-01

Full Text Available Although somewhat in the shadow of the discoveries of new elements, experimental chemical investigations of the heaviest elements have made tremendous progress in the last decades. Indeed, it was possible to experimentally determine thermochemical properties of heavy transactinide elements such as copernicium or flerovium. But will it be possible to chemically study all currently known elements of the periodic table up to element 118? While it is experimentally feasible to work with single atoms, the short half-lives of even the longest currently known isotopes of elements 115 through 118 call for new experimental approaches.

Discovery of Allostery in PKA Signaling.

Science.gov (United States)

Zhang, Ping; Kornev, Alexandr P; Wu, Jian; Taylor, Susan S

2015-06-01

cAMP-dependent protein kinase (PKA) was the second protein kinase to be discovered and the PKA catalytic (C) subunit serves as a prototype for the large protein kinase superfamily that contains over 500 gene products. The protein kinases regulate much of biology in eukaryotic cells and they are now also a major therapeutic target. Although PKA was discovered nearly 50 years ago and the subsequent discovery of the regulatory subunits that bind cAMP and release the catalytic activity from the holoenzyme followed quickly. Thus in PKA we see the convergence of two major signaling mechanisms - protein phosphorylation and second messenger signaling through cAMP. Crystallography provides a foundation for understanding function, and the structure of the isolated regulatory (R) and C-subunits have been extremely informative. Yet it is the R 2 C 2 holoenzyme that predominates in cells, and one can only appreciate the allosteric features of PKA signaling by seeing the full length protein. The symmetry and the quaternary constraints that one R:C hetero-dimer exerts on the other in the holoenzyme simply are not present in the isolated subunits or even in the R:C hetero-dimer.

Nipponium, the element ascribable to rhenium from the modern chemical viewpoint

Energy Technology Data Exchange (ETDEWEB)

Yoshihara, H.K. [Japan Isotope Data Inst., Sendai (Japan)

1997-11-01

Though the discovery of nipponium by Ogawa in 1908 was judged to be false and his work was forgotten for many years, the new element he believed to have found should be ascribed to rhenium (z = 75) by the following reasons: (1) the spectral line of 4882 A agrees well with the present data of rhenium, (2) recalculation of the atomic weight of the element supports the value in the neighbourhood of 185 which is very close to the present value 186.2 of rhenium, and (3) rhenium is actually present in Japanese molybdenite he studied. Therefore, it is concluded that his discovery of the `new` element was correct, but assignment of z = 43 was wrong. (orig.)

Visions of regulatory renewal

International Nuclear Information System (INIS)

Edgeworth, A.

1998-01-01

The economic contribution of the CEPA (Canadian Energy Pipeline Association) member companies to Canada's trade balance was discussed. CEPA member companies transport 95 per cent of the crude oil and natural gas produced in Canada to domestic and export markets. This represents a total of 5.6 Tcf of gas annually. Half of Canada's natural gas and oil production is exported to U.S. markets. All of these exports are transported by pipeline. CEPA member companies operate 90,000 km of pipeline from British Columbia to Quebec. Expansions are needed as a result of a significant increase in demand for natural gas and crude oil since 1990. Several issues exist for regulatory renewal. They include the need to create a level playing field, the overseeing of tolls and contract renewal terms, changing risk/reward trade-offs, the right to confidentiality of information and price discovery mechanism. The drivers for regulatory reform at Westcoast Energy are the need for pricing flexibility, customers desire for toll certainty, decontracting and opposition to rolled-in expansions for gathering and processing. An overview of Westcoast Energy's negotiated toll settlement, its implications, and the components of Westcoast Energy's 'light handed regulation' (LHR) was presented

Asymmetrical distribution of non-conserved regulatory sequences at PHOX2B is reflected at the ENCODE loci and illuminates a possible genome-wide trend

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McCallion Andrew S

2009-01-01

Full Text Available Abstract Background Transcriptional regulatory elements are central to development and interspecific phenotypic variation. Current regulatory element prediction tools rely heavily upon conservation for prediction of putative elements. Recent in vitro observations from the ENCODE project combined with in vivo analyses at the zebrafish phox2b locus suggests that a significant fraction of regulatory elements may fall below commonly applied metrics of conservation. We propose to explore these observations in vivo at the human PHOX2B locus, and also evaluate the potential evidence for genome-wide applicability of these observations through a novel analysis of extant data. Results Transposon-based transgenic analysis utilizing a tiling path proximal to human PHOX2B in zebrafish recapitulates the observations at the zebrafish phox2b locus of both conserved and non-conserved regulatory elements. Analysis of human sequences conserved with previously identified zebrafish phox2b regulatory elements demonstrates that the orthologous sequences exhibit overlapping regulatory control. Additionally, analysis of non-conserved sequences scattered over 135 kb 5' to PHOX2B, provides evidence of non-conserved regulatory elements positively biased with close proximity to the gene. Furthermore, we provide a novel analysis of data from the ENCODE project, finding a non-uniform distribution of regulatory elements consistent with our in vivo observations at PHOX2B. These observations remain largely unchanged when one accounts for the sequence repeat content of the assayed intervals, when the intervals are sub-classified by biological role (developmental versus non-developmental, or by gene density (gene desert versus non-gene desert. Conclusion While regulatory elements frequently display evidence of evolutionary conservation, a fraction appears to be undetected by current metrics of conservation. In vivo observations at the PHOX2B locus, supported by our analyses of in

Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

Science.gov (United States)

2013-03-14

behavioral teaching strategies and best practice for teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

A SINE-derived element constitutes a unique modular enhancer for mammalian diencephalic Fgf8.

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Akiko Nakanishi

Full Text Available Transposable elements, including short interspersed repetitive elements (SINEs, comprise nearly half the mammalian genome. Moreover, they are a major source of conserved non-coding elements (CNEs, which play important functional roles in regulating development-related genes, such as enhancing and silencing, serving for the diversification of morphological and physiological features among species. We previously reported a novel SINE family, AmnSINE1, as part of mammalian-specific CNEs. One AmnSINE1 locus, named AS071, showed an enhancer property in the developing mouse diencephalon. Indeed, AS071 appears to recapitulate the expression of diencephalic fibroblast growth factor 8 (Fgf8. Here we established three independent lines of AS071-transgenic mice and performed detailed expression profiling of AS071-enhanced lacZ in comparison with that of Fgf8 across embryonic stages. We demonstrate that AS071 is a distal enhancer that directs Fgf8 expression in the developing diencephalon. Furthermore, enhancer assays with constructs encoding partially deleted AS071 sequence revealed a unique modular organization in which AS071 contains at least three functionally distinct sub-elements that cooperatively direct the enhancer activity in three diencephalic domains, namely the dorsal midline and the lateral wall of the diencephalon, and the ventral midline of the hypothalamus. Interestingly, the AmnSINE1-derived sub-element was found to specify the enhancer activity to the ventral midline of the hypothalamus. To our knowledge, this is the first discovery of an enhancer element that could be separated into respective sub-elements that determine regional specificity and/or the core enhancing activity. These results potentiate our understanding of the evolution of retroposon-derived cis-regulatory elements as well as the basis for future studies of the molecular mechanism underlying the determination of domain-specificity of an enhancer.

Construction and analysis of the transcription factor-microRNA co-regulatory network response to Mycobacterium tuberculosis: a view from the blood.

Science.gov (United States)

Lin, Yan; Duan, Zipeng; Xu, Feng; Zhang, Jiayuan; Shulgina, Marina V; Li, Fan

2017-01-01

Mycobacterium tuberculosis ( Mtb ) infection has been regional outbreak, recently. The traditional focus on the patterns of "reductionism" which was associated with single molecular changes has been unable to meet the demand of early diagnosis and clinical application when current tuberculosis infection happened. In this study, we employed a systems biology approach to collect large microarray data sets including mRNAs and microRNAs (miRNAs) to identify the differentially expressed mRNAs and miRNAs in the whole blood of TB patients. The aim was to identify key genes associated with the immune response in the pathogenic process of tuberculosis by analyzing the co-regulatory network that was consisted of transcription factors and miRNAs as well as their target genes. The network along with their co-regulatory genes was analyzed utilizing Transcriptional Regulatory Element Database (TRED) and Database for Annotation, Visualization and Integrated Discovery (DAVID). We got 21 (19 up-regulated and 2 down-regulated) differentially expressed genes that were co-regulated by transcription factors and miRNAs. KEGG pathway enrichment analysis showed that the 21 differentially expressed genes were predominantly involved in Tuberculosis signaling pathway, which may play a major role in tuberculosis biological process. Quantitative real-time PCR was performed to verify the over expression of co-regulatory genes ( FCGR1A and CEBPB ). The genetic expression was correlated with clinicopathological characteristics in TB patients and inferences drawn. Our results suggest the TF-miRNA gene co-regulatory network may help us further understand the molecular mechanism of immune response to tuberculosis and provide us a new angle of future biomarker and therapeutic targets.

Improving clinical drug development regulatory procedures for anticonvulsants

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Janković Slobodan

2015-01-01

Full Text Available Background: Clinical development of antiepileptic drugs is demanding due to complex character of the disorder and to diversity of its forms and etiologies. Objective: The aim of this review was to suggest improvements in regulatory procedures for clinical development of antiepileptic drugs. Methods: The following databases of scientific articles were searched: MEDLINE, SCOPUS and SCINDEKS. In total 558 publications were retrieved. The types of articles selected were reviews, reports on clinical trials and letters to the Editor. Results: There are several changes of regulatory documents necessary for improving process of clinical development of antiepileptic drugs: preference of parallel groups design for add-on trials should be explicit; the noninferiority design for monotherapy clinical trials should be acceptable; restrictive formulations when trials of antiepileptic drugs in children are in question should be avoided; requirements in regard to the efficacy measures should be harmonized among the regulatory bodies; proactive attitude towards discovery of adverse events; and precise requirements for clinical trials specifically designed to prove anti-epileptogenic effects should be made clear. Conclusion: Current regulatory documents are incomplete in many aspects; an international effort to improve and harmonize guidelines for clinical development of antiepileptic drugs is necessary for improvement of this process.

Discovery of innovative therapeutics: today's realities and tomorrow's vision. 2. Pharma's challenges and their commitment to innovation.

Science.gov (United States)

Abou-Gharbia, Magid; Childers, Wayne E

2014-07-10

The pharmaceutical industry is facing enormous challenges, including reduced efficiency, stagnant success rate, patent expirations for key drugs, fierce price competition from generics, high regulatory hurdles, and the industry's perceived tarnished image. Pharma has responded by embarking on a range of initiatives. Other sectors, including NIH, have also responded. Academic drug discovery groups have appeared to support the transition of innovative academic discoveries and ideas into attractive drug discovery opportunities. Part 1 of this two-part series discussed the criticisms that have been leveled at the pharmaceutical industry over the past 3 decades and summarized the supporting data for and against these criticisms. This second installment will focus on the current challenges facing the pharmaceutical industry and Pharma's responses, focusing on the industry's changing perspective and new business models for coping with the loss of talent and declining clinical pipelines as well as presenting some examples of recent drug discovery successes.

Discovery of stimulation-responsive immune enhancers with CRISPR activation

Science.gov (United States)

Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K.; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

2017-09-01

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.

Discovery of stimulation-responsive immune enhancers with CRISPR activation

Science.gov (United States)

Simeonov, Dimitre R.; Gowen, Benjamin G.; Boontanrart, Mandy; Roth, Theodore L.; Gagnon, John D.; Mumbach, Maxwell R.; Satpathy, Ansuman T.; Lee, Youjin; Bray, Nicolas L.; Chan, Alice Y.; Lituiev, Dmytro S.; Nguyen, Michelle L.; Gate, Rachel E.; Subramaniam, Meena; Li, Zhongmei; Woo, Jonathan M.; Mitros, Therese; Ray, Graham J.; Curie, Gemma L.; Naddaf, Nicki; Chu, Julia S.; Ma, Hong; Boyer, Eric; Van Gool, Frederic; Huang, Hailiang; Liu, Ruize; Tobin, Victoria R.; Schumann, Kathrin; Daly, Mark J.; Farh, Kyle K; Ansel, K. Mark; Ye, Chun J.; Greenleaf, William J.; Anderson, Mark S.; Bluestone, Jeffrey A.; Chang, Howard Y.; Corn, Jacob E.; Marson, Alexander

2017-01-01

The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues1–3. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption4–6, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa)7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs. PMID:28854172

A novel k-mer set memory (KSM) motif representation improves regulatory variant prediction.

Science.gov (United States)

Guo, Yuchun; Tian, Kevin; Zeng, Haoyang; Guo, Xiaoyun; Gifford, David Kenneth

2018-04-13

The representation and discovery of transcription factor (TF) sequence binding specificities is critical for understanding gene regulatory networks and interpreting the impact of disease-associated noncoding genetic variants. We present a novel TF binding motif representation, the k -mer set memory (KSM), which consists of a set of aligned k -mers that are overrepresented at TF binding sites, and a new method called KMAC for de novo discovery of KSMs. We find that KSMs more accurately predict in vivo binding sites than position weight matrix (PWM) models and other more complex motif models across a large set of ChIP-seq experiments. Furthermore, KSMs outperform PWMs and more complex motif models in predicting in vitro binding sites. KMAC also identifies correct motifs in more experiments than five state-of-the-art motif discovery methods. In addition, KSM-derived features outperform both PWM and deep learning model derived sequence features in predicting differential regulatory activities of expression quantitative trait loci (eQTL) alleles. Finally, we have applied KMAC to 1600 ENCODE TF ChIP-seq data sets and created a public resource of KSM and PWM motifs. We expect that the KSM representation and KMAC method will be valuable in characterizing TF binding specificities and in interpreting the effects of noncoding genetic variations. © 2018 Guo et al.; Published by Cold Spring Harbor Laboratory Press.

Bibliography on transuranium elements

International Nuclear Information System (INIS)

Sood, D.D.

1991-01-01

A selective bibliography of prominent publications on transuranium elements is compiled. Heading papers, symposia proceedings and the textbooks are included in the bibliography. The bibliography is arranged under the headings: (1)Books, Symposia Proceedings, Reviews etc., (2)Discovery, (3)Weighable Isolation, (4)Metal Preparation, (5)Nuclear Properties, (6)Plutonium as Reactor Fuel, (7)Fuel Reprocessing, (8)Solid State Chemistry, Thermochemistry and Spectroscopy, (9)Radiation Safety, (10)Applications, and (11)Some Typical Indian Papers. Total number of references cited are 298. The bibliography, though selective, will serve as a starting point for comprehensive literature search on transuranium elements. (author)

DREAM (Downstream Regulatory Element Antagonist Modulator contributes to synaptic depression and contextual fear memory

Directory of Open Access Journals (Sweden)

Wu Long-Jun

2010-01-01

Full Text Available Abstract The downstream regulatory element antagonist modulator (DREAM, a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM, we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD but not long-term potentiation (LTP, was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory.

Volatility Discovery

DEFF Research Database (Denmark)

Dias, Gustavo Fruet; Scherrer, Cristina; Papailias, Fotis

The price discovery literature investigates how homogenous securities traded on different markets incorporate information into prices. We take this literature one step further and investigate how these markets contribute to stochastic volatility (volatility discovery). We formally show...... that the realized measures from homogenous securities share a fractional stochastic trend, which is a combination of the price and volatility discovery measures. Furthermore, we show that volatility discovery is associated with the way that market participants process information arrival (market sensitivity......). Finally, we compute volatility discovery for 30 actively traded stocks in the U.S. and report that Nyse and Arca dominate Nasdaq....

Predictive modelling of gene expression from transcriptional regulatory elements.

Science.gov (United States)

Budden, David M; Hurley, Daniel G; Crampin, Edmund J

2015-07-01

Predictive modelling of gene expression provides a powerful framework for exploring the regulatory logic underpinning transcriptional regulation. Recent studies have demonstrated the utility of such models in identifying dysregulation of gene and miRNA expression associated with abnormal patterns of transcription factor (TF) binding or nucleosomal histone modifications (HMs). Despite the growing popularity of such approaches, a comparative review of the various modelling algorithms and feature extraction methods is lacking. We define and compare three methods of quantifying pairwise gene-TF/HM interactions and discuss their suitability for integrating the heterogeneous chromatin immunoprecipitation (ChIP)-seq binding patterns exhibited by TFs and HMs. We then construct log-linear and ϵ-support vector regression models from various mouse embryonic stem cell (mESC) and human lymphoblastoid (GM12878) data sets, considering both ChIP-seq- and position weight matrix- (PWM)-derived in silico TF-binding. The two algorithms are evaluated both in terms of their modelling prediction accuracy and ability to identify the established regulatory roles of individual TFs and HMs. Our results demonstrate that TF-binding and HMs are highly predictive of gene expression as measured by mRNA transcript abundance, irrespective of algorithm or cell type selection and considering both ChIP-seq and PWM-derived TF-binding. As we encourage other researchers to explore and develop these results, our framework is implemented using open-source software and made available as a preconfigured bootable virtual environment. © The Author 2014. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

The transcriptional regulatory network mediated by banana (Musa acuminata) dehydration-responsive element binding (MaDREB) transcription factors in fruit ripening.

Science.gov (United States)

Kuang, Jian-Fei; Chen, Jian-Ye; Liu, Xun-Cheng; Han, Yan-Chao; Xiao, Yun-Yi; Shan, Wei; Tang, Yang; Wu, Ke-Qiang; He, Jun-Xian; Lu, Wang-Jin

2017-04-01

Fruit ripening is a complex, genetically programmed process involving the action of critical transcription factors (TFs). Despite the established significance of dehydration-responsive element binding (DREB) TFs in plant abiotic stress responses, the involvement of DREBs in fruit ripening is yet to be determined. Here, we identified four genes encoding ripening-regulated DREB TFs in banana (Musa acuminata), MaDREB1, MaDREB2, MaDREB3, and MaDREB4, and demonstrated that they play regulatory roles in fruit ripening. We showed that MaDREB1-MaDREB4 are nucleus-localized, induced by ethylene and encompass transcriptional activation activities. We performed a genome-wide chromatin immunoprecipitation and high-throughput sequencing (ChIP-Seq) experiment for MaDREB2 and identified 697 genomic regions as potential targets of MaDREB2. MaDREB2 binds to hundreds of loci with diverse functions and its binding sites are distributed in the promoter regions proximal to the transcriptional start site (TSS). Most of the MaDREB2-binding targets contain the conserved (A/G)CC(G/C)AC motif and MaDREB2 appears to directly regulate the expression of a number of genes involved in fruit ripening. In combination with transcriptome profiling (RNA sequencing) data, our results indicate that MaDREB2 may serve as both transcriptional activator and repressor during banana fruit ripening. In conclusion, our study suggests a hierarchical regulatory model of fruit ripening in banana and that the MaDREB TFs may act as transcriptional regulators in the regulatory network. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Evidence for deep regulatory similarities in early developmental programs across highly diverged insects.

Science.gov (United States)

Kazemian, Majid; Suryamohan, Kushal; Chen, Jia-Yu; Zhang, Yinan; Samee, Md Abul Hassan; Halfon, Marc S; Sinha, Saurabh

2014-09-01

Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like "long germband" development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250-350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as "training data" to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene

Evidence for Deep Regulatory Similarities in Early Developmental Programs across Highly Diverged Insects

Science.gov (United States)

Zhang, Yinan; Samee, Md. Abul Hassan; Halfon, Marc S.; Sinha, Saurabh

2014-01-01

Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like “long germband” development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250–350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as “training data” to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary

Phylum-Level Conservation of Regulatory Information in Nematodes despite Extensive Non-coding Sequence Divergence

Science.gov (United States)

Gordon, Kacy L.; Arthur, Robert K.; Ruvinsky, Ilya

2015-01-01

Gene regulatory information guides development and shapes the course of evolution. To test conservation of gene regulation within the phylum Nematoda, we compared the functions of putative cis-regulatory sequences of four sets of orthologs (unc-47, unc-25, mec-3 and elt-2) from distantly-related nematode species. These species, Caenorhabditis elegans, its congeneric C. briggsae, and three parasitic species Meloidogyne hapla, Brugia malayi, and Trichinella spiralis, represent four of the five major clades in the phylum Nematoda. Despite the great phylogenetic distances sampled and the extensive sequence divergence of nematode genomes, all but one of the regulatory elements we tested are able to drive at least a subset of the expected gene expression patterns. We show that functionally conserved cis-regulatory elements have no more extended sequence similarity to their C. elegans orthologs than would be expected by chance, but they do harbor motifs that are important for proper expression of the C. elegans genes. These motifs are too short to be distinguished from the background level of sequence similarity, and while identical in sequence they are not conserved in orientation or position. Functional tests reveal that some of these motifs contribute to proper expression. Our results suggest that conserved regulatory circuitry can persist despite considerable turnover within cis elements. PMID:26020930

Phylum-Level Conservation of Regulatory Information in Nematodes despite Extensive Non-coding Sequence Divergence.

Directory of Open Access Journals (Sweden)

Kacy L Gordon

2015-05-01

Full Text Available Gene regulatory information guides development and shapes the course of evolution. To test conservation of gene regulation within the phylum Nematoda, we compared the functions of putative cis-regulatory sequences of four sets of orthologs (unc-47, unc-25, mec-3 and elt-2 from distantly-related nematode species. These species, Caenorhabditis elegans, its congeneric C. briggsae, and three parasitic species Meloidogyne hapla, Brugia malayi, and Trichinella spiralis, represent four of the five major clades in the phylum Nematoda. Despite the great phylogenetic distances sampled and the extensive sequence divergence of nematode genomes, all but one of the regulatory elements we tested are able to drive at least a subset of the expected gene expression patterns. We show that functionally conserved cis-regulatory elements have no more extended sequence similarity to their C. elegans orthologs than would be expected by chance, but they do harbor motifs that are important for proper expression of the C. elegans genes. These motifs are too short to be distinguished from the background level of sequence similarity, and while identical in sequence they are not conserved in orientation or position. Functional tests reveal that some of these motifs contribute to proper expression. Our results suggest that conserved regulatory circuitry can persist despite considerable turnover within cis elements.

Discovery and Selection of Semantic Web Services

CERN Document Server

Wang, Xia

2013-01-01

For advanced web search engines to be able not only to search for semantically related information dispersed over different web pages, but also for semantic services providing certain functionalities, discovering semantic services is the key issue. Addressing four problems of current solution, this book presents the following contributions. A novel service model independent of semantic service description models is proposed, which clearly defines all elements necessary for service discovery and selection. It takes service selection as its gist and improves efficiency. Corresponding selection algorithms and their implementation as components of the extended Semantically Enabled Service-oriented Architecture in the Web Service Modeling Environment are detailed. Many applications of semantic web services, e.g. discovery, composition and mediation, can benefit from a general approach for building application ontologies. With application ontologies thus built, services are discovered in the same way as with single...

Continuous improvement of the regulatory framework for the control of medical exposure

International Nuclear Information System (INIS)

Larcher, Ana M.; Ortiz Lopez, Pedro; Arias, Cesar; Marechal, Maria H.; Hernandez Alvarez, Ramon; Ferrer Garcia, Natividad; Castaneda Mucino, Antonia; Faller, Blanca

2008-01-01

One of the key elements to guide the improvement of the regulatory control is the availability of a self-assessment tool for regulatory performance. Although there is general guidance on self-assessment for regulators and users (IAEA), there is a need for more specific advice on how to address challenges and difficulties faced by regulatory bodies, when regulating radiation protection of patients. Examples of these challenges are the need for regulatory initiatives, in cooperation with health and education authorities, professional bodies and equipment suppliers, and to put in place necessary elements that are beyond responsibility of individual user of radiation, to enable them compliance with safety standards. Purpose: Within the programme of the Ibero American Forum of Nuclear and Radiation Safety Regulatory Organizations, a project to develop such a self-assessment tool for the regulatory control of medical exposure has been designed. Method: National experiences in transposing and enforcing the international radiation safety standards, as to how the requirements are included in national regulations are reviewed. Further, difficulties to the implementation of safety requirements are analyzed and a self-assessment approach and possible regulatory solutions a are presented. Results and discussion: In this study the following documents are being produced: 1) transposition of international requirements into national regulations in the six countries of the Forum, 2) difficulties to implement and enforce the requirements, 3) guidance on self-assessment of regulatory framework for medical exposure, 4) suggested contribution to the revision of international radiation safety standards. (author)

The discovery of elements 107 to 112

Directory of Open Access Journals (Sweden)

Hofmann Sigurd

2016-01-01

Full Text Available In the 1960s, theoretical concepts prepared the path to nuclear matter with proton and neutron numbers far beyond the nuclei known at that time. The new laboratory GSI was founded for research on reactions with heavy ions, in particular those for production of the predicted super-heavy nuclei. In this contribution it is presented how the interaction between experiment and theory resulted in a continuous improvement of the experimental set-ups on the one hand, and of the knowledge of the processes during the nuclear reaction and of the properties of the produced nuclei on the other hand. In the course of this work six new elements from 107 to 112 were produced and identified. An overview of the present status of experimental results and a comparison with theoretical interpretations is given.

New Generation Discovery: A Systematic View for Its Development, Issues and Future

KAUST Repository

Yu, Yi; Ali, Haider

2012-01-01

and interaction with the internet, the rapidly changing digital environment, and the elements and the chain of library services. To address above issues, this paper overviews the different versions of the definition for the new generation discovery by combining

Regulatory control of maintenance activities in Argentine nuclear power plants

International Nuclear Information System (INIS)

Calvo, J.C.; Caruso, G.

2000-01-01

The main maintenance objective is to assure that the safety features of structures, components and systems of nuclear power plants are kept as designed. Therefore, there is a direct relationship between safety and maintenance. Owing to the above mentioned, maintenance activities are considered a relevant regulatory issue for the Argentine Nuclear Regulatory Authority (ARN). This paper describes the regulatory control to maintenance activities of Argentine nuclear power plants. It also addresses essential elements for maintenance control, routine inspections, special inspections during planned outages, audits and license conditions and requirements. (author)

Discovery of time-delayed gene regulatory networks based on temporal gene expression profiling

Directory of Open Access Journals (Sweden)

Guo Zheng

2006-01-01

Full Text Available Abstract Background It is one of the ultimate goals for modern biological research to fully elucidate the intricate interplays and the regulations of the molecular determinants that propel and characterize the progression of versatile life phenomena, to name a few, cell cycling, developmental biology, aging, and the progressive and recurrent pathogenesis of complex diseases. The vast amount of large-scale and genome-wide time-resolved data is becoming increasing available, which provides the golden opportunity to unravel the challenging reverse-engineering problem of time-delayed gene regulatory networks. Results In particular, this methodological paper aims to reconstruct regulatory networks from temporal gene expression data by using delayed correlations between genes, i.e., pairwise overlaps of expression levels shifted in time relative each other. We have thus developed a novel model-free computational toolbox termed TdGRN (Time-delayed Gene Regulatory Network to address the underlying regulations of genes that can span any unit(s of time intervals. This bioinformatics toolbox has provided a unified approach to uncovering time trends of gene regulations through decision analysis of the newly designed time-delayed gene expression matrix. We have applied the proposed method to yeast cell cycling and human HeLa cell cycling and have discovered most of the underlying time-delayed regulations that are supported by multiple lines of experimental evidence and that are remarkably consistent with the current knowledge on phase characteristics for the cell cyclings. Conclusion We established a usable and powerful model-free approach to dissecting high-order dynamic trends of gene-gene interactions. We have carefully validated the proposed algorithm by applying it to two publicly available cell cycling datasets. In addition to uncovering the time trends of gene regulations for cell cycling, this unified approach can also be used to study the complex

Building Nuclear Safety and Security Culture Within Regulatory Body

International Nuclear Information System (INIS)

Huda, K.

2016-01-01

To achieve a higher level of nuclear safety and security, it needs to develop the safety and security culture not only in the facility but also in the regulatory body. The regulatory body, especially needs to develop the safety and security culture within the organization, because it has a function to promote and oversee the culture in the facilities. In this sense, the regulatory body should become a role model. Development of the nuclear safety and security culture should be started by properly understanding its concept and awakening the awareness of individual and organization on the importance of nuclear safety and security. For effectiveness of the culture development in the regulatory body, the following steps are suggested to be taken: setting up of the regulatory requirements, self-assessment, independent assessment review, communication with the licensee, oversight of management system implementation, and integration with regulatory activities. The paper discusses those steps in the framework of development of nuclear safety and security culture in the regulatory body, as well as some important elements in building of the culture in the nuclear facilities. (author)

Identification of conserved regulatory elements by comparative genome analysis

Directory of Open Access Journals (Sweden)

Jareborg Niclas

2003-05-01

Full Text Available Abstract Background For genes that have been successfully delineated within the human genome sequence, most regulatory sequences remain to be elucidated. The annotation and interpretation process requires additional data resources and significant improvements in computational methods for the detection of regulatory regions. One approach of growing popularity is based on the preferential conservation of functional sequences over the course of evolution by selective pressure, termed 'phylogenetic footprinting'. Mutations are more likely to be disruptive if they appear in functional sites, resulting in a measurable difference in evolution rates between functional and non-functional genomic segments. Results We have devised a flexible suite of methods for the identification and visualization of conserved transcription-factor-binding sites. The system reports those putative transcription-factor-binding sites that are both situated in conserved regions and located as pairs of sites in equivalent positions in alignments between two orthologous sequences. An underlying collection of metazoan transcription-factor-binding profiles was assembled to facilitate the study. This approach results in a significant improvement in the detection of transcription-factor-binding sites because of an increased signal-to-noise ratio, as demonstrated with two sets of promoter sequences. The method is implemented as a graphical web application, ConSite, which is at the disposal of the scientific community at http://www.phylofoot.org/. Conclusions Phylogenetic footprinting dramatically improves the predictive selectivity of bioinformatic approaches to the analysis of promoter sequences. ConSite delivers unparalleled performance using a novel database of high-quality binding models for metazoan transcription factors. With a dynamic interface, this bioinformatics tool provides broad access to promoter analysis with phylogenetic footprinting.

Discovery and characterization of a Higgs-like resonance using the Matrix Element Likelihood Approach

Energy Technology Data Exchange (ETDEWEB)

Whitbeck, Andrew J. [Johns Hopkins Univ., Baltimore, MD (United States)

2013-09-01

Understanding the exact mechanism of electroweak symmetry breaking through the discovery and characterization of the Higgs boson is one of the primary goals of the Large Hadron Collider (LHC). Two searches for a Higgs boson decaying to a pair of Z bosons with subsequent decays to either 2ℓ2q or 4ℓ are presented using data recorded with the Compact Muon Solenoid (CMS). The discovery and characterization of a Higgs-like resonance using a new set of tools is reported. The foundations of such tools are developed and prospects for their use in other Higgs channels and at future colliders are addressed. Although the Standard Model (SM) of electroweak interactions has been extremely successful in describing a number of phenomena, there are still questions to be addressed pertaining to its naturalness and its possible connection to beyond the SM physics. Results are interpreted in the context of possible extensions to the SM and their effect on our understanding of the universe.

77 FR 8072 - Semiannual Regulatory Flexibility Agenda

Science.gov (United States)

2012-02-13

... six months. ADDRESSES: Comments should be addressed to Jennifer J. Johnson, Secretary of the Board... Regulatory and Deregulatory Actions, which is coordinated by the Office of Management and Budget under... pledged; and certain other elements including a strategic analysis of the company's plans for maintaining...

Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.

Science.gov (United States)

Meier, Daniel; Schindler, Detlev

2011-01-01

The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.

Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.

Directory of Open Access Journals (Sweden)

Daniel Meier

Full Text Available The Fanconi anemia (FA gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS. In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs, and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.

Transcription Factor NF-IL6 (C/EBPbeta) Activates the Expression of the Mouse MHC Class I H2-Kb Gene in Response to TNF-alpha via the Intragenic Downstream Regulatory Element

Czech Academy of Sciences Publication Activity Database

Hatina, J.; Jansa, Petr; Reischig, J.

2002-01-01

Roč. 22, - (2002), s. 741-749 ISSN 1079-9907 R&D Projects: GA MŠk(CZ) LN00A079 Institutional research plan: CEZ:AV0Z5052915 Keywords : Mouse MHC Class I Gene, Intragenic Downstream Regulatory Element Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.885, year: 2002

A role for circadian evening elements in cold-regulated gene expression in Arabidopsis.

Science.gov (United States)

Mikkelsen, Michael D; Thomashow, Michael F

2009-10-01

The plant transcriptome is dramatically altered in response to low temperature. The cis-acting DNA regulatory elements and trans-acting factors that regulate the majority of cold-regulated genes are unknown. Previous bioinformatic analysis has indicated that the promoters of cold-induced genes are enriched in the Evening Element (EE), AAAATATCT, a DNA regulatory element that has a role in circadian-regulated gene expression. Here we tested the role of EE and EE-like (EEL) elements in cold-induced expression of two Arabidopsis genes, CONSTANS-like 1 (COL1; At5g54470) and a gene encoding a 27-kDa protein of unknown function that we designated COLD-REGULATED GENE 27 (COR27; At5g42900). Mutational analysis indicated that the EE/EEL elements were required for cold induction of COL1 and COR27, and that their action was amplified through coupling with ABA response element (ABRE)-like (ABREL) motifs. An artificial promoter consisting solely of four EE motifs interspersed with three ABREL motifs was sufficient to impart cold-induced gene expression. Both COL1 and COR27 were found to be regulated by the circadian clock at warm growth temperatures and cold-induction of COR27 was gated by the clock. These results suggest that cold- and clock-regulated gene expression are integrated through regulatory proteins that bind to EE and EEL elements supported by transcription factors acting at ABREL sequences. Bioinformatic analysis indicated that the coupling of EE and EEL motifs with ABREL motifs is highly enriched in cold-induced genes and thus may constitute a DNA regulatory element pair with a significant role in configuring the low-temperature transcriptome.

ABO alleles are linked with haplotypes of an erythroid cell-specific regulatory element in intron 1 with a few exceptions attributable to genetic recombination.

Science.gov (United States)

Nakajima, T; Sano, R; Takahashi, Y; Watanabe, K; Kubo, R; Kobayashi, M; Takahashi, K; Takeshita, H; Kominato, Y

2016-01-01

Recent investigation of transcriptional regulation of the ABO genes has identified a candidate erythroid cell-specific regulatory element, named the +5·8-kb site, in the first intron of ABO. Six haplotypes of the site have been reported previously. The present genetic population study demonstrated that each haplotype was mostly linked with specific ABO alleles with a few exceptions, possibly as a result of hybrid formation between common ABO alleles. Thus, investigation of these haplotypes could provide a clue to further elucidation of ABO alleles. © 2015 International Society of Blood Transfusion.

The cis-regulatory element CCACGTGG is involved in ABA and water-stress responses of the maize gene rab28.

Science.gov (United States)

Pla, M; Vilardell, J; Guiltinan, M J; Marcotte, W R; Niogret, M F; Quatrano, R S; Pagès, M

1993-01-01

The maize gene rab28 has been identified as ABA-inducible in embryos and vegetative tissues. It is also induced by water stress in young leaves. The proximal promoter region contains the conserved cis-acting element CCACGTGG (ABRE) reported for ABA induction in other plant genes. Transient expression assays in rice protoplasts indicate that a 134 bp fragment (-194 to -60 containing the ABRE) fused to a truncated cauliflower mosaic virus promoter (35S) is sufficient to confer ABA-responsiveness upon the GUS reporter gene. Gel retardation experiments indicate that nuclear proteins from tissues in which the rab28 gene is expressed can interact specifically with this 134 bp DNA fragment. Nuclear protein extracts from embryo and water-stressed leaves generate specific complexes of different electrophoretic mobility which are stable in the presence of detergent and high salt. However, by DMS footprinting the same guanine-specific contacts with the ABRE in both the embryo and leaf binding activities were detected. These results indicate that the rab28 promoter sequence CCACGTGG is a functional ABA-responsive element, and suggest that distinct regulatory factors with apparent similar affinity for the ABRE sequence may be involved in the hormone action during embryo development and in vegetative tissues subjected to osmotic stress.

Modeling Dynamic Regulatory Processes in Stroke

Science.gov (United States)

McDermott, Jason E.; Jarman, Kenneth; Taylor, Ronald; Lancaster, Mary; Shankaran, Harish; Vartanian, Keri B.; Stevens, Susan L.; Stenzel-Poore, Mary P.; Sanfilippo, Antonio

2012-01-01

The ability to examine the behavior of biological systems in silico has the potential to greatly accelerate the pace of discovery in diseases, such as stroke, where in vivo analysis is time intensive and costly. In this paper we describe an approach for in silico examination of responses of the blood transcriptome to neuroprotective agents and subsequent stroke through the development of dynamic models of the regulatory processes observed in the experimental gene expression data. First, we identified functional gene clusters from these data. Next, we derived ordinary differential equations (ODEs) from the data relating these functional clusters to each other in terms of their regulatory influence on one another. Dynamic models were developed by coupling these ODEs into a model that simulates the expression of regulated functional clusters. By changing the magnitude of gene expression in the initial input state it was possible to assess the behavior of the networks through time under varying conditions since the dynamic model only requires an initial starting state, and does not require measurement of regulatory influences at each time point in order to make accurate predictions. We discuss the implications of our models on neuroprotection in stroke, explore the limitations of the approach, and report that an optimized dynamic model can provide accurate predictions of overall system behavior under several different neuroprotective paradigms. PMID:23071432

Systematic identification of regulatory variants associated with cancer risk.

Science.gov (United States)

Liu, Song; Liu, Yuwen; Zhang, Qin; Wu, Jiayu; Liang, Junbo; Yu, Shan; Wei, Gong-Hong; White, Kevin P; Wang, Xiaoyue

2017-10-23

Most cancer risk-associated single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) are noncoding and it is challenging to assess their functional impacts. To systematically identify the SNPs that affect gene expression by modulating activities of distal regulatory elements, we adapt the self-transcribing active regulatory region sequencing (STARR-seq) strategy, a high-throughput technique to functionally quantify enhancer activities. From 10,673 SNPs linked with 996 cancer risk-associated SNPs identified in previous GWAS studies, we identify 575 SNPs in the fragments that positively regulate gene expression, and 758 SNPs in the fragments with negative regulatory activities. Among them, 70 variants are regulatory variants for which the two alleles confer different regulatory activities. We analyze in depth two regulatory variants-breast cancer risk SNP rs11055880 and leukemia risk-associated SNP rs12142375-and demonstrate their endogenous regulatory activities on expression of ATF7IP and PDE4B genes, respectively, using a CRISPR-Cas9 approach. By identifying regulatory variants associated with cancer susceptibility and studying their molecular functions, we hope to help the interpretation of GWAS results and provide improved information for cancer risk assessment.

Elements in the history of the Periodic Table.

Science.gov (United States)

Rouvray, Dennis H

2004-06-01

Discovery of the Periodic Table was rendered possible only after four decisive prerequisites had been achieved. These were (i) the abandonment of the metaphysical and occult notions of elements that typified the alchemical era; (ii) the adoption of a modern and workable definition of an element; (iii) the development of analytical chemical techniques for the isolation of the elements and determination of their properties; and (iv) the devising of a means of associating each element with a characteristic natural number. The Periodic Table made its appearance on cue almost as soon as these preconditions had been fulfilled.

Strengthening Regulatory Competence through Techno-managerial Knowledge Integration: Indian Experience

International Nuclear Information System (INIS)

Kuchibhotla, S.

2016-01-01

Competence development is the process of identifying the competencies required to perform a given job, role or set of tasks successfully at workplace. Strengthening regulatory competence, for the nuclear regulator, is essential to ensure skilled and competent human resources for performing the functions of the Regulatory Body. The strengthening of existing competence level for the Indian nuclear regulator, takes into account the understanding of the elements such as legal basis and regulatory processes governing operations of regulatory body, technological competences for performing regulatory functions, competences pertinent to regulatory practices, and competences related to personal and interpersonal effectiveness within the organization. Competency data from AERB divisions was compiled to identify gaps at various positions with recommendations for making specialized training modules and modifications to basic and refresher training modules. The exercise is aimed at providing continual improvement in skills and knowledge of human resources at AERB in a phased manner. (author)

Regulatory agencies and regulatory risk

OpenAIRE

Knieps, Günter; Weiß, Hans-Jörg

2008-01-01

The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

Strengthening Regulatory Competence in Pakistan

International Nuclear Information System (INIS)

Sadiq, M.

2016-01-01

Capacity building of Pakistan Nuclear Regulatory Authority is considered an essential element in pursuit of its vision to become a world class regulatory body. Since its inception in 2001, PNRA has continuously endeavoured to invest in its people, develop training infrastructure and impart sound knowledge and professional skills with the aim to improve its regulatory effectiveness. The use of nuclear and radioactive material in Pakistan has increased manifold in recent years, thus induction of more manpower was needed for regulatory oversight. PNRA adopted two pronged approach for meeting the manpower demand (a) employment of university graduates through fast track recruitment drive and (b) induction of graduates by offering fellowships for Master degree programs. Although, the newly employed staff was selected on the basis of their excellent academic qualifications in basic and applied sciences, but they required rigorous knowledge and skills in regulatory perspectives. In order to implement a structured training program, PNRA conducted Training Needs Assessment (TNA) and identified competency gaps of the regulatory staff in legal, technical, regulatory practice and behavioural domains. PNRA took several initiatives for capacity building which included establishment of a training centre for sustainability of trainings, initiation of a fellowship scheme for Master program, attachment of staff at local institutes for on-the-job training and placement at foreign regulatory bodies and organizations for technical development with the assistance of IAEA. The above strategies have been very beneficial in competence building of the PNRA staff to perform all regulatory activities indigenously for nuclear power plants, research reactors and radiation facilities. Provision of vibrant technical support to IAEA and Member States in various programs by PNRA is a landmark of these competence development efforts. This paper summarizes PNRA initiatives and the International Atomic

78 FR 14840 - U.S.-EU High Level Regulatory Cooperation Forum-Stakeholder Session

Science.gov (United States)

2013-03-07

... OFFICE OF MANAGEMENT AND BUDGET U.S.-EU High Level Regulatory Cooperation Forum--Stakeholder... the future. Time constraints may prevent some stakeholders from making presentations on April 10th or... stakeholder session agenda will in no way prejudge the specific elements of a future transatlantic regulatory...

Identification of cis-acting regulatory elements in the human oxytocin gene promoter.

Science.gov (United States)

Richard, S; Zingg, H H

1991-12-01

The expression of hormone-inducible genes is determined by the interaction of trans-acting factors with hormone-inducible elements and elements mediating basal and cell-specific expression. We have shown earlier that the gene encoding the hypothalamic nonapeptide oxytocin (OT) is under the control of an estrogen response element (ERE). The present study was aimed at identifying cis-acting elements mediating basal expression of the OT gene. A construct containing sequences -381 to +36 of the human OT gene was linked to a reporter gene and transiently transfected into a series of neuronal and nonneuronal cell lines. Expression of this construct was cell specific: it was highest in the neuroblastoma-derived cell line, Neuro-2a, and lowest in NIH 3T3 and JEG-3 cells. By 5' deletion analysis, we determined that a segment from -49 to +36 was capable of mediating cells-pecific promoter activity. Within this segment, we identified three proximal promoter elements (PPE-1, PPE-2, and PPE-3) that are each required for promoter activity. Most notably, mutation of a conserved purine-rich element (GAGAGA) contained within PPE-2 leads to a 10-fold decrease in promoter strength. Gel mobility shift analysis with three different double-stranded oligonucleotides demonstrated that each proximal promoter element binds distinct nuclear factors. In each case, only the homologous oligonucleotide, but neither of the oligonucleotides corresponding to adjacent elements, was able to act as a competitor. Thus, a different set of factors appears to bind independently to each element. By reinserting the homologous ERE or a heterologous glucocorticoid response element upstream of intact or altered proximal promoter segments we determined that removal or mutation of proximal promoter elements decreases basal expression, but does not abrogate the hormone responsiveness of the promoter. In conclusion, these results indicate that an important component of the transcriptional activity of the OT

The limits of de novo DNA motif discovery.

Directory of Open Access Journals (Sweden)

David Simcha

Full Text Available A major challenge in molecular biology is reverse-engineering the cis-regulatory logic that plays a major role in the control of gene expression. This program includes searching through DNA sequences to identify "motifs" that serve as the binding sites for transcription factors or, more generally, are predictive of gene expression across cellular conditions. Several approaches have been proposed for de novo motif discovery-searching sequences without prior knowledge of binding sites or nucleotide patterns. However, unbiased validation is not straightforward. We consider two approaches to unbiased validation of discovered motifs: testing the statistical significance of a motif using a DNA "background" sequence model to represent the null hypothesis and measuring performance in predicting membership in gene clusters. We demonstrate that the background models typically used are "too null," resulting in overly optimistic assessments of significance, and argue that performance in predicting TF binding or expression patterns from DNA motifs should be assessed by held-out data, as in predictive learning. Applying this criterion to common motif discovery methods resulted in universally poor performance, although there is a marked improvement when motifs are statistically significant against real background sequences. Moreover, on synthetic data where "ground truth" is known, discriminative performance of all algorithms is far below the theoretical upper bound, with pronounced "over-fitting" in training. A key conclusion from this work is that the failure of de novo discovery approaches to accurately identify motifs is basically due to statistical intractability resulting from the fixed size of co-regulated gene clusters, and thus such failures do not necessarily provide evidence that unfound motifs are not active biologically. Consequently, the use of prior knowledge to enhance motif discovery is not just advantageous but necessary. An implementation of

Casein kinase 1 regulates sterol regulatory element-binding protein (SREBP) to control sterol homeostasis.

Science.gov (United States)

Brookheart, Rita T; Lee, Chih-Yung S; Espenshade, Peter J

2014-01-31

Sterol homeostasis is tightly controlled by the sterol regulatory element-binding protein (SREBP) transcription factor that is highly conserved from fungi to mammals. In fission yeast, SREBP functions in an oxygen-sensing pathway to promote adaptation to decreased oxygen supply that limits oxygen-dependent sterol synthesis. Low oxygen stimulates proteolytic cleavage of the SREBP homolog Sre1, generating the active transcription factor Sre1N that drives expression of sterol biosynthetic enzymes. In addition, low oxygen increases the stability and DNA binding activity of Sre1N. To identify additional signals controlling Sre1 activity, we conducted a genetic overexpression screen. Here, we describe our isolation and characterization of the casein kinase 1 family member Hhp2 as a novel regulator of Sre1N. Deletion of Hhp2 increases Sre1N protein stability and ergosterol levels in the presence of oxygen. Hhp2-dependent Sre1N degradation by the proteasome requires Hhp2 kinase activity, and Hhp2 binds and phosphorylates Sre1N at specific residues. Our results describe a role for casein kinase 1 as a direct regulator of sterol homeostasis. Given the role of mammalian Hhp2 homologs, casein kinase 1δ and 1ε, in regulation of the circadian clock, these findings may provide a mechanism for coordinating circadian rhythm and lipid metabolism.

76 FR 34786 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

Science.gov (United States)

2011-06-14

...-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate Effectiveness of... is hereby given that, on May 25, 2011, The NASDAQ Stock Market LLC (the ``Exchange'' or ``NASDAQ... markets in a large number of stocks and that contribute to price discovery by posting attributable quotes...

New Generation Discovery: A Systematic View for Its Development, Issues and Future

KAUST Repository

Yu, Yi

2012-11-01

Collecting, storing, discovering, and locating are integral parts of the composition of the library. To fully utilize the library and achieve its ultimate value, the construction and production of discovery has always been a central part of the library’s practice and identity. That is the reason why the new generation (also called the next-generation discovery) discovery gets such striking effect since it came into library automation arena. However, when we talk about the new generation of discovery in the library domain, we should see it in the entirety of the library as one of its organic parts and consider its progress along with the evolution of the whole library world. We should have a deeper understanding about its relationship and interaction with the internet, the rapidly changing digital environment, and the elements and the chain of library services. To address above issues, this paper overviews the different versions of the definition for the new generation discovery by combining our own understanding. The paper also gives our own description for its properties and characteristics. The paper points out what challenges, which extends the technology domain to commercial interests and business strategy, are faced by the discovery applications, and how library and library professionals deal with those challenges. Finally, the paper elaborates on the promise brought by the new discovery development and what the next exploration might be for its future.

Continuous Improvement of the Regulatory Framework for the Control of Medical Exposure

International Nuclear Information System (INIS)

Larcher, A.M.; Ortiz lopez, Pedro; Arias, Cesar; Marechal, Maria H.; Hernandez Alvarez, Ramon; Ferrer Garcia, Natividad; Castaneda Mucino, Antonia; Faller, Blanca

2011-01-01

Background: One of the key elements to guide the improvement of the regulatory control is the availability of a self-assessment tool for regulatory performance. Although there is general guidance on self-assessment for regulators and users (IAEA), there is a need for specific advice on how to address challenges and difficulties faced by regulatory bodies, when regulating radiation protection of patients. Examples of these challenges are the need of regulatory initiatives, in cooperation with health and education authorities, professional bodies and equipment suppliers, and to put in place necessary elements that are beyond responsibility of individual users of radiation, to enable them compliance with safety standards. Purpose: within the programme of the Ibero American Forum of Nuclear and Radiation Safety Regulatory Organizations, a project to develop such a self assessment tool for the regulatory control of medical exposure has been designed. Method: national experiences in transposing and enforcing the international radiation safety standards, as to how the requirements are included in national regulations are reviewed. Further, difficulties to the implementation of safety requirements are included in national regulations are analyzed and a self assessment approach and possible regulatory solutions are presented. Results and discussion: in tis study the following documents are being produced: 1) Transposition of international requirements into national regulations in the six countries of the Forum, 2) difficulties to implement and enforce the requirements, 3) guidance on self assessment of regulatory framework for medical exposure, 4) suggested contribution to the revision of international radiation safety standards. (authors)

Regulatory Oversight for New Projects - Challenges and Improvement in Regulation

International Nuclear Information System (INIS)

Lall, F.

2016-01-01

From inception, there has been rise in number of Nuclear Power Plants (NPP) even though very few accidents / events led to intermittent setbacks. However these accidents / events have posed challenges towards enhancement of safety and scope of regulation in all phases of NPP such as siting, design, construction, commissioning and decommissioning. It is essential to ensure compliance to these enhanced safety requirements during all phases of NPP. New and evolutionary reactors are under threshold for regulatory consideration world over. The variety of technologies and genres by themselves pose challenges to regulatory bodies. These challenges are to be addressed through systematic enhancement of the regulation including updating of regulatory documents. The paper touches upon some key elements to be considered towards such enhancement of regulation during all stages of NPP. These being; ensuring quality assurance, regulatory oversight especially over supply chain and contractors, counterfeit material specifically in case of international dealings, emergency handling in case of multi-unit site, feedback and associated enhancements from international events, construction experience database and feedback for safety enhancement, qualification and acceptance of first of a kind systems, regulatory enforcement specifically in case of imported reactors and maintaining interface between safety and security. Regulation in present context has become dynamic and Regulatory bodies need to continue enhancement of its current regulation taking into account the technological developments, feedback from construction, operation and accidents in the current fleet of plants. The paper touches upon some of these elements and highlights the challenges and improvements in regulation. (author)

Postinduction represssion of the β-interferon gene is mediated through two positive regulatory domains

International Nuclear Information System (INIS)

Whittemore, L.A.; Maniatis, T.

1990-01-01

Virus induction of the human β-interferon (β-IFN) gene results in an increase in the rate of β-IFN mRNA synthesis, followed by a rapid postinduction decrease. In this paper, the authors show that two β-IFN promoter elements, positive regulatory domains I and II (PRDI and PRDII), which are required for virus induction of the β-IFN gene are also required for the postinduction turnoff. Although protein synthesis is not necessary for activation, it is necessary for repression of these promoter elements. Examination of nuclear extracts from cells infected with virus reveals the presence of virus-inducible, cycloheximide-sensitive, DNA-binding activities that interact specifically with PRDI or PRDII. They propose that the postinduction repression of β-IFN gene transcription involves virus inducible repressors that either bind directly to the positive regulatory elements of the β-IFN promoter or inactivate the positive regulatory factors bound to PRDI and PRDII

Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis.

Science.gov (United States)

Song, Zhenhua; Zhang, Chi; He, Lingxiao; Sui, Yanfang; Lin, Xiafei; Pan, Jingjing

2018-05-01

Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post-transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes. Copyright © 2018 Elsevier Inc. All rights reserved.

The Secret Life of the Periodic Table - Unlocking the mysteries of all 118 elements

International Nuclear Information System (INIS)

Still, Ben; Davis, Jon; Depovere, Paul

2017-01-01

Every element has character, be it volatile, aloof, gregarious or enigmatic. They also have incredible stories of how they came to be, how they were discovered and how their qualities have been harnessed to make everything we have in the world. This book gives a fascinating insight into the discovery and use of all 118 elements. It uncovers incredible stories of how Mendeleev's table was formulated and the individual elements found, as well as explaining the fundamentals of atomic science and each element's place in the table and our universe. Each element description includes a fact box showing atomic number, atomic weight, radius, melting point, boiling point, density, and the year of its discovery and by whom. There are many side-bars, boxes and extended captions covering topics of interest and also fascinating trivia about the elements. This book is the French translation of 'The Secret Life of the Periodic Table' published by Firefly Books (Canada, Sep 2016)

LDsplit: screening for cis-regulatory motifs stimulating meiotic recombination hotspots by analysis of DNA sequence polymorphisms.

Science.gov (United States)

Yang, Peng; Wu, Min; Guo, Jing; Kwoh, Chee Keong; Przytycka, Teresa M; Zheng, Jie

2014-02-17

As a fundamental genomic element, meiotic recombination hotspot plays important roles in life sciences. Thus uncovering its regulatory mechanisms has broad impact on biomedical research. Despite the recent identification of the zinc finger protein PRDM9 and its 13-mer binding motif as major regulators for meiotic recombination hotspots, other regulators remain to be discovered. Existing methods for finding DNA sequence motifs of recombination hotspots often rely on the enrichment of co-localizations between hotspots and short DNA patterns, which ignore the cross-individual variation of recombination rates and sequence polymorphisms in the population. Our objective in this paper is to capture signals encoded in genetic variations for the discovery of recombination-associated DNA motifs. Recently, an algorithm called "LDsplit" has been designed to detect the association between single nucleotide polymorphisms (SNPs) and proximal meiotic recombination hotspots. The association is measured by the difference of population recombination rates at a hotspot between two alleles of a candidate SNP. Here we present an open source software tool of LDsplit, with integrative data visualization for recombination hotspots and their proximal SNPs. Applying LDsplit on SNPs inside an established 7-mer motif bound by PRDM9 we observed that SNP alleles preserving the original motif tend to have higher recombination rates than the opposite alleles that disrupt the motif. Running on SNP windows around hotspots each containing an occurrence of the 7-mer motif, LDsplit is able to guide the established motif finding algorithm of MEME to recover the 7-mer motif. In contrast, without LDsplit the 7-mer motif could not be identified. LDsplit is a software tool for the discovery of cis-regulatory DNA sequence motifs stimulating meiotic recombination hotspots by screening and narrowing down to hotspot associated SNPs. It is the first computational method that utilizes the genetic variation of

Regulatory Expectations for Safety Culture

Energy Technology Data Exchange (ETDEWEB)

Jung, Su Jin; Oh, Jang Jin; Choi, Young Sung [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

2014-05-15

The oversight of licensee's safety culture becomes an important issue that attracts great public and political concerns recently in Korea. Beginning from the intended violation of rules, a series of corruptions, documents forgery and disclosure of wrong-doings made the public think that the whole mindset of nuclear workers has been inadequate. Thus, they are demanding that safety culture shall be improved and that regulatory body shall play more roles and responsibilities for the improvements and oversight for them. This paper introduces, as an effort of regulatory side, recent changes in the role of regulators in safety culture, regulatory expectations on the desired status of licensee's safety culture, the pilot inspection program for safety culture and research activity for the development of oversight system. After the Fukushima accident in Japan 2011, many critics has searched for cultural factors that caused the unacceptable negligence pervaded in Japan nuclear society and the renewed emphasis has been placed on rebuilding safety culture by operators, regulators, and relevant institutions globally. Significant progress has been made in how to approach safety culture and led to a new perspective different from the existing normative assessment method both in operators and regulatory side. Regulatory expectations and oversight of them are based on such a new holistic concept for human, organizational and cultural elements to maintain and strengthen the integrity of defense in depth and consequently nuclear safety.

Regulatory Expectations for Safety Culture

International Nuclear Information System (INIS)

Jung, Su Jin; Oh, Jang Jin; Choi, Young Sung

2014-01-01

The oversight of licensee's safety culture becomes an important issue that attracts great public and political concerns recently in Korea. Beginning from the intended violation of rules, a series of corruptions, documents forgery and disclosure of wrong-doings made the public think that the whole mindset of nuclear workers has been inadequate. Thus, they are demanding that safety culture shall be improved and that regulatory body shall play more roles and responsibilities for the improvements and oversight for them. This paper introduces, as an effort of regulatory side, recent changes in the role of regulators in safety culture, regulatory expectations on the desired status of licensee's safety culture, the pilot inspection program for safety culture and research activity for the development of oversight system. After the Fukushima accident in Japan 2011, many critics has searched for cultural factors that caused the unacceptable negligence pervaded in Japan nuclear society and the renewed emphasis has been placed on rebuilding safety culture by operators, regulators, and relevant institutions globally. Significant progress has been made in how to approach safety culture and led to a new perspective different from the existing normative assessment method both in operators and regulatory side. Regulatory expectations and oversight of them are based on such a new holistic concept for human, organizational and cultural elements to maintain and strengthen the integrity of defense in depth and consequently nuclear safety

Nuclear regulatory review of licensee self-assessment (LSA)

International Nuclear Information System (INIS)

2003-01-01

Licensee self-assessment (LSA) by nuclear power plant operators is described as all the activities that a licensee performs in order to identify opportunities for improvements. An LSA is part of an organisation's holistic management system, which must include other process elements. Particularly important elements are: a process for choosing which identified potential improvements should be implemented and a process of project management for implementing the improvements chosen. Nuclear regulators expect the licensee to run an effective LSA programme, which reflects the licensee's 'priority to safety'. Based on contributions from members of the NEA Committee on Nuclear Regulatory Activities (CNRA), this publication provides an overview of the current regulatory philosophy on and approaches to LSA as performed by licensees. The publication's intended audience is primarily nuclear safety regulators, but government authorities, nuclear power plant operators and the general public may also be interested. (author)

Enriching Discovery Layers: A Product Comparison of Content Enrichment Services Syndetic Solutions and Content Café 2

Directory of Open Access Journals (Sweden)

Allison DaSilva

2014-10-01

Full Text Available A comparative analysis of content enrichment services, Syndetic Solutions and Content Café 2, was undertaken to explore which service would provide public library users with a superior online search and discovery experience through the enriched data elements offered, specifically looking at the cover image data element and exploring what factors impact the display of said element. A data-set of 250 items in five different formats, including books, CDs, DVDs, e-books, and video games, was searched in four North American public libraries’ discovery layers to compare the integration, extent, and quality of the cover image data element supplied by Syndetic Solutions and Content Café 2. Based on an analysis of the URLs, ISBNs, and UPCs for each of the 250 items, it was determined that the integration, and therefore the display, of the cover image data element was impacted by: (1 whether or not an ISBN or UPC was listed in the MARC bibliographic record; (2 which ISBN or UPC was listed, as items could potentially have more than one; (3 the inclusion of both ISBNs and UPCs in the record and the settings of the discovery tool; (4 the order in which the ISBNs or UPCs were listed in the record; and (5 whether or not Syndetic Solutions or Content Café 2 had the image data in its database at the time of the search. The quality of the cover image displayed was found to be impacted by the size requested by the library and the size of the image provided by the publisher. These findings may also have implications for the integration of other enriched data elements.

Information system fur the management of a regulatory programme

International Nuclear Information System (INIS)

Ortiz, P.; Mrabit, K.; Miaw, S.

1998-01-01

A Regulatory Programme to monitor safety of activities involving radiation sources, implies the existence of a Regulatory Authority empowered by legislation to issue radiation protection regulations and to monitor compliance with those regulations. The core element of the programme is a system of notification and authorization (registration and licensing), inspection and enforcement. The efficiency of this system is largely dependent on the availability of reliable information on the inventory of radiation sources and installations, the administrative status of the facilities (authorization), prompt processing of inspection reports and follow up of regulatory actions, including monitoring deadlines. Essential data relevant to safety, such as personal dosimetry for occupationally exposed individuals, inspection findings and incident reports would provide, in addition, an insight on the overall safety of the country. A simple but comprehensive Regulatory Authority Information System (RAIS) linked to the authorization and inspection process will largely facilitate regulatory decisions and actions. A readily available and reliable information from the various regulatory activities will facilitate planning, optimization of resources, monitoring safety related data, disseminating safety information, making decisions and follow up regulatory actions including monitoring dead lines. The implementation of the system in more than 50 countries will contribute to experience exchange and harmonization of regulatory activities. (author)

FORECAST: Regulatory effects cost analysis software annual

International Nuclear Information System (INIS)

Lopez, B.; Sciacca, F.W.

1991-11-01

Over the past several years the NRC has developed a generic cost methodology for the quantification of cost/economic impacts associated with a wide range of new or revised regulatory requirements. This methodology has been developed to aid the NRC in preparing Regulatory Impact Analyses (RIAs). These generic costing methods can be useful in quantifying impacts both to industry and to the NRC. The FORECAST program was developed to facilitate the use of the generic costing methodology. This PC program integrates the major cost considerations that may be required because of a regulatory change. FORECAST automates much of the calculations typically needed in an RIA and thus reduces the time and labor required to perform these analysis. More importantly, its integrated and consistent treatment of the different cost elements should help assure comprehensiveness, uniformity, and accuracy in the preparation of needed cost estimates

An empirical model of Onecut binding activity at the sea urchin SM50 C-element gene regulatory region.

Science.gov (United States)

Otim, Ochan

2017-01-01

Studying the formation of endoskeleton in many species is complex and difficult. The sea urchin embryo offers an unparalleled platform for understanding this process because of the ease with which its skeletogenic mesenchyme cells can be manipulated. In this study, preliminary evidence from biochemical studies towards understanding the role of the Onecut transcription factor during sea urchin skeletogenic mesenchyme cell specification is presented. Based on the evidence, an empirical model is proposed showing how Onecut, together with associated co-factors, may be using the C-element of the SM50 gene regulatory region in advance of the sea urchin Strongylocentrotus purpuratus spicule development. In the model, Onecut recognizes and binds the DNA sequence CATCGATCTC in the C-element without temporal restriction. Onecut then utilizes different sets of co-factors to switch from its unknown function early in development (four cell stage to the mesenchyme blastula stage), to its known role in the oral-aboral boundary thereafter. At the writing of this report, definitive evidence as to whether the "early" factors are expressed in all cells except the micromere lineages, or whether the "late" factors are expressed in micromere descendants or ectodermal precursors only are lacking. The former would suggest a possible Onecut repression function for the early co-factors outside the micromere lineages; the latter scenario would suggest a Onecut activation function for the late co-factors in the presumptive ciliary band.

Regulatory RNA design through evolutionary computation and strand displacement.

Science.gov (United States)

Rostain, William; Landrain, Thomas E; Rodrigo, Guillermo; Jaramillo, Alfonso

2015-01-01

The discovery and study of a vast number of regulatory RNAs in all kingdoms of life over the past decades has allowed the design of new synthetic RNAs that can regulate gene expression in vivo. Riboregulators, in particular, have been used to activate or repress gene expression. However, to accelerate and scale up the design process, synthetic biologists require computer-assisted design tools, without which riboregulator engineering will remain a case-by-case design process requiring expert attention. Recently, the design of RNA circuits by evolutionary computation and adapting strand displacement techniques from nanotechnology has proven to be suited to the automated generation of DNA sequences implementing regulatory RNA systems in bacteria. Herein, we present our method to carry out such evolutionary design and how to use it to create various types of riboregulators, allowing the systematic de novo design of genetic control systems in synthetic biology.

Elemental characterization of coal ash and its leachates using sequential extraction techniques

International Nuclear Information System (INIS)

Landsberger, S.; Cerbus, J.F.; Larson, S.

1995-01-01

Over 50 million tons of coal ash are produced annually in North America. Technological improvements in air pollution control have decreased stack emissions but have also increased contaminant concentrations in the ash of coal-fired boiler applications. The leaching of heavy metals and other elements during regulatory tests may cause coal ash to be classified as hazardous waste, complicating land disposal. The hazardous nature of coal ash remains unclear because current toxicity tests fail to effectively characterize the elemental distribution and chemical solubility of trace metals in the landfill environment. Leaching characteristics of ash samples can be investigated with various laboratory extraction procedures in association with multi-elemental analytical techniques (e.g., neutron activation analysis and inductively coupled plasma - atomic emission spectroscopy). Such methods provide more thorough analyses of coal ash leaching dynamics than the regulatory assessments can demonstrate. Regulatory elements including Ag, As, Ba, Cd, Cr, Hg, Pb, and Se were shown to remain in largely insoluble forms while elements such as B and S leached at higher levels. Experimental results may assist operators of coal-fired boiler industries in selecting coal types and disposal options to curtail the leaching of potentially toxic inorganic contaminants. (author) 12 refs.; 4 figs.; 3 tabs

A system-level model for the microbial regulatory genome.

Science.gov (United States)

Brooks, Aaron N; Reiss, David J; Allard, Antoine; Wu, Wei-Ju; Salvanha, Diego M; Plaisier, Christopher L; Chandrasekaran, Sriram; Pan, Min; Kaur, Amardeep; Baliga, Nitin S

2014-07-15

Microbes can tailor transcriptional responses to diverse environmental challenges despite having streamlined genomes and a limited number of regulators. Here, we present data-driven models that capture the dynamic interplay of the environment and genome-encoded regulatory programs of two types of prokaryotes: Escherichia coli (a bacterium) and Halobacterium salinarum (an archaeon). The models reveal how the genome-wide distributions of cis-acting gene regulatory elements and the conditional influences of transcription factors at each of those elements encode programs for eliciting a wide array of environment-specific responses. We demonstrate how these programs partition transcriptional regulation of genes within regulons and operons to re-organize gene-gene functional associations in each environment. The models capture fitness-relevant co-regulation by different transcriptional control mechanisms acting across the entire genome, to define a generalized, system-level organizing principle for prokaryotic gene regulatory networks that goes well beyond existing paradigms of gene regulation. An online resource (http://egrin2.systemsbiology.net) has been developed to facilitate multiscale exploration of conditional gene regulation in the two prokaryotes. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Maria Goeppert Mayer's Theoretical Work on Rare-Earth and Transuranic Elements

OpenAIRE

Wang, Frank Y.

2008-01-01

After the discovery of element 93 neptunium by Edwin McMillan and Philip H. Abelson in 1941, Maria Goeppert Mayer applied the Thomas-Fermi model to calculate the electronic configuration of heavy elements and predicted the occurrence of a second rare-earth series in the vicinity of elements 91 or 92 extending to the transuranic elements. Mayer was motivated by Enrico Fermi, who was at the time contemplating military uses of nuclear energy. Historical development of nuclear science research le...

Sterol regulatory element-binding proteins are regulators of the rat thyroid peroxidase gene in thyroid cells.

Directory of Open Access Journals (Sweden)

Christine Rauer

Full Text Available Sterol regulatory element-binding proteins (SREBPs-1c and -2, which were initially discovered as master transcriptional regulators of lipid biosynthesis and uptake, were recently identified as novel transcriptional regulators of the sodium-iodide symporter gene in the thyroid, which is essential for thyroid hormone synthesis. Based on this observation that SREBPs play a role for thyroid hormone synthesis, we hypothesized that another gene involved in thyroid hormone synthesis, the thyroid peroxidase (TPO gene, is also a target of SREBP-1c and -2. Thyroid epithelial cells treated with 25-hydroxycholesterol, which is known to inhibit SREBP activation, had about 50% decreased mRNA levels of TPO. Similarly, the mRNA level of TPO was reduced by about 50% in response to siRNA mediated knockdown of both, SREBP-1 and SREBP-2. Reporter gene assays revealed that overexpression of active SREBP-1c and -2 causes a strong transcriptional activation of the rat TPO gene, which was localized to an approximately 80 bp region in the intron 1 of the rat TPO gene. In vitro- and in vivo-binding of both, SREBP-1c and SREBP-2, to this region in the rat TPO gene could be demonstrated using gel-shift assays and chromatin immunoprecipitation. Mutation analysis of the 80 bp region of rat TPO intron 1 revealed two isolated and two overlapping SREBP-binding elements from which one, the overlapping SRE+609/InvSRE+614, was shown to be functional in reporter gene assays. In connection with recent findings that the rat NIS gene is also a SREBP target gene in the thyroid, the present findings suggest that SREBPs may be possible novel targets for pharmacological modulation of thyroid hormone synthesis.

The pairwise disconnectivity index as a new metric for the topological analysis of regulatory networks

Directory of Open Access Journals (Sweden)

Wingender Edgar

2008-05-01

Full Text Available Abstract Background Currently, there is a gap between purely theoretical studies of the topology of large bioregulatory networks and the practical traditions and interests of experimentalists. While the theoretical approaches emphasize the global characterization of regulatory systems, the practical approaches focus on the role of distinct molecules and genes in regulation. To bridge the gap between these opposite approaches, one needs to combine 'general' with 'particular' properties and translate abstract topological features of large systems into testable functional characteristics of individual components. Here, we propose a new topological parameter – the pairwise disconnectivity index of a network's element – that is capable of such bridging. Results The pairwise disconnectivity index quantifies how crucial an individual element is for sustaining the communication ability between connected pairs of vertices in a network that is displayed as a directed graph. Such an element might be a vertex (i.e., molecules, genes, an edge (i.e., reactions, interactions, as well as a group of vertices and/or edges. The index can be viewed as a measure of topological redundancy of regulatory paths which connect different parts of a given network and as a measure of sensitivity (robustness of this network to the presence (absence of each individual element. Accordingly, we introduce the notion of a path-degree of a vertex in terms of its corresponding incoming, outgoing and mediated paths, respectively. The pairwise disconnectivity index has been applied to the analysis of several regulatory networks from various organisms. The importance of an individual vertex or edge for the coherence of the network is determined by the particular position of the given element in the whole network. Conclusion Our approach enables to evaluate the effect of removing each element (i.e., vertex, edge, or their combinations from a network. The greatest potential value of

The Regulatory Framework for Privacy and Security

Science.gov (United States)

Hiller, Janine S.

The internet enables the easy collection of massive amounts of personally identifiable information. Unregulated data collection causes distrust and conflicts with widely accepted principles of privacy. The regulatory framework in the United States for ensuring privacy and security in the online environment consists of federal, state, and self-regulatory elements. New laws have been passed to address technological and internet practices that conflict with privacy protecting policies. The United States and the European Union approaches to privacy differ significantly, and the global internet environment will likely cause regulators to face the challenge of balancing privacy interests with data collection for many years to come.

Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases

Directory of Open Access Journals (Sweden)

Min Kyung Sung

2014-12-01

Full Text Available Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE data: type 2 diabetes mellitus (DM, hypertension (HT, and coronary artery disease (CAD. We showed that epistatic single-nucleotide polymorphisms (SNPs were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012, which suggested that the disruption of the regulatory regions where transcription factors bind may be involved in the disease mechanism. Accordingly, to identify the genes affected by the SNPs, we employed whole-genome multiple-cell-type enhancer data which discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE. Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD.

Topology Discovery Using Cisco Discovery Protocol

OpenAIRE

Rodriguez, Sergio R.

2009-01-01

In this paper we address the problem of discovering network topology in proprietary networks. Namely, we investigate topology discovery in Cisco-based networks. Cisco devices run Cisco Discovery Protocol (CDP) which holds information about these devices. We first compare properties of topologies that can be obtained from networks deploying CDP versus Spanning Tree Protocol (STP) and Management Information Base (MIB) Forwarding Database (FDB). Then we describe a method of discovering topology ...

From transuranic to superheavy elements a story of dispute and creation

CERN Document Server

Kragh, Helge

2018-01-01

The story of superheavy elements  - those at the very end of the periodic table  - is not well known outside the community of heavy-ion physicists and nuclear chemists. But it is a most interesting story which deserves to be known also to historians, philosophers, and sociologists of science and indeed to the general public. This is what the present work aims at. It tells the story or rather parts of the story, of how physicists and chemists created elements heavier than uranium or searched for them in nature. And it does so with an emphasis on the frequent discovery and naming disputes concerning the synthesis of very heavy elements. Moreover, it calls attention to the criteria which scientists have adopted for what it means to have discovered a new element. In this branch of modern science it may be more appropriate to speak of creation instead of discovery. The work will be of interest to scientists as well as to scholars studying modern science from a meta-perspective.

Natural Products in the Discovery of Agrochemicals.

Science.gov (United States)

Loiseleur, Olivier

2017-12-01

Natural products have a long history of being used as, or serving as inspiration for, novel crop protection agents. Many of the discoveries in agrochemical research in the last decades have their origin in a wide range of natural products from a variety of sources. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, new agricultural practices and evolving regulatory requirements, the needs for new agrochemical tools remains as critical as ever. In that respect, nature continues to be an important source for novel chemical structures and biological mechanisms to be applied for the development of pest control agents. Here we review several of the natural products and their derivatives which contributed to shape crop protection research in past and present.

Fifty years of herbicide research: comparing the discovery of trifluralin and halauxifen-methyl.

Science.gov (United States)

Epp, Jeffrey B; Schmitzer, Paul R; Crouse, Gary D

2018-01-01

Fifty years separate the commercialization of the herbicides trifluralin and halauxifen-methyl. Despite the vast degree of technological change that occurred over that time frame, some aspects of their discovery stories are remarkably similar. For example, both herbicides were prepared very early in the iterative discovery process and both were developed from known lead compound structures by hypothesis-driven research efforts without the use of in vitro assays or computer-aided molecular design. However, there are aspects of the halauxifen-methyl and trifluralin discovery stories that are substantially different. For example, the chemical technology required for the cost-effective production of halauxifen-methyl simply did not exist just two decades prior to its commercial launch. By contrast, the chemical technology required for the cost-effective production of trifluralin was reported in the chemical literature more than two decades prior to its commercial launch. In addition, changes in regulatory environment since the early 1960s ensured that their respective discovery to commercial launch stories would also differ in substantial ways. Ultimately, the time and cost required to develop and register halauxifen-methyl demanded a global initial business case while the lower registration hurdles that trifluralin cleared enabled a narrow initial business case mainly focused on the USA. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

WeederH: an algorithm for finding conserved regulatory motifs and regions in homologous sequences

Directory of Open Access Journals (Sweden)

Pesole Graziano

2007-02-01

Full Text Available Abstract Background This work addresses the problem of detecting conserved transcription factor binding sites and in general regulatory regions through the analysis of sequences from homologous genes, an approach that is becoming more and more widely used given the ever increasing amount of genomic data available. Results We present an algorithm that identifies conserved transcription factor binding sites in a given sequence by comparing it to one or more homologs, adapting a framework we previously introduced for the discovery of sites in sequences from co-regulated genes. Differently from the most commonly used methods, the approach we present does not need or compute an alignment of the sequences investigated, nor resorts to descriptors of the binding specificity of known transcription factors. The main novel idea we introduce is a relative measure of conservation, assuming that true functional elements should present a higher level of conservation with respect to the rest of the sequence surrounding them. We present tests where we applied the algorithm to the identification of conserved annotated sites in homologous promoters, as well as in distal regions like enhancers. Conclusion Results of the tests show how the algorithm can provide fast and reliable predictions of conserved transcription factor binding sites regulating the transcription of a gene, with better performances than other available methods for the same task. We also show examples on how the algorithm can be successfully employed when promoter annotations of the genes investigated are missing, or when regulatory sites and regions are located far away from the genes.

Nomadic enhancers: tissue-specific cis-regulatory elements of yellow have divergent genomic positions among Drosophila species.

Directory of Open Access Journals (Sweden)

Gizem Kalay

2010-11-01

Full Text Available cis-regulatory DNA sequences known as enhancers control gene expression in space and time. They are central to metazoan development and are often responsible for changes in gene regulation that contribute to phenotypic evolution. Here, we examine the sequence, function, and genomic location of enhancers controlling tissue- and cell-type specific expression of the yellow gene in six Drosophila species. yellow is required for the production of dark pigment, and its expression has evolved largely in concert with divergent pigment patterns. Using Drosophila melanogaster as a transgenic host, we examined the expression of reporter genes in which either 5' intergenic or intronic sequences of yellow from each species controlled the expression of Green Fluorescent Protein. Surprisingly, we found that sequences controlling expression in the wing veins, as well as sequences controlling expression in epidermal cells of the abdomen, thorax, and wing, were located in different genomic regions in different species. By contrast, sequences controlling expression in bristle-associated cells were located in the intron of all species. Differences in the precise pattern of spatial expression within the developing epidermis of D. melanogaster transformants usually correlated with adult pigmentation in the species from which the cis-regulatory sequences were derived, which is consistent with cis-regulatory evolution affecting yellow expression playing a central role in Drosophila pigmentation divergence. Sequence comparisons among species favored a model in which sequential nucleotide substitutions were responsible for the observed changes in cis-regulatory architecture. Taken together, these data demonstrate frequent changes in yellow cis-regulatory architecture among Drosophila species. Similar analyses of other genes, combining in vivo functional tests of enhancer activity with in silico comparative genomics, are needed to determine whether the pattern of

Communication planning by the nuclear regulatory body

International Nuclear Information System (INIS)

2002-01-01

The national regulatory body, whose primary mission is to exercise regulatory control over nuclear facilities and the use of radiation sources, but not to promote their use, may be the most credible source of neutral, balanced and accurate information about issues relating to nuclear and radiation safety. It is therefore important for a regulatory body to establish and exercise an effective communication programme to acquaint the public with its oversight functions, capabilities and effectiveness. If the regulatory body is to maintain credibility and to deal promptly and effectively with nuclear or radiological accidents and any other events that may give rise to significant public concerns, and is to communicate clearly and effectively with the public, it must have adequate resources, including experts in nuclear safety. And if maintaining public confidence in the authorities and avoiding unnecessary concerns are among its principal objectives, it must be able to communicate understandably and truthfully about the known extent of any accident, the actions taken in response to it and its implications. In the past, psychological effects as a result of certain severe nuclear and radiological accidents have been compounded by a lack of candour with the public on the part of the authorities and an absence of an appropriate programme of public information. This publication describes good practices and gives practical examples of how the regulatory body can establish a systematic and structured programme for enhancing effective communication with various parties and under various circumstances. The report presupposes an adequate national infrastructure, including an independent regulatory body with sufficient authority and resources to discharge its responsibilities for the regulation of safety. This Safety Report covers the elements of a regulatory body's programme for communication with various audiences and under the different circumstances that may be encountered

Contribution of transposable elements in the plant's genome.

Science.gov (United States)

Sahebi, Mahbod; Hanafi, Mohamed M; van Wijnen, Andre J; Rice, David; Rafii, M Y; Azizi, Parisa; Osman, Mohamad; Taheri, Sima; Bakar, Mohd Faizal Abu; Isa, Mohd Noor Mat; Noor, Yusuf Muhammad

2018-07-30

Plants maintain extensive growth flexibility under different environmental conditions, allowing them to continuously and rapidly adapt to alterations in their environment. A large portion of many plant genomes consists of transposable elements (TEs) that create new genetic variations within plant species. Different types of mutations may be created by TEs in plants. Many TEs can avoid the host's defense mechanisms and survive alterations in transposition activity, internal sequence and target site. Thus, plant genomes are expected to utilize a variety of mechanisms to tolerate TEs that are near or within genes. TEs affect the expression of not only nearby genes but also unlinked inserted genes. TEs can create new promoters, leading to novel expression patterns or alternative coding regions to generate alternate transcripts in plant species. TEs can also provide novel cis-acting regulatory elements that act as enhancers or inserts within original enhancers that are required for transcription. Thus, the regulation of plant gene expression is strongly managed by the insertion of TEs into nearby genes. TEs can also lead to chromatin modifications and thereby affect gene expression in plants. TEs are able to generate new genes and modify existing gene structures by duplicating, mobilizing and recombining gene fragments. They can also facilitate cellular functions by sharing their transposase-coding regions. Hence, TE insertions can not only act as simple mutagens but can also alter the elementary functions of the plant genome. Here, we review recent discoveries concerning the contribution of TEs to gene expression in plant genomes and discuss the different mechanisms by which TEs can affect plant gene expression and reduce host defense mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

The changing regulatory environment

International Nuclear Information System (INIS)

Caron, G.

1999-01-01

The role and value of regulation in the energy sector was discussed, demonstrating how, despite common perception, regulation is an essential part of Canada's strategy to find and develop new opportunities. The future vision of regulation for industry participants was presented with particular focus on issues related to streamlining the regulatory process. As far as pipelines are concerned, regulatory actions are necessary to facilitate capacity increases and to ensure the line's integrity, safety and environmental record. Furthermore, regulation provides economic solutions where market forces cannot provide them, as for example where business has elements of monopoly. It arbitrates interests of landowners, business, consumers, and environmental groups. It looks for ways to ensure conditions under which competition can flourish. It acts as the guardian of citizens' rights in a democratic society by providing citizens with an opportunity to be heard on the building or expansion of pipelines and associated facilities. As citizens become more and more concerned about their property and the land that surrounds them, citizen involvement in decision making about how industry activity affects their quality of life will become correspondingly more important. Regulatory agencies are committed to facilitate this engagement by flexible hearing procedures and by making use of evolving communication and information technology

Pre-salt new regulatory mark and the economic order: constitutionality analysis

International Nuclear Information System (INIS)

Pinheiro, Marcela Brasil Pedrosa; Araujo, Mayara de Carvalho; Xavier, Yanko Marcius; Guimaraes, Patricia Borba Vilar

2010-01-01

The discovery of vast reserves of hydrocarbons in the pre-salt layer that extends from Espirito Santo to Santa Catarina, added with the economic and strategic value of oil and natural gas, has brought discussion about the reasonableness of the regulatory model adopted so far. Would be prudent to explore these resources through the concession model? From detailed analysis of the doctrinal and bills that aim to inaugurate the new regulatory bills, we sought to answer this question, based majorly on the principles of economic activity applied in our constitutional system. Motivated by the analysis of these constitutional principles proposed, the State is seen as a regulating agent of the economic activities, fulfilling its role to supervise, encourage and plan the direction of national economic system. The sharing model gives greater state involvement and is able to convert the wealth of pre-salt in citizenship, but only if well implemented. Thus, based on constitutional principles and the notion of development as freedom, the conclusion of this paperwork is for the constitutionality of the new regulatory bills. (author)

GmWRKY53, a water- and salt-inducible soybean gene for rapid dissection of regulatory elements in BY-2 cell culture

Science.gov (United States)

Tripathi, Prateek; Rabara, Roel C.; Lin, Jun; Rushton, Paul J.

2013-01-01

Drought is the major cause of crop losses worldwide. Water stress-inducible promoters are important for understanding the mechanisms of water stress responses in crop plants. Here we utilized tobacco (Nicotiana tabacum L.) Bright Yellow 2 (BY-2) cell system in presence of polyethylene glycol, salt and phytohormones. Extension of the system to 85 mM NaCl led to inducibility of up to 10-fold with the water stress and salt responsive soybean GmWRKY53 promoter. Upon ABA and JA treatment fold inducibility was up to 5-fold and 14-fold, respectively. Thus, we hypothesize that GmWRKY53 could be used as potential model candidate for dissecting drought regulatory elements as well as understanding crosstalk utilizing a rapid heterologous system of BY-2 culture. PMID:23511199

Coordinate Regulation of Yeast Sterol Regulatory Element-binding Protein (SREBP) and Mga2 Transcription Factors.

Science.gov (United States)

Burr, Risa; Stewart, Emerson V; Espenshade, Peter J

2017-03-31

The Mga2 and Sre1 transcription factors regulate oxygen-responsive lipid homeostasis in the fission yeast Schizosaccharomyces pombe in a manner analogous to the mammalian sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 transcription factors. Mga2 and SREBP-1 regulate triacylglycerol and glycerophospholipid synthesis, whereas Sre1 and SREBP-2 regulate sterol synthesis. In mammals, a shared activation mechanism allows for coordinate regulation of SREBP-1 and SREBP-2. In contrast, distinct pathways activate fission yeast Mga2 and Sre1. Therefore, it is unclear whether and how these two related pathways are coordinated to maintain lipid balance in fission yeast. Previously, we showed that Sre1 cleavage is defective in the absence of mga2 Here, we report that this defect is due to deficient unsaturated fatty acid synthesis, resulting in aberrant membrane transport. This defect is recapitulated by treatment with the fatty acid synthase inhibitor cerulenin and is rescued by addition of exogenous unsaturated fatty acids. Furthermore, sterol synthesis inhibition blocks Mga2 pathway activation. Together, these data demonstrate that Sre1 and Mga2 are each regulated by the lipid product of the other transcription factor pathway, providing a source of coordination for these two branches of lipid synthesis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The synthesis of ammonia from its elements

Indian Academy of Sciences (India)

The discovery of the process for economically viable manufacture of ... present century that the production of ammonia from the elements has been discovered, ... with the advent of the industrial age, the products of the soil are carried off from ..... also discovered an improvement in the design of the oven which overcame the ...

Phylogenetic Conflict in Bears Identified by Automated Discovery of Transposable Element Insertions in Low-Coverage Genomes

Science.gov (United States)

Gallus, Susanne; Janke, Axel

2017-01-01

Abstract Phylogenetic reconstruction from transposable elements (TEs) offers an additional perspective to study evolutionary processes. However, detecting phylogenetically informative TE insertions requires tedious experimental work, limiting the power of phylogenetic inference. Here, we analyzed the genomes of seven bear species using high-throughput sequencing data to detect thousands of TE insertions. The newly developed pipeline for TE detection called TeddyPi (TE detection and discovery for Phylogenetic Inference) identified 150,513 high-quality TE insertions in the genomes of ursine and tremarctine bears. By integrating different TE insertion callers and using a stringent filtering approach, the TeddyPi pipeline produced highly reliable TE insertion calls, which were confirmed by extensive in vitro validation experiments. Analysis of single nucleotide substitutions in the flanking regions of the TEs shows that these substitutions correlate with the phylogenetic signal from the TE insertions. Our phylogenomic analyses show that TEs are a major driver of genomic variation in bears and enabled phylogenetic reconstruction of a well-resolved species tree, despite strong signals for incomplete lineage sorting and introgression. The analyses show that the Asiatic black, sun, and sloth bear form a monophyletic clade, in which phylogenetic incongruence originates from incomplete lineage sorting. TeddyPi is open source and can be adapted to various TE and structural variation callers. The pipeline makes it possible to confidently extract thousands of TE insertions even from low-coverage genomes (∼10×) of nonmodel organisms. This opens new possibilities for biologists to study phylogenies and evolutionary processes as well as rates and patterns of (retro-)transposition and structural variation. PMID:28985298

Screening of MITF and SOX10 regulatory regions in Waardenburg syndrome type 2.

Directory of Open Access Journals (Sweden)

Viviane Baral

Full Text Available Waardenburg syndrome (WS is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2 can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.

Screening of MITF and SOX10 Regulatory Regions in Waardenburg Syndrome Type 2

Science.gov (United States)

Baral, Viviane; Chaoui, Asma; Watanabe, Yuli; Goossens, Michel; Attie-Bitach, Tania; Marlin, Sandrine; Pingault, Veronique; Bondurand, Nadege

2012-01-01

Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy. PMID:22848661

Screening of MITF and SOX10 regulatory regions in Waardenburg syndrome type 2.

Science.gov (United States)

Baral, Viviane; Chaoui, Asma; Watanabe, Yuli; Goossens, Michel; Attie-Bitach, Tania; Marlin, Sandrine; Pingault, Veronique; Bondurand, Nadege

2012-01-01

Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.

The impact of data integrity on decision making in early lead discovery

Science.gov (United States)

Beck, Bernd; Seeliger, Daniel; Kriegl, Jan M.

2015-09-01

Data driven decision making is a key element of today's pharmaceutical research, including early drug discovery. It comprises questions like which target to pursue, which chemical series to pursue, which compound to make next, or which compound to select for advanced profiling and promotion to pre-clinical development. In the following paper we will exemplify how data integrity, i.e. the context data is generated in and auxiliary information that is provided for individual result records, can influence decision making in early lead discovery programs. In addition we will describe some approaches which we pursue at Boehringer Ingelheim to reduce the risk for getting misguided.

Small regulatory RNAs control the multi-cellular adhesive lifestyle of Escherichia coli

DEFF Research Database (Denmark)

Jørgensen, Mikkel Girke; Nielsen, Jesper Sejrup; Boysen, Anders

2012-01-01

Small regulatory RNA molecules have recently been recognized as important regulatory elements of developmental processes in both eukaryotes and bacteria. We here describe a striking example in Escherichia coli that can switch between a single-cell motile lifestyle and a multi-cellular, sessile....... Our demonstration that basal expression of each of the three RNA species is sufficient to downregulate CsgD synthesis and prevent curli formation indicates that all play a prominent role in the curli regulatory network. Our findings provide the first clue as to how the Rcs signalling pathway...... negatively regulates curli synthesis and increase the number of small regulatory RNAs that act directly on the csgD mRNA to five....

Regulatory capture by default: Offshore exploratory drilling for oil and gas

International Nuclear Information System (INIS)

Portman, Michelle E.

2014-01-01

This article examines a form of regulatory capture that occurs when significant ambiguity exists regarding the environmental protection standards for new types of activities in the marine environment. To begin with, there is little research that categorizes the typologies of regulatory capture despite the ubiquity of the phenomenon. After a discussion of theoretical approaches to regulatory capture, I describe the operative definition and theory appropriate to the situation related to authorization of oil and natural gas production in Israel following the discovery of large offshore reserves in 2010. This approach, embodying several facets of existing typologies, is applied to decisions made authorizing construction of the Gabriella offshore exploratory drilling platform. The analysis highlights the nature of capture in the absence of clear agency jurisdiction over new activities located in offshore environs organized as temporal and spatial “vacuums”. I conclude that comprehensive marine spatial planning would result in less capture and the development of more capture-resistant regulations. - Highlights: • Regulatory capture occurs when ambiguity exists about environmental protection standards for new types of activities in the marine environment. • A typology is developed from theories of regulatory capture (RC) and applied to cases of offshore exploratory drilling. • The typology is applied to offshore natural gas reserves discovered in 2010 offshore of Israel in the Mediterranean Sea. • Temporal aspects (anachronistic laws and regulations) and spatial aspects (jurisdictional ambiguity) have created regulatory vacuums leading to RC. • Comprehensive marine spatial planning would result in less capture and the development of more capture-resistant regulations

Scalable human ES culture for therapeutic use: propagation, differentiation, genetic modification and regulatory issues.

Science.gov (United States)

Rao, M

2008-01-01

Embryonic stem cells unlike most adult stem cell populations can replicate indefinitely while preserving genetic, epigenetic, mitochondrial and functional profiles. ESCs are therefore an excellent candidate cell type for providing a bank of cells for allogenic therapy and for introducing targeted genetic modifications for therapeutic intervention. This ability of prolonged self-renewal of stem cells and the unique advantages that this offers for gene therapy, discovery efforts, cell replacement, personalized medicine and other more direct applications requires the resolution of several important manufacturing, gene targeting and regulatory issues. In this review, we assess some of the advance made in developing scalable culture systems, improvement in vector design and gene insertion technology and the changing regulatory landscape.

14 CFR 406.143 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Discovery. 406.143 Section 406.143... Transportation Adjudications § 406.143 Discovery. (a) Initiation of discovery. Any party may initiate discovery... after a complaint has been filed. (b) Methods of discovery. The following methods of discovery are...

Infrastructure of the Regulatory Authority and Performance Indexes

International Nuclear Information System (INIS)

Velasquez, Silvia

2001-01-01

This presentation overviews the following issues: elements of a control regulatory program, inspections program, procedures, indexes of users performance, priorities on: registration, criteria for practices of low risk, dose levels in medical exposures, dose constraints and training of personnel. These aspects are considered in the guides prepared within ARCAL XX framework

RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells.

Science.gov (United States)

Zhang, Honglian; Gan, Haiyun; Wang, Zhiquan; Lee, Jeong-Heon; Zhou, Hui; Ordog, Tamas; Wold, Marc S; Ljungman, Mats; Zhang, Zhiguo

2017-01-19

The histone chaperone HIRA is involved in depositing histone variant H3.3 into distinct genic regions, including promoters, enhancers, and gene bodies. However, how HIRA deposits H3.3 to these regions remains elusive. Through a short hairpin RNA (shRNA) screening, we identified single-stranded DNA binding protein replication protein A (RPA) as a regulator of the deposition of newly synthesized H3.3 into chromatin. We show that RPA physically interacts with HIRA to form RPA-HIRA-H3.3 complexes, and it co-localizes with HIRA and H3.3 at gene promoters and enhancers. Depletion of RPA1, the largest subunit of the RPA complex, dramatically reduces both HIRA association with chromatin and the deposition of newly synthesized H3.3 at promoters and enhancers and leads to altered transcription at gene promoters. These results support a model whereby RPA, best known for its role in DNA replication and repair, recruits HIRA to promoters and enhancers and regulates deposition of newly synthesized H3.3 to these regulatory elements for gene regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

The discovery of uranium fission

International Nuclear Information System (INIS)

Brix, P.

1990-01-01

Uranium was discovered 200 years ago. Its radioactive character was first demonstrated in 1896 and two years later radium was extracted from uranium minerals. In 1911 studies with alpha rays from radioactive decay led to the unexpected discovery of the atomic nucleus. Exposure of beryllium to alpha rays yielded neutrons, first detected in 1932. Starting in 1934, neutron irradiation of uranium produced radioactive substances erroneously attributed to transuranium elements but with confusing properties. Painstaking experiments by chemists left no doubt on 17 December 1938 that barium was produced by these irradiations: the neutrons had split some uranium nuclei. The physics of the fission process was understood two weeks later; after a few months, neutron multiplication was found to be probable. This review deals with the eminent scientists involved, their successes, errors and disappointments, and the unexpected insights which occurred on the paths and detours of scientific research. It is, therefore, instructive also to discuss how fission was not discovered. The momentous discovery must be considered inevitable; the great tragedy was that Germany started World War II just at the time when the possibility of nuclear chain reactions and bombs became known. The consequences and anxieties that remain after 50 years of nuclear fission demand that mankind act with reason and conscience to maintain peace. (author)

Higgs Discovery

DEFF Research Database (Denmark)

Sannino, Francesco

2013-01-01

has been challenged by the discovery of a not-so-heavy Higgs-like state. I will therefore review the recent discovery \\cite{Foadi:2012bb} that the standard model top-induced radiative corrections naturally reduce the intrinsic non-perturbative mass of the composite Higgs state towards the desired...... via first principle lattice simulations with encouraging results. The new findings show that the recent naive claims made about new strong dynamics at the electroweak scale being disfavoured by the discovery of a not-so-heavy composite Higgs are unwarranted. I will then introduce the more speculative......I discuss the impact of the discovery of a Higgs-like state on composite dynamics starting by critically examining the reasons in favour of either an elementary or composite nature of this state. Accepting the standard model interpretation I re-address the standard model vacuum stability within...

New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes.

Science.gov (United States)

Parker, Brian J; Moltke, Ida; Roth, Adam; Washietl, Stefan; Wen, Jiayu; Kellis, Manolis; Breaker, Ronald; Pedersen, Jakob Skou

2011-11-01

Regulatory RNA structures are often members of families with multiple paralogous instances across the genome. Family members share functional and structural properties, which allow them to be studied as a whole, facilitating both bioinformatic and experimental characterization. We have developed a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein-coding regions comprising 725 individual structures, including 48 families with known structural RNA elements. Known families identified include both noncoding RNAs, e.g., miRNAs and the recently identified MALAT1/MEN β lincRNA family; and cis-regulatory structures, e.g., iron-responsive elements. We also identify tens of new families supported by strong evolutionary evidence and other statistical evidence, such as GO term enrichments. For some of these, detailed analysis has led to the formulation of specific functional hypotheses. Examples include two hypothesized auto-regulatory feedback mechanisms: one involving six long hairpins in the 3'-UTR of MAT2A, a key metabolic gene that produces the primary human methyl donor S-adenosylmethionine; the other involving a tRNA-like structure in the intron of the tRNA maturation gene POP1. We experimentally validate the predicted MAT2A structures. Finally, we identify potential new regulatory networks, including large families of short hairpins enriched in immunity-related genes, e.g., TNF, FOS, and CTLA4, which include known transcript destabilizing elements. Our findings exemplify the diversity of post-transcriptional regulation and provide a resource for further characterization of new regulatory mechanisms and families of noncoding RNAs.

Bladder inflammatory transcriptome in response to tachykinins: Neurokinin 1 receptor-dependent genes and transcription regulatory elements

Directory of Open Access Journals (Sweden)

Dozmorov Igor

2007-05-01

Full Text Available Abstract Background Tachykinins (TK, such as substance P, and their neurokinin receptors which are ubiquitously expressed in the human urinary tract, represent an endogenous system regulating bladder inflammatory, immune responses, and visceral hypersensitivity. Increasing evidence correlates alterations in the TK system with urinary tract diseases such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis. However, despite promising effects in animal models, there seems to be no published clinical study showing that NK-receptor antagonists are an effective treatment of pain in general or urinary tract disorders, such as detrusor overactivity. In order to search for therapeutic targets that could block the tachykinin system, we set forth to determine the regulatory network downstream of NK1 receptor activation. First, NK1R-dependent transcripts were determined and used to query known databases for their respective transcription regulatory elements (TREs. Methods An expression analysis was performed using urinary bladders isolated from sensitized wild type (WT and NK1R-/- mice that were stimulated with saline, LPS, or antigen to provoke inflammation. Based on cDNA array results, NK1R-dependent genes were selected. PAINT software was used to query TRANSFAC database and to retrieve upstream TREs that were confirmed by electrophoretic mobility shift assays. Results The regulatory network of TREs driving NK1R-dependent genes presented cRel in a central position driving 22% of all genes, followed by AP-1, NF-kappaB, v-Myb, CRE-BP1/c-Jun, USF, Pax-6, Efr-1, Egr-3, and AREB6. A comparison between NK1R-dependent and NK1R-independent genes revealed Nkx-2.5 as a unique discriminator. In the presence of NK1R, Nkx2-5 _01 was significantly correlated with 36 transcripts which included several candidates for mediating bladder development (FGF and inflammation (PAR-3, IL-1R, IL-6, α-NGF, TSP2. In the absence of

Generic antibiotic industries: Challenges and implied strategies with regulatory perspectives

Directory of Open Access Journals (Sweden)

M Venkatesh

2011-01-01

Full Text Available Ever since the discovery of antibiotics, the quality of human life greatly improved in the 20 th century. The discovery of penicillin transformed the medicine industry and initiated a search for a better antibiotic every time resulting in several synthetic and semi-synthetic antibiotics. Beginning with the 1937 sulfa drug tragedy, the drug regulations had a parallel growth along with the antibiotics and the antibiotic-based generic Pharma industries. This review article is focused on the scenario depicting current global Pharma industries based on generic antibiotics. Several regulatory aspects involved with these industries have been discussed along with the complexity of the market, issues that could affect their growth, their struggle for quality, and their compliance with the tightened regulations. With the skyrocketing commercialization of antibiotics through generics and the leveraging technologic renaissance, generic industries are involved in providing maximum safer benefits for the welfare of the people, highlighting its need today.

Generic antibiotic industries: Challenges and implied strategies with regulatory perspectives

Science.gov (United States)

Venkatesh, M.; Bairavi, V. G.; Sasikumar, K. C.

2011-01-01

Ever since the discovery of antibiotics, the quality of human life greatly improved in the 20th century. The discovery of penicillin transformed the medicine industry and initiated a search for a better antibiotic every time resulting in several synthetic and semi-synthetic antibiotics. Beginning with the 1937 sulfa drug tragedy, the drug regulations had a parallel growth along with the antibiotics and the antibiotic-based generic Pharma industries. This review article is focused on the scenario depicting current global Pharma industries based on generic antibiotics. Several regulatory aspects involved with these industries have been discussed along with the complexity of the market, issues that could affect their growth, their struggle for quality, and their compliance with the tightened regulations. With the skyrocketing commercialization of antibiotics through generics and the leveraging technologic renaissance, generic industries are involved in providing maximum safer benefits for the welfare of the people, highlighting its need today.. PMID:21430959

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements

Science.gov (United States)

Allou, Lila; Lambert, Laetitia; Amsallem, Daniel; Bieth, Eric; Edery, Patrick; Destrée, Anne; Rivier, François; Amor, David; Thompson, Elizabeth; Nicholl, Julian; Harbord, Michael; Nemos, Christophe; Saunier, Aline; Moustaïne, Aissa; Vigouroux, Adeline; Jonveaux, Philippe; Philippe, Christophe

2012-01-01

The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (−4 to−6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype. PMID:22739344

Small RNA-Controlled Gene Regulatory Networks in Pseudomonas putida

DEFF Research Database (Denmark)

Bojanovic, Klara

evolved numerous mechanisms to controlgene expression in response to specific environmental signals. In addition to two-component systems, small regulatory RNAs (sRNAs) have emerged as major regulators of gene expression. The majority of sRNAs bind to mRNA and regulate their expression. They often have...... multiple targets and are incorporated into large regulatory networks and the RNA chaper one Hfq in many cases facilitates interactions between sRNAs and their targets. Some sRNAs also act by binding to protein targets and sequestering their function. In this PhD thesis we investigated the transcriptional....... Detailed insights into the mechanisms through which P. putida responds to different stress conditions and increased understanding of bacterial adaptation in natural and industrial settings were gained. Additionally, we identified genome-wide transcription start sites, andmany regulatory RNA elements...

Employee Development Capabilities of the Regulatory Authority in the Nuclear Field in Romania

International Nuclear Information System (INIS)

Ghinea, P.

2016-01-01

Full text: The paper provides information about CNCAN (general presentation of CNCAN responsibilities as a regulatory body) and about the general human resources management within our institution regarding the following: legal framework regarding resources; knowledge management; staff employment financial resources continuous focus on improvement of staff performances through dedicated training programmes. The process to develop and maintain the necessary competence and skills of staff of the regulatory body, as an element of knowledge management. Training for CNCAN staff is provided either in-house or through technical cooperation programmes with the IAEA. CNCAN has made arrangements for specific staff training using training courses and programmes provided by international organizations. The specific training is provided predominantly with the economic support from outside of the country. CNCAN has a process to develop and maintain the necessary competence and skills of staff of the regulatory body, as an element of knowledge management. To maintain an appropriate competence level, an annual plan for staff training is in place and each staff member has an individual training plan. Project supports CNCAN in the development of knowledge management and capacity building frameworks to secure long-term availability of regulatory competency. (author

The discovery of the periodic table as a case of simultaneous discovery.

Science.gov (United States)

Scerri, Eric

2015-03-13

The article examines the question of priority and simultaneous discovery in the context of the discovery of the periodic system. It is argued that rather than being anomalous, simultaneous discovery is the rule. Moreover, I argue that the discovery of the periodic system by at least six authors in over a period of 7 years represents one of the best examples of a multiple discovery. This notion is supported by a new view of the evolutionary development of science through a mechanism that is dubbed Sci-Gaia by analogy with Lovelock's Gaia hypothesis. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Beyond Discovery

DEFF Research Database (Denmark)

Korsgaard, Steffen; Sassmannshausen, Sean Patrick

2017-01-01

In this chapter we explore four alternatives to the dominant discovery view of entrepreneurship; the development view, the construction view, the evolutionary view, and the Neo-Austrian view. We outline the main critique points of the discovery presented in these four alternatives, as well...

Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence of Homo sapiens.

Science.gov (United States)

Glinsky, Gennadi V

2016-09-19

Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Collectively, a compendium of multiple diverse families of HSRS that are functionally and structurally divergent from Great Apes could be defined as the backbone of human-specific genomic regulatory networks. Here, the conservation patterns analysis of 18,364 candidate HSRS was carried out requiring that 100% of bases must remap during the alignments of human, chimpanzee, and bonobo sequences. A total of 5,535 candidate HSRS were identified that are: (i) highly conserved in Great Apes; (ii) evolved by the exaptation of highly conserved ancestral DNA; (iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from non-human primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Genome-wide proximity placement analysis of HSRS revealed that a small fraction of topologically associating domains (TADs) contain more than half of HSRS from four distinct families. TADs that are enriched for HSRS and termed rapidly evolving in humans TADs (revTADs) comprise 0.8-10.3% of 3,127 TADs in the hESC genome. RevTADs manifest distinct correlation patterns between placements of human accelerated regions, human-specific transcription factor-binding sites, and recombination rates. There is a significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (P sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of

"Eureka, Eureka!" Discoveries in Science

Science.gov (United States)

Agarwal, Pankaj

2011-01-01

Accidental discoveries have been of significant value in the progress of science. Although accidental discoveries are more common in pharmacology and chemistry, other branches of science have also benefited from such discoveries. While most discoveries are the result of persistent research, famous accidental discoveries provide a fascinating…

Identification of new TSGA10 transcript variants in human testis with conserved regulatory RNA elements in 5'untranslated region and distinct expression in breast cancer.

Science.gov (United States)

Salehipour, Pouya; Nematzadeh, Mahsa; Mobasheri, Maryam Beigom; Afsharpad, Mandana; Mansouri, Kamran; Modarressi, Mohammad Hossein

2017-09-01

Testis specific gene antigen 10 (TSGA10) is a cancer testis antigen involved in the process of spermatogenesis. TSGA10 could also play an important role in the inhibition of angiogenesis by preventing nuclear localization of HIF-1α. Although it has been shown that TSGA10 messenger RNA (mRNA) is mainly expressed in testis and some tumors, the transcription pattern and regulatory mechanisms of this gene remain largely unknown. Here, we report that human TSGA10 comprises at least 22 exons and generates four different transcript variants. It was identified that using two distinct promoters and splicing of exons 4 and 7 produced these transcript variants, which have the same coding sequence, but the sequence of 5'untanslated region (5'UTR) is different between them. This is significant because conserved regulatory RNA elements like upstream open reading frame (uORF) and putative internal ribosome entry site (IRES) were found in this region which have different combinations in each transcript variant and it may influence translational efficiency of them in normal or unusual environmental conditions like hypoxia. To indicate the transcription pattern of TSGA10 in breast cancer, expression of identified transcript variants was analyzed in 62 breast cancer samples. We found that TSGA10 tends to express variants with shorter 5'UTR and fewer uORF elements in breast cancer tissues. Our study demonstrates for the first time the expression of different TSGA10 transcript variants in testis and breast cancer tissues and provides a first clue to a role of TSGA10 5'UTR in regulation of translation in unusual environmental conditions like hypoxia. Copyright © 2017. Published by Elsevier B.V.

30 CFR 44.24 - Discovery.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Discovery. 44.24 Section 44.24 Mineral... Discovery. Parties shall be governed in their conduct of discovery by appropriate provisions of the Federal... discovery. Alternative periods of time for discovery may be prescribed by the presiding administrative law...

19 CFR 356.20 - Discovery.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Discovery. 356.20 Section 356.20 Customs Duties... § 356.20 Discovery. (a) Voluntary discovery. All parties are encouraged to engage in voluntary discovery... sanctions proceeding. (b) Limitations on discovery. The administrative law judge shall place such limits...

Chemical Discovery

Science.gov (United States)

Brown, Herbert C.

1974-01-01

The role of discovery in the advance of the science of chemistry and the factors that are currently operating to handicap that function are considered. Examples are drawn from the author's work with boranes. The thesis that exploratory research and discovery should be encouraged is stressed. (DT)

24 CFR 180.500 - Discovery.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 180.500 Section 180.500... OPPORTUNITY CONSOLIDATED HUD HEARING PROCEDURES FOR CIVIL RIGHTS MATTERS Discovery § 180.500 Discovery. (a) In general. This subpart governs discovery in aid of administrative proceedings under this part. Discovery in...

22 CFR 224.21 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 224.21 Section 224.21 Foreign....21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of... parties, discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery...

Phylogenetic Conflict in Bears Identified by Automated Discovery of Transposable Element Insertions in Low-Coverage Genomes.

Science.gov (United States)

Lammers, Fritjof; Gallus, Susanne; Janke, Axel; Nilsson, Maria A

2017-10-01

Phylogenetic reconstruction from transposable elements (TEs) offers an additional perspective to study evolutionary processes. However, detecting phylogenetically informative TE insertions requires tedious experimental work, limiting the power of phylogenetic inference. Here, we analyzed the genomes of seven bear species using high-throughput sequencing data to detect thousands of TE insertions. The newly developed pipeline for TE detection called TeddyPi (TE detection and discovery for Phylogenetic Inference) identified 150,513 high-quality TE insertions in the genomes of ursine and tremarctine bears. By integrating different TE insertion callers and using a stringent filtering approach, the TeddyPi pipeline produced highly reliable TE insertion calls, which were confirmed by extensive in vitro validation experiments. Analysis of single nucleotide substitutions in the flanking regions of the TEs shows that these substitutions correlate with the phylogenetic signal from the TE insertions. Our phylogenomic analyses show that TEs are a major driver of genomic variation in bears and enabled phylogenetic reconstruction of a well-resolved species tree, despite strong signals for incomplete lineage sorting and introgression. The analyses show that the Asiatic black, sun, and sloth bear form a monophyletic clade, in which phylogenetic incongruence originates from incomplete lineage sorting. TeddyPi is open source and can be adapted to various TE and structural variation callers. The pipeline makes it possible to confidently extract thousands of TE insertions even from low-coverage genomes (∼10×) of nonmodel organisms. This opens new possibilities for biologists to study phylogenies and evolutionary processes as well as rates and patterns of (retro-)transposition and structural variation. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Discussion of Regulatory Guide 7.10, emphasizing the graded approach for establishing QA programs

International Nuclear Information System (INIS)

Gordon, L.; Lake, W.H.

1983-01-01

To assist applicants in establishing an acceptable QA program to meet the programmatic elements of Appendix E to 10 CFR Part 71, Regulatory Guide 7.10 was developed. Regulatory Guide 7.10 is organized in three self-contained ANNEXES. Guidance applicable to designer/fabricators, to users, and users of radiographic devices are in separate annexes. QA programs for packaging to transport radioactive material are similar in regard to the various operations a licensee may be involved in. However, the appropriate QA/QC effort to verify the program elements may vary significantly. This is referred to as the graded approach. Appendix A in the guide addresses the graded approach

19 CFR 207.109 - Discovery.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Discovery. 207.109 Section 207.109 Customs Duties... and Committee Proceedings § 207.109 Discovery. (a) Discovery methods. All parties may obtain discovery under such terms and limitations as the administrative law judge may order. Discovery may be by one or...

15 CFR 25.21 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Discovery. 25.21 Section 25.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the ALJ. The ALJ shall regulate the timing of discovery. (d...

[From discovery to innovation: the example of hypereosinophilic syndrome].

Science.gov (United States)

Goldman, M

2007-01-01

Biomedical research is extremely productive so that each day new discoveries reveal novel (mechanisms and) molecular pathways of diseases. However, the number of innovative therapies approved each year by regulatory authorities is decreasing. The causes of this "innovation breakdown" are multiple and should be explored both in academic institutions and in the industrial world. New initiatives are underway in the Walloon Region to improve this situation, such as the setting up of the BioWin Health Cluster gathering pharmaceutical and biotechnology enterprises and university laboratories. This new vision of the partnership between academia and the private sector should be based on strong fundamental research activities. We illustrate this concept by discussing recent advances in the diagnosis and treatment of the hypereosinophilic syndrome.

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

Directory of Open Access Journals (Sweden)

Allan Andrew C

2008-07-01

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

39 CFR 963.14 - Discovery.

Science.gov (United States)

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Discovery. 963.14 Section 963.14 Postal Service... PANDERING ADVERTISEMENTS STATUTE, 39 U.S.C. 3008 § 963.14 Discovery. Discovery is to be conducted on a... such discovery as he or she deems reasonable and necessary. Discovery may include one or more of the...

Overlapping positive and negative regulatory domains of the human β-interferon gene

International Nuclear Information System (INIS)

Goodbourn, S.; Maniatis, T.

1988-01-01

Virus of poly(I) x poly(C) induction of human β-interferon gene expression requires a 40-base-pair DNA sequence designated the interferon gene regulatory element (IRE). Previous studies have shown that the IRE contains both positive and negative regulatory DNA sequences. To localize these sequences and study their interactions, the authors have examined the effects of a large number of single-base mutations within the IRE on β-interferon gene regulation. They find that the IRE consists of two genetically separable positive regulatory domains and an overlapping negative control sequence. They propose that the β-interferon gene is switched off in uninduced cells by a repressor that blocks the interaction between one of the two positive regulatory sequences and a specific transcription factor. Induction would then lead to inactivation or displacement of the repressor and binding of transcription factors to both positive regulatory domains

Transcriptional Regulatory Network Analysis of MYB Transcription Factor Family Genes in Rice

Directory of Open Access Journals (Sweden)

Shuchi eSmita

2015-12-01

Full Text Available MYB transcription factor (TF is one of the largest TF families and regulates defense responses to various stresses, hormone signaling as well as many metabolic and developmental processes in plants. Understanding these regulatory hierarchies of gene expression networks in response to developmental and environmental cues is a major challenge due to the complex interactions between the genetic elements. Correlation analyses are useful to unravel co-regulated gene pairs governing biological process as well as identification of new candidate hub genes in response to these complex processes. High throughput expression profiling data are highly useful for construction of co-expression networks. In the present study, we utilized transcriptome data for comprehensive regulatory network studies of MYB TFs by top down and guide gene approaches. More than 50% of OsMYBs were strongly correlated under fifty experimental conditions with 51 hub genes via top down approach. Further, clusters were identified using Markov Clustering (MCL. To maximize the clustering performance, parameter evaluation of the MCL inflation score (I was performed in terms of enriched GO categories by measuring F-score. Comparison of co-expressed cluster and clads analyzed from phylogenetic analysis signifies their evolutionarily conserved co-regulatory role. We utilized compendium of known interaction and biological role with Gene Ontology enrichment analysis to hypothesize function of coexpressed OsMYBs. In the other part, the transcriptional regulatory network analysis by guide gene approach revealed 40 putative targets of 26 OsMYB TF hubs with high correlation value utilizing 815 microarray data. The putative targets with MYB-binding cis-elements enrichment in their promoter region, functional co-occurrence as well as nuclear localization supports our finding. Specially, enrichment of MYB binding regions involved in drought-inducibility implying their regulatory role in drought

Innovations in the Delivery of Regulatory Services in Australia

International Nuclear Information System (INIS)

Dillich, J.

2016-01-01

The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) is the country’s primary authority on radiation protection and nuclear safety. ARPANSA aims to promote safety, security, and emergency preparedness through efficient and effective regulation of nuclear installations, controlled facilities, and radiation sources. Recent initiatives to improve regulation by ‘cutting red tape’ and reducing regulatory burden have been introduced. ARPANSA’s Regulatory Delivery Model emphasises the key elements to good regulation and describes initiatives such as baseline inspection schedule, Performance Objectives and Criteria, and performance deficiencies. These and other initiatives have streamlined inspection efforts, increased risk-based oversight and risk-informed decision making, leading to increased efficiencies for both regulator and licence holder. In addition, ARPANSA has introduced 12 key performance indicators in its self-assessment of regulatory performance against the Australian Government’s Regulator Performance Framework. (author)

Development of an air-operated actuator performance monitoring system for regulatory usage

International Nuclear Information System (INIS)

Sung, K. Y.; Kwon, S. J.

2004-01-01

The performance monitoring system of air-operated actuators for regulatory usage has been being developed. Essential elements and operating parameters affecting the actuator performance have been investigated to provide basic information for system development. The monitoring system including an air-operated actuator testing facility and analysis softwares for monitoring and evaluation are also introduced in this paper. As a result of simulated tests, it was known that the system could be a useful tool for the effective monitoring of actuator performance change and fault conditions. This system would be applied to regulatory inspection for utility's data validation and to the training of regulatory staff in future after some modification and expansion

Reaction mechanisms for the synthesis of the heaviest elements from heavy ion reactions

International Nuclear Information System (INIS)

Gaeggeler, H.W.

1988-10-01

This review paper concerns fusion reactions with light heavy-ions, cold fusion, transfer reactions using light heavy-ions or heavy ions. In two appendices, methods for the separation and detection of nuclides in the domain of heaviest elements are described and a comment on the discovery of the element 104 is given. 51 figs., 10 tabs., 335 refs

Genetic characterization of the oxytocin-neurophysin I gene (OXT) and its regulatory regions analysis in domestic Old and New World camelids.

Science.gov (United States)

Pauciullo, Alfredo; Ogah, Danlami Moses; Iannaccone, Marco; Erhardt, Georg; Di Stasio, Liliana; Cosenza, Gianfranco

2018-01-01

Oxytocin is a neurohypophysial peptide linked to a wide range of biological functions, including milk ejection, temperament and reproduction. Aims of the present study were a) the characterization of the OXT (Oxytocin-neurophysin I) gene and its regulatory regions in Old and New world camelids; b) the investigation of the genetic diversity and the discovery of markers potentially affecting the gene regulation. On average, the gene extends over 814 bp, ranging between 825 bp in dromedary, 811 bp in Bactrian and 810 bp in llama and alpaca. Such difference in size is due to a duplication event of 21 bp in dromedary. The main regulatory elements, including the composite hormone response elements (CHREs), were identified in the promoter, whereas the presence of mature microRNAs binding sequences in the 3'UTR improves the knowledge on the factors putatively involved in the OXT gene regulation, although their specific biological effect needs to be still elucidated. The sequencing of genomic DNA allowed the identification of 17 intraspecific polymorphisms and 69 nucleotide differences among the four species. One of these (MF464535:g.622C>G) is responsible, in alpaca, for the loss of a consensus sequence for the transcription factor SP1. Furthermore, the same SNP falls within a CpG island and it creates a new methylation site, thus opening future possibilities of investigation to verify the influence of the novel allelic variant in the OXT gene regulation. A PCR-RFLP method was setup for the genotyping and the frequency of the allele C was 0.93 in a population of 71 alpacas. The obtained data clarify the structure of OXT gene in domestic camelids and add knowledge to the genetic variability of a genomic region, which has received little investigation so far. These findings open the opportunity for new investigations, including association studies with productive and reproductive traits.

Optimizing Combinations of Flavonoids Deriving from Astragali Radix in Activating the Regulatory Element of Erythropoietin by a Feedback System Control Scheme

Directory of Open Access Journals (Sweden)

Hui Yu

2013-01-01

Full Text Available Identifying potent drug combination from a herbal mixture is usually quite challenging, due to a large number of possible trials. Using an engineering approach of the feedback system control (FSC scheme, we identified the potential best combinations of four flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O-β-D-glucoside deriving from Astragali Radix (AR; Huangqi, which provided the best biological action at minimal doses. Out of more than one thousand possible combinations, only tens of trials were required to optimize the flavonoid combinations that stimulated a maximal transcriptional activity of hypoxia response element (HRE, a critical regulator for erythropoietin (EPO transcription, in cultured human embryonic kidney fibroblast (HEK293T. By using FSC scheme, 90% of the work and time can be saved, and the optimized flavonoid combinations increased the HRE mediated transcriptional activity by ~3-fold as compared with individual flavonoid, while the amount of flavonoids was reduced by ~10-fold. Our study suggests that the optimized combination of flavonoids may have strong effect in activating the regulatory element of erythropoietin at very low dosage, which may be used as new source of natural hematopoietic agent. The present work also indicates that the FSC scheme is able to serve as an efficient and model-free approach to optimize the drug combination of different ingredients within a herbal decoction.

As to achieve regulatory action, regulatory approaches

International Nuclear Information System (INIS)

Cid, R.; Encinas, D.

2014-01-01

The achievement of the effectiveness in the performance of a nuclear regulatory body has been a permanent challenge in the recent history of nuclear regulation. In the post-Fukushima era this challenge is even more important. This article addresses the subject from two complementary points of view: the characteristics of an effective regulatory body and the regulatory approaches. This work is based on the most recent studies carried out by the Committee on Nuclear Regulatory Activities, CNRA (OECD/NEA), as well as on the experience of the Consejo de Seguridad Nuclear, CSN, the Spanish regulatory body. Rafael Cid is the representative of CSN in these project: Diego Encinas has participated in the study on regulatory approaches. (Author)

Usability of Discovery Portals

OpenAIRE

Bulens, J.D.; Vullings, L.A.E.; Houtkamp, J.M.; Vanmeulebrouk, B.

2013-01-01

As INSPIRE progresses to be implemented in the EU, many new discovery portals are built to facilitate finding spatial data. Currently the structure of the discovery portals is determined by the way spatial data experts like to work. However, we argue that the main target group for discovery portals are not spatial data experts but professionals with limited spatial knowledge, and a focus outside the spatial domain. An exploratory usability experiment was carried out in which three discovery p...

Helium the disappearing element

CERN Document Server

Sears, Wheeler M

2015-01-01

The subject of the book is helium, the element, and its use in myriad applications including MRI machines, particle accelerators, space telescopes, and of course balloons and blimps. It was at the birth of our Universe, or the Big Bang, where the majority of cosmic helium was created; and stellar helium production continues. Although helium is the second most abundant element in the Universe, it is actually quite rare here on Earth and only exists because of radioactive elements deep within the Earth. This book includes a detailed history of the discovery of helium, of the commercial industry built around it, how the helium we actually encounter is produced within the Earth, and the state of the helium industry today. The gas that most people associate with birthday party balloons is running out. “Who cares?” you might ask. Well, without helium, MRI machines could not function, rockets could not go into space, particle accelerators such as those used by CERN could not operate, fiber optic cables would not...

Biomarkers as drug development tools: discovery, validation, qualification and use.

Science.gov (United States)

Kraus, Virginia B

2018-06-01

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.

Role of cooperation activities for capacity building of Romanian Regulatory Authority (CNCAN)

International Nuclear Information System (INIS)

Biro, L.; Ciurea-Ercau, C.

2010-01-01

With a slow but active nuclear development program of sector since 1980, Romanian regulatory authority had to permanently adapt to the changes in national and international environment in order ensure continuously increase of capacity building and effectiveness, commensurate with the growing nuclear sector. Limited human resources available at the national level put the Romanian Regulatory Authority in the position of building the Technical Support Organization as part of its on organization. International cooperation played an important role in capacity building of Romanian regulatory body and providing necessary assistance in performing regulatory activities or support in development of regulatory framework. Fellowships and technical visits, workshops and training courses provided through IAEA TC at national or regional level, technical assistance provided by European Commission (EC) through PHARE Projects, all provided valuable contribution in assuring training of regulatory staff and development of proper regulatory framework in Romania. Therefore, Romanian Regulatory Authority is putting a strong accent on strengthening and promoting international cooperation through IAEA Technical Cooperation Programme, Molls between regulatory bodies, as one of the key elements in supporting capacity building of regulatory authorities in countries having small or embarking on nuclear power program. Building networks between training centers and research facilities and establishments of regional training centers represent one of the future viable options in preserving knowledge in nuclear field. (author)

A design for a V and V and UQ discovery process

International Nuclear Information System (INIS)

Knupp, Patrick Michael; Urbina, Angel

2011-01-01

There is currently sparse literature on how to implement systematic and comprehensive processes for modern V and V/UQ (VU) within large computational simulation projects. Important design requirements have been identified in order to construct a viable 'system' of processes. Significant processes that are needed include discovery, accumulation, and assessment. A preliminary design is presented for a VU Discovery process that accounts for an important subset of the requirements. The design uses a hierarchical approach to set context and a series of place-holders that identify the evidence and artifacts that need to be created in order to tell the VU story and to perform assessments. The hierarchy incorporates VU elements from a Predictive Capability Maturity Model and uses questionnaires to define critical issues in VU. The place-holders organize VU data within a central repository that serves as the official VU record of the project. A review process ensures that those who will contribute to the record have agreed to provide the evidence identified by the Discovery process. VU expertise is an essential part of this process and ensures that the roadmap provided by the Discovery process is adequate. Both the requirements and the design were developed to support the Nuclear Energy Advanced Modeling and Simulation Waste project, which is developing a set of advanced codes for simulating the performance of nuclear waste storage sites. The Waste project served as an example to keep the design of the VU Discovery process grounded in practicalities. However, the system is represented abstractly so that it can be applied to other M and S projects.

19 CFR 354.10 - Discovery.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Discovery. 354.10 Section 354.10 Customs Duties... ANTIDUMPING OR COUNTERVAILING DUTY ADMINISTRATIVE PROTECTIVE ORDER § 354.10 Discovery. (a) Voluntary discovery. All parties are encouraged to engage in voluntary discovery procedures regarding any matter, not...

36 CFR 1150.63 - Discovery.

Science.gov (United States)

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Discovery. 1150.63 Section... PRACTICE AND PROCEDURES FOR COMPLIANCE HEARINGS Prehearing Conferences and Discovery § 1150.63 Discovery. (a) Parties are encouraged to engage in voluntary discovery procedures. For good cause shown under...

37 CFR 11.52 - Discovery.

Science.gov (United States)

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 11.52 Section 11... Disciplinary Proceedings; Jurisdiction, Sanctions, Investigations, and Proceedings § 11.52 Discovery. Discovery... establishes that discovery is reasonable and relevant, the hearing officer, under such conditions as he or she...

Towards a predictive theory for genetic regulatory networks

Science.gov (United States)

Tkacik, Gasper

When cells respond to changes in the environment by regulating the expression levels of their genes, we often draw parallels between these biological processes and engineered information processing systems. One can go beyond this qualitative analogy, however, by analyzing information transmission in biochemical ``hardware'' using Shannon's information theory. Here, gene regulation is viewed as a transmission channel operating under restrictive constraints set by the resource costs and intracellular noise. We present a series of results demonstrating that a theory of information transmission in genetic regulatory circuits feasibly yields non-trivial, testable predictions. These predictions concern strategies by which individual gene regulatory elements, e.g., promoters or enhancers, read out their signals; as well as strategies by which small networks of genes, independently or in spatially coupled settings, respond to their inputs. These predictions can be quantitatively compared to the known regulatory networks and their function, and can elucidate how reproducible biological processes, such as embryonic development, can be orchestrated by networks built out of noisy components. Preliminary successes in the gap gene network of the fruit fly Drosophila indicate that a full ab initio theoretical prediction of a regulatory network is possible, a feat that has not yet been achieved for any real regulatory network. We end by describing open challenges on the path towards such a prediction.

Specificity of discoveries in radiochemistry

International Nuclear Information System (INIS)

Krivomazov, A.N.

1977-01-01

The development of radiochemistry as a science is elucidated. On the basis of original papers and archives materials which have become available only recently, specific features of opening the law of radioactive displacements and isotopy of radioactive elements are presented in detail. A contribution of Hevesy, Russel, Fajans, and Soddy into the solution of this problem is considered; an important role of Rutherford in putting down the priority conflict is shown. Two stages of scientific generalization are singled out in the history of opening the law of radioactive displacements: the stage of the rules and the stage of the laws. On this basis the solutions of the priority problems have been reconsidered. It is shown that the history of radiochemistry is rich in discoveries which have undergone a relatively long evolution

Usability of Discovery Portals

NARCIS (Netherlands)

Bulens, J.D.; Vullings, L.A.E.; Houtkamp, J.M.; Vanmeulebrouk, B.

2013-01-01

As INSPIRE progresses to be implemented in the EU, many new discovery portals are built to facilitate finding spatial data. Currently the structure of the discovery portals is determined by the way spatial data experts like to work. However, we argue that the main target group for discovery portals

CHEMENGL/CHIMISTE, Chemical and Physical Properties of Elements

International Nuclear Information System (INIS)

Levart, Eugene

2007-01-01

Description of program or function: Data Base on basic chemical, physical, and nuclear properties of the elements in the Mendeleev Table (118 elements, 4435 nuclides comprising isotopes and isomers). Example: density electric and thermal conductivity, masses of isotopes and isomers, ionisation potential, etc. from H to Ei (Z=118). Both French and English versions are available. In addition, the French version (513 pages) contains other general information about the elements such as mineralogy, industrial applications, toxicity, historical information on discovery of the elements, etc. The latest version contains updates of atomic masses, the names of symbols of transuranium elements have been updated in accordance with the IUPAC recommendations. The values of the abundance of elements in the sun have been corrected according to Grevesse et al. The price of the different elements have been updated, some minor errors have been corrected and the presentation of the cover page has been improved. Several pages have been added to the last chapter of the French version (CHIMISTE), this chapter is not available in the English version (CHEMENGL)

14 CFR 16.213 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Discovery. 16.213 Section 16.213... PRACTICE FOR FEDERALLY-ASSISTED AIRPORT ENFORCEMENT PROCEEDINGS Hearings § 16.213 Discovery. (a) Discovery... discovery permitted by this section if a party shows that— (1) The information requested is cumulative or...

28 CFR 76.21 - Discovery.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

Genome-wide decoding of hierarchical modular structure of transcriptional regulation by cis-element and expression clustering.

Science.gov (United States)

Leyfer, Dmitriy; Weng, Zhiping

2005-09-01

A holistic approach to the study of cellular processes is identifying both gene-expression changes and regulatory elements promoting such changes. Cellular regulatory processes can be viewed as transcriptional modules (TMs), groups of coexpressed genes regulated by groups of transcription factors (TFs). We set out to devise a method that would identify TMs while avoiding arbitrary thresholds on TM sizes and number. Assuming that gene expression is determined by TFs that bind to the gene's promoter, clustering of genes based on TF binding sites (cis-elements) should create gene groups similar to those obtained by gene expression clustering. Intersections between the expression and cis-element-based gene clusters reveal TMs. Statistical significance assigned to each TM allows identification of regulatory units of any size. Our method correctly identifies the number and sizes of TMs on simulated datasets. We demonstrate that yeast experimental TMs are biologically relevant by comparing them with MIPS and GO categories. Our modules are in statistically significant agreement with TMs from other research groups. This work suggests that there is no preferential division of biological processes into regulatory units; each degree of partitioning exhibits a slice of biological network revealing hierarchical modular organization of transcriptional regulation.

Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery

Directory of Open Access Journals (Sweden)

Daura Xavier

2010-03-01

Full Text Available Abstract Background With the classical, active-site oriented drug-development approach reaching its limits, protein ligand-binding sites in general and allosteric sites in particular are increasingly attracting the interest of medicinal chemists in the search for new types of targets and strategies to drug development. Given that allostery represents one of the most common and powerful means to regulate protein function, the traditional drug discovery approach of targeting active sites can be extended by targeting allosteric or regulatory protein pockets that may allow the discovery of not only novel drug-like inhibitors, but activators as well. The wealth of available protein structural data can be exploited to further increase our understanding of allosterism, which in turn may have therapeutic applications. A first step in this direction is to identify and characterize putative effector sites that may be present in already available structural data. Results We performed a large-scale study of protein cavities as potential allosteric and functional sites, by integrating publicly available information on protein sequences, structures and active sites for more than a thousand protein families. By identifying common pockets across different structures of the same protein family we developed a method to measure the pocket's structural conservation. The method was first parameterized using known active sites. We characterized the predicted pockets in terms of sequence and structural conservation, backbone flexibility and electrostatic potential. Although these different measures do not tend to correlate, their combination is useful in selecting functional and regulatory sites, as a detailed analysis of a handful of protein families shows. We finally estimated the numbers of potential allosteric or regulatory pockets that may be present in the data set, finding that pockets with putative functional and effector characteristics are widespread across

40 CFR 27.21 - Discovery.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Discovery. 27.21 Section 27.21... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

37 CFR 41.150 - Discovery.

Science.gov (United States)

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 41.150 Section 41... COMMERCE PRACTICE BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES Contested Cases § 41.150 Discovery. (a) Limited discovery. A party is not entitled to discovery except as authorized in this subpart. The...

14 CFR 13.220 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Discovery. 13.220 Section 13.220... INVESTIGATIVE AND ENFORCEMENT PROCEDURES Rules of Practice in FAA Civil Penalty Actions § 13.220 Discovery. (a) Initiation of discovery. Any party may initiate discovery described in this section, without the consent or...

49 CFR 604.38 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Discovery. 604.38 Section 604.38 Transportation... TRANSPORTATION CHARTER SERVICE Hearings. § 604.38 Discovery. (a) Permissible forms of discovery shall be within the discretion of the PO. (b) The PO shall limit the frequency and extent of discovery permitted by...

15 CFR 719.10 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 719.10 Section 719.10... Discovery. (a) General. The parties are encouraged to engage in voluntary discovery regarding any matter... the Federal Rules of Civil Procedure relating to discovery apply to the extent consistent with this...

24 CFR 26.18 - Discovery.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 26.18 Section 26.18... PROCEDURES Hearings Before Hearing Officers Discovery § 26.18 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery procedures, which may commence at any time after an answer has...

42 CFR 426.532 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Discovery. 426.532 Section 426.532 Public Health... § 426.532 Discovery. (a) General rule. If the Board orders discovery, the Board must establish a reasonable timeframe for discovery. (b) Protective order—(1) Request for a protective order. Any party...

49 CFR 1503.633 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 9 2010-10-01 2010-10-01 false Discovery. 1503.633 Section 1503.633... Rules of Practice in TSA Civil Penalty Actions § 1503.633 Discovery. (a) Initiation of discovery. Any party may initiate discovery described in this section, without the consent or approval of the ALJ, at...

14 CFR 1264.120 - Discovery.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Discovery. 1264.120 Section 1264.120... PENALTIES ACT OF 1986 § 1264.120 Discovery. (a) The following types of discovery are authorized: (1..., discovery is available only as ordered by the presiding officer. The presiding officer shall regulate the...

22 CFR 128.6 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 128.6 Section 128.6 Foreign... Discovery. (a) Discovery by the respondent. The respondent, through the Administrative Law Judge, may... discovery if the interests of national security or foreign policy so require, or if necessary to comply with...

24 CFR 26.42 - Discovery.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Discovery. 26.42 Section 26.42... PROCEDURES Hearings Pursuant to the Administrative Procedure Act Discovery § 26.42 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery procedures, which may commence at any time...

49 CFR 386.37 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Discovery. 386.37 Section 386.37 Transportation... and Hearings § 386.37 Discovery. (a) Parties may obtain discovery by one or more of the following...; and requests for admission. (b) Discovery may not commence until the matter is pending before the...

29 CFR 1955.32 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Discovery. 1955.32 Section 1955.32 Labor Regulations...) PROCEDURES FOR WITHDRAWAL OF APPROVAL OF STATE PLANS Preliminary Conference and Discovery § 1955.32 Discovery... allow discovery by any other appropriate procedure, such as by interrogatories upon a party or request...

Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression

Directory of Open Access Journals (Sweden)

Andreas Bitter

2015-01-01

Full Text Available Background/Aims: Sterol regulatory element-binding protein (SREBP 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.

42 CFR 426.432 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Discovery. 426.432 Section 426.432 Public Health... § 426.432 Discovery. (a) General rule. If the ALJ orders discovery, the ALJ must establish a reasonable timeframe for discovery. (b) Protective order—(1) Request for a protective order. Any party receiving a...

49 CFR 1121.2 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 8 2010-10-01 2010-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...

38 CFR 42.21 - Discovery.

Science.gov (United States)

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Discovery. 42.21 Section... IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.21 Discovery. (a) The following types of discovery are... creation of a document. (c) Unless mutually agreed to by the parties, discovery is available only as...

22 CFR 521.21 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Discovery. 521.21 Section 521.21 Foreign... Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for... interpreted to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

31 CFR 10.71 - Discovery.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 10.71 Section 10.71 Money... SERVICE Rules Applicable to Disciplinary Proceedings § 10.71 Discovery. (a) In general. Discovery may be... relevance, materiality and reasonableness of the requested discovery and subject to the requirements of § 10...

39 CFR 955.15 - Discovery.

Science.gov (United States)

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Discovery. 955.15 Section 955.15 Postal Service... APPEALS § 955.15 Discovery. (a) The parties are encouraged to engage in voluntary discovery procedures. In connection with any deposition or other discovery procedure, the Board may issue any order which justice...

43 CFR 35.21 - Discovery.

Science.gov (United States)

2010-10-01

... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Discovery. 35.21 Section 35.21 Public... AND STATEMENTS § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests...) Unless mutually agreed to by the parties, discovery is available only as ordered by the ALJ. The ALJ...

15 CFR 766.9 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 766.9 Section 766.9... PROCEEDINGS § 766.9 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery... provisions of the Federal Rules of Civil Procedure relating to discovery apply to the extent consistent with...

Get Involved in Planetary Discoveries through New Worlds, New Discoveries

Science.gov (United States)

Shupla, Christine; Shipp, S. S.; Halligan, E.; Dalton, H.; Boonstra, D.; Buxner, S.; SMD Planetary Forum, NASA

2013-01-01

"New Worlds, New Discoveries" is a synthesis of NASA’s 50-year exploration history which provides an integrated picture of our new understanding of our solar system. As NASA spacecraft head to and arrive at key locations in our solar system, "New Worlds, New Discoveries" provides an integrated picture of our new understanding of the solar system to educators and the general public! The site combines the amazing discoveries of past NASA planetary missions with the most recent findings of ongoing missions, and connects them to the related planetary science topics. "New Worlds, New Discoveries," which includes the "Year of the Solar System" and the ongoing celebration of the "50 Years of Exploration," includes 20 topics that share thematic solar system educational resources and activities, tied to the national science standards. This online site and ongoing event offers numerous opportunities for the science community - including researchers and education and public outreach professionals - to raise awareness, build excitement, and make connections with educators, students, and the public about planetary science. Visitors to the site will find valuable hands-on science activities, resources and educational materials, as well as the latest news, to engage audiences in planetary science topics and their related mission discoveries. The topics are tied to the big questions of planetary science: how did the Sun’s family of planets and bodies originate and how have they evolved? How did life begin and evolve on Earth, and has it evolved elsewhere in our solar system? Scientists and educators are encouraged to get involved either directly or by sharing "New Worlds, New Discoveries" and its resources with educators, by conducting presentations and events, sharing their resources and events to add to the site, and adding their own public events to the site’s event calendar! Visit to find quality resources and ideas. Connect with educators, students and the public to

13 CFR 134.213 - Discovery.

Science.gov (United States)

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Discovery. 134.213 Section 134.213... OFFICE OF HEARINGS AND APPEALS Rules of Practice for Most Cases § 134.213 Discovery. (a) Motion. A party may obtain discovery only upon motion, and for good cause shown. (b) Forms. The forms of discovery...

31 CFR 16.21 - Discovery.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Discovery. 16.21 Section 16.21 Money... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.21 Discovery. (a) The following types of discovery are authorized... to require the creation of a document. (c) Unless mutually agreed to by the parties, discovery is...

Regulatory challenges of historic uranium mines in Canada

International Nuclear Information System (INIS)

Clement, C.H.; Stenson, R.E.

2002-01-01

The radium and uranium mining industry began in Canada in 1930 with the discovery of the Port Radium deposit in the Northwest Territories. During the 1950s more uranium mines opened across Canada. Most of these mines ceased operation by the end of the 1960s. Some were remediated by their owners, while others were abandoned. The Atomic Energy Control Board (AECB), predecessor to the Canadian Nuclear Safety Commission (CNSC), was created in 1946. However, it was not until the mid-1970s that the AECB took an active role in regulating health, safety and environmental aspects of uranium mining; so many of the older mines have never been licensed. With the coming into force of the Nuclear Safety and Control Act (NSCA) in May 2000, this situation has been reviewed. The NSCA requires a licence for the possession of nuclear substances (including uranium mine tailings), or the decommissioning of nuclear facilities (including uranium mines and mills). Furthermore, governments (federal and provincial) are also subject to the NSCA, a change from the previous legislation. The CNSC has an obligation to assess these sites, regardless of ownership, and to proceed with licensing or other appropriate regulatory action. The CNSC has reviewed the status of the twenty sites in Canada where uranium milling took place historically. Eight are already licensed. Licensing actions are being pursued at the other sites. A review of nearly 100 small uranium mining or exploration sites is also underway to determine the most appropriate regulatory approach. This paper focuses on regulatory issues surrounding the historic mining and milling sites, and the regulatory approach being taken, including licensing provincial and federal government bodies who own some of the sites, and ensuring the safe management of sites that were abandoned. (author)

Transparency as an element of public confidence

International Nuclear Information System (INIS)

Kim, H.K.

2007-01-01

In the modern society, there is increasing demands for greater transparency. It has been discussed with respect to corruption or ethics issues in social science. The need for greater openness and transparency in nuclear regulation is widely recognised as public expectations on regulator grow. It is also related to the digital and information technology that enables disclosures of every activity and information of individual and organisation, characterised by numerous 'small brothers'. Transparency has become a key word in this ubiquitous era. Transparency in regulatory activities needs to be understood in following contexts. First, transparency is one of elements to build public confidence in regulator and eventually to achieve regulatory goal of providing the public with satisfaction at nuclear safety. Transparent bases of competence, independence, ethics and integrity of working process of regulatory body would enhance public confidence. Second, activities transmitting information on nuclear safety and preparedness to be accessed are different types of transparency. Communication is an active method of transparency. With increasing use of web-sites, 'digital transparency' is also discussed as passive one. Transparency in regulatory process may be more important than that of contents. Simply providing more information is of little value and specific information may need to be protected for security reason. Third, transparency should be discussed in international, national and organizational perspectives. It has been demanded through international instruments. for each country, transparency is demanded by residents, public, NGOs, media and other stakeholders. Employees also demand more transparency in operating and regulatory organisations. Whistle-blower may appear unless they are satisfied. Fourth, pursuing transparency may cause undue social cost or adverse effects. Over-transparency may decrease public confidence and the process for transparency may also hinder

Skin too thin? The developing utility of zebrafish skin (neuro)pharmacology for CNS drug discovery research.

Science.gov (United States)

Nguyen, Michael; Poudel, Manoj K; Stewart, Adam Michael; Kalueff, Allan V

2013-09-01

Skin coloration can be affected by many genetic, environmental and pharmacological factors. Zebrafish (Danio rerio) are a useful and versatile model organism in biomedical research due to their genetic tractability, physiological homology to mammals, low cost, reproducibility and high throughput. Zebrafish coloration is mediated by chromatophores - the skin color pigment cells largely controlled by endocrine and neural mechanisms. The characteristic darkening of zebrafish skin is caused by the dispersion (and paling - by aggregation) of melanosomes (pigment-containing organelles), which show high homology to mammalian structures. Various pharmacological agents potently affect zebrafish coloration - the phenotype that often accompanies behavioral effects of the drugs, and may be used for drug discovery. Although zebrafish behavior and skin responses are usually not directly related, they share common regulatory (neural, endocrine) mechanisms, and therefore may be assessed in parallel during psychotropic drug screening. For example, some psychoactive drugs can potently affect zebrafish skin coloration. Can we use this knowledge to refine phenotype-driven psychotropic drug discovery? Here, we present current models using zebrafish skin coloration assays, and discuss how these models may be applied to enhance in vivo CNS drug discovery. Copyright © 2013 Elsevier Inc. All rights reserved.

HPV-16 L1 genes with inactivated negative RNA elements induce potent immune responses

International Nuclear Information System (INIS)

Rollman, Erik; Arnheim, Lisen; Collier, Brian; Oeberg, Daniel; Hall, Haakan; Klingstroem, Jonas; Dillner, Joakim; Pastrana, Diana V.; Buck, Chris B.; Hinkula, Jorma; Wahren, Britta; Schwartz, Stefan

2004-01-01

Introduction of point mutations in the 5' end of the human papillomavirus type 16 (HPV-16) L1 gene specifically inactivates negative regulatory RNA processing elements. DNA vaccination of C57Bl/6 mice with the mutated L1 gene resulted in improved immunogenicity for both neutralizing antibodies as well as for broad cellular immune responses. Previous reports on the activation of L1 by codon optimization may be explained by inactivation of the regulatory RNA elements. The modified HPV-16 L1 DNA that induced anti-HPV-16 immunity may be seen as a complementary approach to protein subunit immunization against papillomavirus

Regulatory aspects of low doses control in Albania

International Nuclear Information System (INIS)

Dollani, K.; Kushe, R.

1997-01-01

In the present paper are described the status of regulatory aspects of low doses control as well as the existing procedures for their implementation in Albania. According to new Radiological Protection Act, approved by Parliament in 1995, the establishment of the infrastructures in radiation protection area is in course, accompanied by the installation and functioning of new equipment for low dose control. Based in many years experience it is concluded that personal doses of the workers added by practices in Albania are 1/10 of dose Emits. Some particular cases of overexposured workers were investigated. Last times the elements of the optimisation procedures (QA and QC) are outlined in the frame of improving regulatory aspects of low doses control. (author)

Decades of Discovery

Science.gov (United States)

2011-06-01

For the past two-and-a-half decades, the Office of Science at the U.S. Department of Energy has been at the forefront of scientific discovery. Over 100 important discoveries supported by the Office of Science are represented in this document.

Comparative genome sequencing of drosophila pseudoobscura: Chromosomal, gene and cis-element evolution

Energy Technology Data Exchange (ETDEWEB)

Richards, Stephen; Liu, Yue; Bettencourt, Brian R.; Hradecky, Pavel; Letovsky, Stan; Nielsen, Rasmus; Thornton, Kevin; Todd, Melissa J.; Chen, Rui; Meisel, Richard P.; Couronne, Olivier; Hua, Sujun; Smith, Mark A.; Bussemaker, Harmen J.; van Batenburg, Marinus F.; Howells, Sally L.; Scherer, Steven E.; Sodergren, Erica; Matthews, Beverly B.; Crosby, Madeline A.; Schroeder, Andrew J.; Ortiz-Barrientos, Daniel; Rives, Catherine M.; Metzker, Michael L.; Muzny, Donna M.; Scott, Graham; Steffen, David; Wheeler, David A.; Worley, Kim C.; Havlak, Paul; Durbin, K. James; Egan, Amy; Gill, Rachel; Hume, Jennifer; Morgan, Margaret B.; Miner, George; Hamilton, Cerissa; Huang, Yanmei; Waldron, Lenee; Verduzco, Daniel; Blankenburg, Kerstin P.; Dubchak, Inna; Noor, Mohamed A.F.; Anderson, Wyatt; White, Kevin P.; Clark, Andrew G.; Schaeffer, Stephen W.; Gelbart, William; Weinstock, George M.; Gibbs, Richard A.

2004-04-01

The genome sequence of a second fruit fly, D. pseudoobscura, presents an opportunity for comparative analysis of a primary model organism D. melanogaster. The vast majority of Drosophila genes have remained on the same arm, but within each arm gene order has been extensively reshuffled leading to the identification of approximately 1300 syntenic blocks. A repetitive sequence is found in the D. pseudoobscura genome at many junctions between adjacent syntenic blocks. Analysis of this novel repetitive element family suggests that recombination between offset elements may have given rise to many paracentric inversions, thereby contributing to the shuffling of gene order in the D. pseudoobscura lineage. Based on sequence similarity and synteny, 10,516 putative orthologs have been identified as a core gene set conserved over 35 My since divergence. Genes expressed in the testes had higher amino acid sequence divergence than the genome wide average consistent with the rapid evolution of sex-specific proteins. Cis-regulatory sequences are more conserved than control sequences between the species but the difference is slight, suggesting that the evolution of cis-regulatory elements is flexible. Overall, a picture of repeat mediated chromosomal rearrangement, and high co-adaptation of both male genes and cis-regulatory sequences emerges as important themes of genome divergence between these species of Drosophila.

Discovery and the atom

International Nuclear Information System (INIS)

1989-01-01

''Discovery and the Atom'' tells the story of the founding of nuclear physics. This programme looks at nuclear physics up to the discovery of the neutron in 1932. Animation explains the science of the classic experiments, such as the scattering of alpha particles by Rutherford and the discovery of the nucleus. Archive film shows the people: Lord Rutherford, James Chadwick, Marie Curie. (author)

Validation of new superheavy elements and IUPAC-IUPAP joint working group

International Nuclear Information System (INIS)

Jarlskog, Cecilia

2016-01-01

The great chemist Glenn Seaborg has written a delightful little book “Man-made Transuranium Elements”, published in 1963, in which he points out that: “The former basic criterion for the discovery of a new element – namely, chemical identification and separation from all previously-known elements – had to be changed in the case of lawrencium (element 103). This also may be true for elements beyond lawrencium.” Indeed this is what has happened. The elements with Z ≥ 103 are produced in nuclear reactions and are detected by counters. The detectors have undergone substantial refinement. For example one uses multiwire proportional chambers [for which George Charpak received the 1992 Nobel Prize in Physics] as well as solid state micro-strip detectors. In spite of this remarkable shift from chemistry to physics, the managerial staff of the International Union of Pure and Applied Chemistry (IUPAC) does not seem to be aware of what has been going on. The validation of superheavy elements should be done by physicists as the chemists lack the relevant competence as I will discuss here below. This article is about a collaboration between International Union of Pure and Applied Chemistry (IUPAC) and its sister organization International Union of Pure and Applied Physics (IUPAP), to deal with discovery of superheavy elements beyond Z = 112. I spent a great deal of time on this issue. In my opinion, the collaboration turned out to be a failure. For the sake of science, which should be our most important concern (and not politics), the rules for the future collaborations, if any, should be accurately defined and respected. The validation of new elements should be done by people who have the relevant competence – the physicists.

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression

Science.gov (United States)

Mars, Ruben A. T.; Nicolas, Pierre; Denham, Emma L.

2016-01-01

SUMMARY Bacteria can employ widely diverse RNA molecules to regulate their gene expression. Such molecules include trans-acting small regulatory RNAs, antisense RNAs, and a variety of transcriptional attenuation mechanisms in the 5′ untranslated region. Thus far, most regulatory RNA research has focused on Gram-negative bacteria, such as Escherichia coli and Salmonella. Hence, there is uncertainty about whether the resulting insights can be extrapolated directly to other bacteria, such as the Gram-positive soil bacterium Bacillus subtilis. A recent study identified 1,583 putative regulatory RNAs in B. subtilis, whose expression was assessed across 104 conditions. Here, we review the current understanding of RNA-based regulation in B. subtilis, and we categorize the newly identified putative regulatory RNAs on the basis of their conservation in other bacilli and the stability of their predicted secondary structures. Our present evaluation of the publicly available data indicates that RNA-mediated gene regulation in B. subtilis mostly involves elements at the 5′ ends of mRNA molecules. These can include 5′ secondary structure elements and metabolite-, tRNA-, or protein-binding sites. Importantly, sense-independent segments are identified as the most conserved and structured potential regulatory RNAs in B. subtilis. Altogether, the present survey provides many leads for the identification of new regulatory RNA functions in B. subtilis. PMID:27784798

Regulatory RNAs in Bacillus subtilis: a Gram-Positive Perspective on Bacterial RNA-Mediated Regulation of Gene Expression.

Science.gov (United States)

Mars, Ruben A T; Nicolas, Pierre; Denham, Emma L; van Dijl, Jan Maarten

2016-12-01

Bacteria can employ widely diverse RNA molecules to regulate their gene expression. Such molecules include trans-acting small regulatory RNAs, antisense RNAs, and a variety of transcriptional attenuation mechanisms in the 5' untranslated region. Thus far, most regulatory RNA research has focused on Gram-negative bacteria, such as Escherichia coli and Salmonella. Hence, there is uncertainty about whether the resulting insights can be extrapolated directly to other bacteria, such as the Gram-positive soil bacterium Bacillus subtilis. A recent study identified 1,583 putative regulatory RNAs in B. subtilis, whose expression was assessed across 104 conditions. Here, we review the current understanding of RNA-based regulation in B. subtilis, and we categorize the newly identified putative regulatory RNAs on the basis of their conservation in other bacilli and the stability of their predicted secondary structures. Our present evaluation of the publicly available data indicates that RNA-mediated gene regulation in B. subtilis mostly involves elements at the 5' ends of mRNA molecules. These can include 5' secondary structure elements and metabolite-, tRNA-, or protein-binding sites. Importantly, sense-independent segments are identified as the most conserved and structured potential regulatory RNAs in B. subtilis. Altogether, the present survey provides many leads for the identification of new regulatory RNA functions in B. subtilis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

29 CFR 2700.56 - Discovery; general.

Science.gov (United States)

2010-07-01

...(c) or 111 of the Act has been filed. 30 U.S.C. 815(c) and 821. (e) Completion of discovery... 29 Labor 9 2010-07-01 2010-07-01 false Discovery; general. 2700.56 Section 2700.56 Labor... Hearings § 2700.56 Discovery; general. (a) Discovery methods. Parties may obtain discovery by one or more...

Regulatory inspection of the egyptian gamma irradiator using a proposed inspection checklist

International Nuclear Information System (INIS)

Abdel-Ghani, A.H.

2000-01-01

Regulatory inspections are one of the most important elements of a regulatory programme. It shall be performed in all areas of the regulatory responsibility and during all phases of siting, design, construction, commissioning, operation, maintenance and decommissioning of an irradiator facility. The egyptian mega gamma irradiator operating since december 1979 has a Co-60 source of about 400 kilo curies and is used mainly for sterilization of medical supplies and pharmaceuticals and for preservation of some food stuffs. The constructor (Nordion international Inc.) recommended an extensive inspection programme. In accordance with the international and national (2.3) regulations as well as the licensing conditions, the competent authority (NCNSRC) shall perform regulatory inspections both announced and unannounced. In order to facilitate the inspection task and to harmonize the inspection reports a checklist for inspection is proposed which can be used also as an inspection report form

De Novo Discovery of Structured ncRNA Motifs in Genomic Sequences

DEFF Research Database (Denmark)

Ruzzo, Walter L; Gorodkin, Jan

2014-01-01

De novo discovery of "motifs" capturing the commonalities among related noncoding ncRNA structured RNAs is among the most difficult problems in computational biology. This chapter outlines the challenges presented by this problem, together with some approaches towards solving them, with an emphas...... on an approach based on the CMfinder CMfinder program as a case study. Applications to genomic screens for novel de novo structured ncRNA ncRNA s, including structured RNA elements in untranslated portions of protein-coding genes, are presented.......De novo discovery of "motifs" capturing the commonalities among related noncoding ncRNA structured RNAs is among the most difficult problems in computational biology. This chapter outlines the challenges presented by this problem, together with some approaches towards solving them, with an emphasis...

The regulatory actions in the management of disuse radioactive sources

International Nuclear Information System (INIS)

Truppa, W.A.; Cordoba, M.F.; Poletti, M.; Calabria, M.A.; Pirez, C.

2010-01-01

During the last years, different incidents related to the discovery of inadvertent radioactive material have been reported through the international information systems available. From the analysis of the information received it can be concluded that those situations are derived from the inadequate application of concepts such as 'safety culture' and 'risk perception' or inadequate physical safety measures towards radioactive sources by the licensee. Among the activities that the regulators perform during the use of radioactive material, the most important are the ones related to avoiding the existence of disused radioactive sources. In this regard, the Nuclear Regulatory Authority (NRA) has implemented, through its Standards, regulatory mechanisms to adequately control and dispose of radioactive material. Concerning this matter, actions were taken in Argentina with the aim of disposing or keeping the custody in an authorized long term storage of every radioactive source used to measure thickness, humidity, level, weight, etc. that remained within the facilities without use and/or a suitable program to be reutilized within a period larger than six months. The objective of the present piece of work is to present the analysis and results of the actions fulfilled between 2002 and 2009, giving details about the regulatory activities performed in relation to the disposal and withdrawal of radioactive sources and the physical safety measures taken. (authors) [es

Sustaining Nuclear Safety: Upholding the Core Regulatory Values

International Nuclear Information System (INIS)

Kumar, S.

2016-01-01

Nuclear Energy and management of safety therein, has a somewhat distinct streak in that from its early days it has had the privilege of being shaped and supervised by the eminent scientists and engineers, in fact it owes its very origin to them. This unique engagement has resulted in culmination of the several safety elements like defence-in-depth in the form of multiple safety layers, redundancy, diversity and physical separation of components, protection against single failures as well as common cause failures right at the beginning of designing a nuclear reactor. The fundamental principles followed by regulators across the globe have many similarities such as, creation of an organization which has a conflict-free primary responsibility of safety supervision, laying down the safety criteria and requirements for the respective industry and developing and using various tools and regulatory methodology to ensure adherence to the laid down regulatory requirements. Yet the regulatory regimes in different States have evolved differently and therefore, has certain attributes which are unique to these and confer on them their identity.

Evaluation of New Chemical Entities as Substrates of Liver Transporters in the Pharmaceutical Industry: Response to Regulatory Requirements and Future Steps.

Science.gov (United States)

Okudaira, Noriko

2017-09-01

This article discusses the evaluation of drug candidates as hepatic transporter substrates. Recently, research on the applications of hepatic transporters in the pharmaceutical industry has improved to meet the requirements of the regulatory guidelines for the evaluation of drug interactions. To identify the risk of transporter-mediated drug-drug interactions at an early stage of drug development, we used a strategy of reviewing the in vivo animal pharmacokinetics and tissue distribution data obtained in the discovery stage together with the in vitro data obtained for regulatory submission. In the context of nonclinical evaluation of new chemical entities as medicines, we believe that transporter studies are emerging as a key strategy to predict their pharmacological and toxicological effects. In combination with the recent progress in systems approaches, the estimation of effective concentrations in the target tissues, by using mathematical models to describe the transporter-mediated distribution and elimination, has enabled us to identify promising compounds for clinical development at the discovery stage. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Regulatory Challenges for Cartilage Repair Technologies.

Science.gov (United States)

McGowan, Kevin B; Stiegman, Glenn

2013-01-01

In the United States, few Food and Drug Administration (FDA)-approved options exist for the treatment of focal cartilage and osteochondral lesions. Developers of products for cartilage repair face many challenges to obtain marketing approval from the FDA. The objective of this review is to discuss the necessary steps for FDA application and approval for a new cartilage repair product. FDA Guidance Documents, FDA Panel Meetings, scientific organization recommendations, and clinicaltrials.gov were reviewed to demonstrate the current thinking of FDA and the scientific community on the regulatory process for cartilage repair therapies. Cartilage repair therapies can receive market approval from FDA as medical devices, drugs, or biologics, and the specific classification of product can affect the nonclinical, clinical, and regulatory strategy to bring the product to market. Recent FDA guidance gives an outline of the required elements to bring a cartilage repair product to market, although these standards are often very general. As a result, companies have to carefully craft their study patient population, comparator group, and clinical endpoint to best showcase their product's attributes. In addition, regulatory strategy and manufacturing process validation need to be considered early in the clinical study process to allow for timely product approval following the completion of clinical study. Although the path to regulatory approval for a cartilage repair therapy is challenging and time-consuming, proper clinical trial planning and attention to the details can eventually save companies time and money by bringing a product to the market in the most expeditious process possible.

Fuel element transfer cask modelling using MCNP technique

International Nuclear Information System (INIS)

Rosli Darmawan

2009-01-01

Full text: After operating for more than 25 years, some of the Reaktor TRIGA PUSPATI (RTP) fuel elements would have been depleted. A few addition and fuel reconfiguration exercises have to be conducted in order to maintain RTP capacity. Presently, RTP spent fuels are stored at the storage area inside RTP tank. The need to transfer the fuel element outside of RTP tank may be prevalence in the near future. The preparation shall be started from now. A fuel element transfer cask has been designed according to the recommendation by the fuel manufacturer and experience of other countries. A modelling using MCNP code has been conducted to analyse the design. The result shows that the design of transfer cask fuel element is safe for handling outside the RTP tank according to recent regulatory requirement. (author)

Fuel Element Transfer Cask Modelling Using MCNP Technique

International Nuclear Information System (INIS)

Darmawan, Rosli; Topah, Budiman Naim

2010-01-01

After operating for more than 25 years, some of the Reaktor TRIGA Puspati (RTP) fuel elements would have been depleted. A few addition and fuel reconfiguration exercises have to be conducted in order to maintain RTP capacity. Presently, RTP spent fuels are stored at the storage area inside RTP tank. The need to transfer the fuel element outside of RTP tank may be prevalence in the near future. The preparation shall be started from now. A fuel element transfer cask has been designed according to the recommendation by the fuel manufacturer and experience of other countries. A modelling using MCNP code has been conducted to analyse the design. The result shows that the design of transfer cask fuel element is safe for handling outside the RTP tank according to recent regulatory requirement.

Testing external surface of fuel element tubes for power nuclear reactors

International Nuclear Information System (INIS)

Naugol'nykh, O.G.; Nelyubin, Yu.V.

1987-01-01

Optical methods are regarded perspective for discovery and detection of flaws of external surfaces of fuel element tubes. The TV method has highest information content among them. Two mock-ups of facilities based on the TV method using a ''dissector'' type TV device and a TV tube with charge accumulation (vidikon) have been developed. It is concluded that complex testing - combination of ultrasonic, photoelectric and TV methods in a facility is necessary for discovery and analysis of the whole variety of flaws, though sensitivity of the TV method is enough for disclosure of all the main defects

Altered expression of hypoxia-inducible factor-1α (HIF-1α and its regulatory genes in gastric cancer tissues.

Directory of Open Access Journals (Sweden)

Jihan Wang

Full Text Available Tissue hypoxia induces reprogramming of cell metabolism and may result in normal cell transformation and cancer progression. Hypoxia-inducible factor 1-alpha (HIF-1α, the key transcription factor, plays an important role in gastric cancer development and progression. This study aimed to investigate the underlying regulatory signaling pathway in gastric cancer using gastric cancer tissue specimens. The integration of gene expression profile and transcriptional regulatory element database (TRED was pursued to identify HIF-1α ↔ NFκB1 → BRCA1 → STAT3 ← STAT1 gene pathways and their regulated genes. The data showed that there were 82 differentially expressed genes that could be regulated by these five transcription factors in gastric cancer tissues and these genes formed 95 regulation modes, among which seven genes (MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS, and TFF3 were hub molecules that are regulated at least by two of these five transcription factors simultaneously and were associated with hypoxia, inflammation, and immune disorder. Real-Time PCR and western blot showed increasing of HIF-1α in mRNA and protein levels as well as TIMP1, TFF3 in mRNA levels in gastric cancer tissues. The data are the first study to demonstrate HIF-1α-regulated transcription factors and their corresponding network genes in gastric cancer. Further study with a larger sample size and more functional experiments is needed to confirm these data and then translate into clinical biomarker discovery and treatment strategy for gastric cancer.

Trends and needs in regulatory approaches for future reactors. Annex 16

International Nuclear Information System (INIS)

Kress, T.S.

2002-01-01

For nuclear power to be the future alternative of choice for electric generation capacity, there are two essential elements: (1) cost competitiveness, and (2) an acceptable level of safety. To meet these perhaps conflicting elements, there will need to be significant risk-informed modifications to the regulatory approaches for the licensing and oversight of reactors. This paper discusses some of the trends in the U.S. in this direction and identifies what the author believes will be technical and policy issues that stand in the way. (author)

Radioactivity in consumer products : radiation safety and regulatory appraisal

International Nuclear Information System (INIS)

Murthy, B.K.S.; Venkataraman, G.; Subrahmanym, P.

1993-01-01

Use of radioactive materials in consumer products is in vogue almost since the discovery of radioactivity. There has been a rapid growth in the use of radioactive material in various consumer products such as Ionization Chamber Smoke Detectors (ICSD), Static eliminators, etc. In addition, there are certain manufacturing processes wherein the Naturally Occurring Radioactive Material (NORM) get incorporated in the consumer products. Certain phosphatic fertilizers, titanium dioxide pigments, phospho gypsum plaster boards are some examples in this category. The manufacture and use of these products result in radiation dose to the public apart from radiation exposure to the personnel involved in the manufacturing process. Appropriate radiation control measures have to be taken in the design, manufacture and use of consumer products to ensure that the radiation doses to the public and the population at large do not exceed the relevant limits. While appropriate regulatory controls and surveillance are established for manufacture and use of certain products, these are still to be recognised and established in respect of certain other processes and products. The current status of radiation safety and regulatory control and the lack of these in respect of some products are discussed in this paper. (author). 5 refs

A Tale of Two Discoveries: Comparing the Usability of Summon and EBSCO Discovery Service

Science.gov (United States)

Foster, Anita K.; MacDonald, Jean B.

2013-01-01

Web-scale discovery systems are gaining momentum among academic libraries as libraries seek a means to provide their users with a one-stop searching experience. Illinois State University's Milner Library found itself in the unique position of having access to two distinct discovery products, EBSCO Discovery Service and Serials Solutions' Summon.…

29 CFR 2200.208 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Discovery. 2200.208 Section 2200.208 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH REVIEW COMMISSION RULES OF PROCEDURE Simplified Proceedings § 2200.208 Discovery. Discovery, including requests for admissions, will only be...

47 CFR 65.105 - Discovery.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 3 2010-10-01 2010-10-01 false Discovery. 65.105 Section 65.105... OF RETURN PRESCRIPTION PROCEDURES AND METHODOLOGIES Procedures § 65.105 Discovery. (a) Participants... evidence. (c) Discovery requests pursuant to § 65.105(b), including written interrogatories, shall be filed...

49 CFR 209.313 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Discovery. 209.313 Section 209.313 Transportation... TRANSPORTATION RAILROAD SAFETY ENFORCEMENT PROCEDURES Disqualification Procedures § 209.313 Discovery. (a... parties. Discovery is designed to enable a party to obtain relevant information needed for preparation of...

CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors

NARCIS (Netherlands)

J.C. Corbo (Joseph); K.A. Lawrence (Karen); M. Karlstetter (Marcus); C.A. Myers (Connie); M. Abdelaziz (Musa); W. Dirkes (William); K. Weigelt (Karin); M. Seifert (Martin); V. Benes (Vladimir); L.G. Fritsche (Lars); B.H.F. Weber (Bernhard); T. Langmann (Thomas)

2010-01-01

textabstractApproximately 98% of mammalian DNA is noncoding, yet we understand relatively little about the function of this enigmatic portion of the genome. The cis-regulatory elements that control gene expression reside in noncoding regions and can be identified by mapping the binding sites of

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

Directory of Open Access Journals (Sweden)

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.

On the Concept of Cis-regulatory Information: From Sequence Motifs to Logic Functions

Science.gov (United States)

Tarpine, Ryan; Istrail, Sorin

The regulatory genome is about the “system level organization of the core genomic regulatory apparatus, and how this is the locus of causality underlying the twin phenomena of animal development and animal evolution” (E.H. Davidson. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution, Academic Press, 2006). Information processing in the regulatory genome is done through regulatory states, defined as sets of transcription factors (sequence-specific DNA binding proteins which determine gene expression) that are expressed and active at the same time. The core information processing machinery consists of modular DNA sequence elements, called cis-modules, that interact with transcription factors. The cis-modules “read” the information contained in the regulatory state of the cell through transcription factor binding, “process” it, and directly or indirectly communicate with the basal transcription apparatus to determine gene expression. This endowment of each gene with the information-receiving capacity through their cis-regulatory modules is essential for the response to every possible regulatory state to which it might be exposed during all phases of the life cycle and in all cell types. We present here a set of challenges addressed by our CYRENE research project aimed at studying the cis-regulatory code of the regulatory genome. The CYRENE Project is devoted to (1) the construction of a database, the cis-Lexicon, containing comprehensive information across species about experimentally validated cis-regulatory modules; and (2) the software development of a next-generation genome browser, the cis-Browser, specialized for the regulatory genome. The presentation is anchored on three main computational challenges: the Gene Naming Problem, the Consensus Sequence Bottleneck Problem, and the Logic Function Inference Problem.

Sequence-based model of gap gene regulatory network.

Science.gov (United States)

Kozlov, Konstantin; Gursky, Vitaly; Kulakovskiy, Ivan; Samsonova, Maria

2014-01-01

) functional important sites are not exclusively located in cis-regulatory elements, but are rather dispersed through regulatory region. It is of importance that some of the sites with high functional impact in hb, Kr and kni regulatory regions coincide with strong sites annotated and verified in Dnase I footprint assays.

15 CFR 280.210 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Discovery. 280.210 Section 280.210... STANDARDS AND TECHNOLOGY, DEPARTMENT OF COMMERCE ACCREDITATION AND ASSESSMENT PROGRAMS FASTENER QUALITY Enforcement § 280.210 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery...

H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element.

Science.gov (United States)

Hamada, K; Gleason, S L; Levi, B Z; Hirschfeld, S; Appella, E; Ozato, K

1989-11-01

Transcription of major histocompatibility complex (MHC) class I genes is regulated by the conserved MHC class I regulatory element (CRE). The CRE has two factor-binding sites, region I and region II, both of which elicit enhancer function. By screening a mouse lambda gt 11 library with the CRE as a probe, we isolated a cDNA clone that encodes a protein capable of binding to region II of the CRE. This protein, H-2RIIBP (H-2 region II binding protein), bound to the native region II sequence, but not to other MHC cis-acting sequences or to mutant region II sequences, similar to the naturally occurring region II factor in mouse cells. The deduced amino acid sequence of H-2RIIBP revealed two putative zinc fingers homologous to the DNA-binding domain of steroid/thyroid hormone receptors. Although sequence similarity in other regions was minimal, H-2RIIBP has apparent modular domains characteristic of the nuclear hormone receptors. Further analyses showed that both H-2RIIBP and the natural region II factor bind to the estrogen response element (ERE) of the vitellogenin A2 gene. The ERE is composed of a palindrome, and half of this palindrome resembles the region II binding site of the MHC CRE. These results indicate that H-2RIIBP (i) is a member of the superfamily of nuclear hormone receptors and (ii) may regulate not only MHC class I genes but also genes containing the ERE and related sequences. Sequences homologous to the H-2RIIBP gene are widely conserved in the animal kingdom. H-2RIIBP mRNA is expressed in many mouse tissues, in agreement with the distribution of the natural region II factor.

10 CFR 1013.21 - Discovery.

Science.gov (United States)

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Discovery. 1013.21 Section 1013.21 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) PROGRAM FRAUD CIVIL REMEDIES AND PROCEDURES § 1013.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

37 CFR 2.120 - Discovery.

Science.gov (United States)

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Discovery. 2.120 Section 2... COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Procedure in Inter Partes Proceedings § 2.120 Discovery. (a... to disclosure and discovery shall apply in opposition, cancellation, interference and concurrent use...

46 CFR 550.502 - Discovery.

Science.gov (United States)

2010-10-01

... 46 Shipping 9 2010-10-01 2010-10-01 false Discovery. 550.502 Section 550.502 Shipping FEDERAL... Proceedings § 550.502 Discovery. The Commission may authorize a party to a proceeding to use depositions, written interrogatories, and discovery procedures that, to the extent practicable, are in conformity with...

15 CFR 785.8 - Discovery.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Discovery. 785.8 Section 785.8... INDUSTRY AND SECURITY, DEPARTMENT OF COMMERCE ADDITIONAL PROTOCOL REGULATIONS ENFORCEMENT § 785.8 Discovery. (a) General. The parties are encouraged to engage in voluntary discovery regarding any matter, not...

22 CFR 35.21 - Discovery.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Discovery. 35.21 Section 35.21 Foreign Relations DEPARTMENT OF STATE CLAIMS AND STOLEN PROPERTY PROGRAM FRAUD CIVIL REMEDIES § 35.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

45 CFR 96.65 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 96.65 Section 96.65 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION BLOCK GRANTS Hearing Procedure § 96.65 Discovery. The use of interrogatories, depositions, and other forms of discovery shall not be allowed. ...

49 CFR 31.21 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

43 CFR 4.1130 - Discovery methods.

Science.gov (United States)

2010-10-01

... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Discovery methods. 4.1130 Section 4.1130... Special Rules Applicable to Surface Coal Mining Hearings and Appeals Discovery § 4.1130 Discovery methods. Parties may obtain discovery by one or more of the following methods— (a) Depositions upon oral...

6 CFR 13.21 - Discovery.

Science.gov (United States)

2010-01-01

... 6 Domestic Security 1 2010-01-01 2010-01-01 false Discovery. 13.21 Section 13.21 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY PROGRAM FRAUD CIVIL REMEDIES § 13.21 Discovery. (a) In general. (1) The following types of discovery are authorized: (i) Requests for production of...

45 CFR 99.23 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 99.23 Section 99.23 Public Welfare... DEVELOPMENT FUND Hearing Procedures § 99.23 Discovery. The Department, the Lead Agency, and any individuals or groups recognized as parties shall have the right to conduct discovery (including depositions) against...

20 CFR 355.21 - Discovery.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Discovery. 355.21 Section 355.21 Employees... UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

28 CFR 71.21 - Discovery.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Discovery. 71.21 Section 71.21 Judicial... REMEDIES ACT OF 1986 Implementation for Actions Initiated by the Department of Justice § 71.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

13 CFR 134.310 - Discovery.

Science.gov (United States)

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Discovery. 134.310 Section 134.310 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION RULES OF PROCEDURE GOVERNING CASES BEFORE THE... Designations § 134.310 Discovery. Discovery will not be permitted in appeals from size determinations or NAICS...

34 CFR 33.21 - Discovery.

Science.gov (United States)

2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Discovery. 33.21 Section 33.21 Education Office of the Secretary, Department of Education PROGRAM FRAUD CIVIL REMEDIES ACT § 33.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying...

28 CFR 18.7 - Discovery.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Discovery. 18.7 Section 18.7 Judicial Administration DEPARTMENT OF JUSTICE OFFICE OF JUSTICE PROGRAMS HEARING AND APPEAL PROCEDURES § 18.7 Discovery.... Such order may be entered upon a showing that the deposition is necessary for discovery purposes, and...

7 CFR 1.322 - Discovery.

Science.gov (United States)

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Discovery. 1.322 Section 1.322 Agriculture Office of... Under the Program Fraud Civil Remedies Act of 1986 § 1.322 Discovery. (a) The following types of discovery are authorized: (1) Requests for production, inspection and photocopying of documents; (2...

45 CFR 1386.103 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false Discovery. 1386.103 Section 1386.103 Public... Hearing Procedures § 1386.103 Discovery. The Department and any party named in the Notice issued pursuant to § 1386.90 has the right to conduct discovery (including depositions) against opposing parties as...

45 CFR 79.21 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 79.21 Section 79.21 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROGRAM FRAUD CIVIL REMEDIES § 79.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for...

12 CFR 308.520 - Discovery.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Discovery. 308.520 Section 308.520 Banks and... PROCEDURE Program Fraud Civil Remedies and Procedures § 308.520 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and copying; (2) Requests...

47 CFR 1.729 - Discovery.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Discovery. 1.729 Section 1.729..., and Reports Involving Common Carriers Formal Complaints § 1.729 Discovery. (a) Subject to paragraph (i... seek discovery of any non-privileged matter that is relevant to the material facts in dispute in the...

7 CFR 283.12 - Discovery.

Science.gov (United States)

2010-01-01

... 7 Agriculture 4 2010-01-01 2010-01-01 false Discovery. 283.12 Section 283.12 Agriculture... of $50,000 or More § 283.12 Discovery. (a) Dispositions—(1) Motion for taking deposition. Only upon a... exist if the information sought appears reasonably calculated to lead to the discovery of admissible...

41 CFR 102-2.140 - What elements of plain language appear in the FMR?

Science.gov (United States)

2010-07-01

... MANAGEMENT REGULATION SYSTEM Plain Language Regulatory Style § 102-2.140 What elements of plain language... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false What elements of plain language appear in the FMR? 102-2.140 Section 102-2.140 Public Contracts and Property Management Federal...

Elements of a regulatory strategy for the consideration of future human actions in safety assessments

Energy Technology Data Exchange (ETDEWEB)

Wilmot, R.D.; Wickham, S.M.; Galson, D.A. [Galson Sciences Ltd, Oakham (United Kingdom)

1999-09-01

The objective of this report is to discuss issues that should be considered in the development of a regulatory strategy for assessing future human actions in any forthcoming license application for a deep repository for spent fuel in Sweden and for sites of other repositories. The report comprises an outline of key issues concerning the treatment of future human actions in safety assessment, reviews of regulatory developments, recent safety assessments and supporting studies, and international initiatives on the treatment of future human actions in safety assessment, and the principal elements of a regulatory strategy. Performance assessments (PAs) are generally accepted as providing illustrations of system performance under given sets of assumptions. The results of PAs are clearer and easier tounderstand if certain large uncertainties are accounted for by determining performance under several different sets of assumptions or scenarios, each of which defines a possible evolution of the disposal system. A number of assumptions can be made that would restrict the scope of an assessment without reducing the credibility of the corresponding safety case. Reducing speculation about technological development, by assuming that the techniques used in future human activities are similar to those currently in use in the region or at similar sites, will simplify the assessment. A distinction is generally made between inadvertent and intentional intrusion, with intentional activities excluded because society cannot protect future populations from their own actions if they understand the potential consequences. A division of human activities into 'recent and ongoing' and 'future' activities considers not only the timing of the activities but also the degree of control or influence that can be imposed on them. Recent and ongoing human activities are those that affect an area beyond the immediate vicinity of the disposal facility and which neither the proponent

Elements of a regulatory strategy for the consideration of future human actions in safety assessments

International Nuclear Information System (INIS)

Wilmot, R.D.; Wickham, S.M.; Galson, D.A.

1999-09-01

The objective of this report is to discuss issues that should be considered in the development of a regulatory strategy for assessing future human actions in any forthcoming license application for a deep repository for spent fuel in Sweden and for sites of other repositories. The report comprises an outline of key issues concerning the treatment of future human actions in safety assessment, reviews of regulatory developments, recent safety assessments and supporting studies, and international initiatives on the treatment of future human actions in safety assessment, and the principal elements of a regulatory strategy. Performance assessments (PAs) are generally accepted as providing illustrations of system performance under given sets of assumptions. The results of PAs are clearer and easier to understand if certain large uncertainties are accounted for by determining performance under several different sets of assumptions or scenarios, each of which defines a possible evolution of the disposal system. A number of assumptions can be made that would restrict the scope of an assessment without reducing the credibility of the corresponding safety case. Reducing speculation about technological development, by assuming that the techniques used in future human activities are similar to those currently in use in the region or at similar sites, will simplify the assessment. A distinction is generally made between inadvertent and intentional intrusion, with intentional activities excluded because society cannot protect future populations from their own actions if they understand the potential consequences. A division of human activities into 'recent and ongoing' and 'future' activities considers not only the timing of the activities but also the degree of control or influence that can be imposed on them. Recent and ongoing human activities are those that affect an area beyond the immediate vicinity of the disposal facility and which neither the proponent nor the regulator

Regulatory requirements for the use of consumer products containing radioactive substances

International Nuclear Information System (INIS)

Mason, G.C.; Paynter, R.A.; Schmitt-Hannig, A.; Sztanyik, L.B.

1996-01-01

In almost 100 years since the discovery of radioactivity, the properties of radioactive materials have been exploited in products such as clocks and watches incorporating luminous paint which are freely available to members of the public. Over time, regulatory authorities have felt it necessary to apply some degree of control to the supply and use of such products in order to protect public health. In many areas of radiation protection, national authorities take note of international recommendations when developing national standards, but the existing detailed guidance of the International Atomic Energy Agency (IAEA) for consumer products is incomplete and out of date. Recently, a thorough revision of the International Basic Safety Standards (BSS) has occurred, which has prompted a review and revision of the related guidance published by the IAEA. A draft Guide on Regulatory Requirements for the Use of Consumer Products Containing Radioactive Substances has now been completed and is currently under review within the IAEA's system for development of documents in its Safety Series of publications. (author)

Using hexamers to predict cis-regulatory motifs in Drosophila

Directory of Open Access Journals (Sweden)

Kibler Dennis

2005-10-01

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

42 CFR 1005.7 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Discovery. 1005.7 Section 1005.7 Public Health... OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.7 Discovery. (a) A party may make a... and any forms of discovery, other than those permitted under paragraph (a) of this section, are not...

29 CFR 1603.210 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Discovery. 1603.210 Section 1603.210 Labor Regulations... GOVERNMENT EMPLOYEE RIGHTS ACT OF 1991 Hearings § 1603.210 Discovery. (a) Unless otherwise ordered by the administrative law judge, discovery may begin as soon as the complaint has been transmitted to the administrative...

45 CFR 150.435 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 150.435 Section 150.435 Public Welfare... AND INDIVIDUAL INSURANCE MARKETS Administrative Hearings § 150.435 Discovery. (a) The parties must identify any need for discovery from the opposing party as soon as possible, but no later than the time for...

34 CFR 81.16 - Discovery.

Science.gov (United States)

2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Discovery. 81.16 Section 81.16 Education Office of the... Discovery. (a) The parties to a case are encouraged to exchange relevant documents and information voluntarily. (b) The ALJ, at a party's request, may order compulsory discovery described in paragraph (c) of...

29 CFR 1905.25 - Discovery.

Science.gov (United States)

2010-07-01

... 29 Labor 5 2010-07-01 2010-07-01 false Discovery. 1905.25 Section 1905.25 Labor Regulations... OCCUPATIONAL SAFETY AND HEALTH ACT OF 1970 Hearings § 1905.25 Discovery. (a) Depositions. (1) For reasons of... discovery. Whenever appropriate to a just disposition of any issue in a hearing, the presiding hearing...

12 CFR 1780.26 - Discovery.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Discovery. 1780.26 Section 1780.26 Banks and... OF PRACTICE AND PROCEDURE RULES OF PRACTICE AND PROCEDURE Prehearing Proceedings § 1780.26 Discovery. (a) Limits on discovery. Subject to the limitations set out in paragraphs (b), (d), and (e) of this...

45 CFR 160.516 - Discovery.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Discovery. 160.516 Section 160.516 Public Welfare... ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.516 Discovery. (a) A party may make a request to... forms of discovery, other than those permitted under paragraph (a) of this section, are not authorized...

42 CFR 430.86 - Discovery.

Science.gov (United States)

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Discovery. 430.86 Section 430.86 Public Health... Plans and Practice to Federal Requirements § 430.86 Discovery. CMS and any party named in the notice issued under § 430.70 has the right to conduct discovery (including depositions) against opposing parties...

Synthesis and chemistry of elemental 2D materials

Energy Technology Data Exchange (ETDEWEB)

Mannix, Andrew J.; Kiraly, Brian; Hersam, Mark C.; Guisinger, Nathan P.

2017-01-25

2D materials have attracted considerable attention in the past decade for their superlative physical properties. These materials consist of atomically thin sheets exhibiting covalent in-plane bonding and weak interlayer and layer-substrate bonding. Following the example of graphene, most emerging 2D materials are derived from structures that can be isolated from bulk phases of layered materials, which form a limited library for new materials discovery. Entirely synthetic 2D materials provide access to a greater range of properties through the choice of constituent elements and substrates. Of particular interest are elemental 2D materials, because they provide the most chemically tractable case for synthetic exploration. In this Review, we explore the progress made in the synthesis and chemistry of synthetic elemental 2D materials, and offer perspectives and challenges for the future of this emerging field.